BioFactura-CBMS VRP Proposal

1.
COVER PAGE
1.1
BAA number:
CBMS BAA-07-01
1.2
Lead Organization Submitting Proposal: BioFactura, Inc.
1.3
Type of Business:
1.4
Contractors Reference Number:
1.5
Proposal Title:
1.6
Technical Point of Contact:
Other Small Business

n/a
An Improved Production Process for the Manufacture of

VEE VRP Vaccines
Mr. Darryl Sampey, President & CEO

BioFactura, Inc.
9430 Key West Ave., Suite 125
Rockville, MD 20850
dsampey@biofactura.com
Tel: (301) 315-8002
fax: (240) 597-6340
1.7
Administrative Point of Contact:

Mr. Alex. Matschiner, COO & CFO
BioFactura, Inc.
Rockville, MD 20850
amatschiner@biofactura.com
Tel: (301) 315-8002
fax: (240) 597-6340
1.8
Date Proposal Prepared:
BioFactura, Inc.
March 15, 2012
Page 1 of 218
1.9
Table of Contents
Page
1. COVER PAGE ............................................................................................................................1

2. TECHNICAL SECTION .............................................................................................................3
2.1 Acronyms, Abbreviations, and Symbols .......................................................................3
2.2 Project Objectives ..........................................................................................................4
2.3 Background Data ...........................................................................................................5
2.4 Proposed Technical Approach .......................................................................................7
2.5 References Cited ..........................................................................................................19
3. PROJECT MANAGEMENT SECTION ...................................................................................20
3.1 Statement of Work .......................................................................................................20
3.2 CWBS and CWBS Dictionary .....................................................................................25
3.3 IMS ..............................................................................................................................26
3.4 Project Management Approach....................................................................................26
3.5 Risk Management Plan ...............................................................................................29
4. PAST PERFORMANCE SECTION .........................................................................................35
4.1 Contract Title: Generation of Stable Eukaryotic Cell Lines Expressing
High Yields of Therapeutic Human Antibodies Against Biowarfare Viral
Threat Agents ...............................................................................................................35
4.2 Contract Title: Generation of Stable Cell Lines and Monoclonal
Antibodies Against B. anthracis Capsule Protein........................................................36
4.3 Contract Title: Recombinant Antigen Multiagent Diagnostic Assays for
Lassa and Other Arenaviruses .....................................................................................37
4.4 Contract Title: Optimization and Development of Transfection
Methodology for YB2/0 Rat Myeloma Cell Line ........................................................39
5. COST SECTION .......................................................................................................................41
5.1 Overview ......................................................................................................................41
5.2 Cost Proposal ...............................................................................................................41
5.3 Cost Elements .............................................................................................................42
6. APPENDICES ...........................................................................................................................78
6.1 Key Personnel Qualifications ......................................................................................78
6.2 CWBS Dictionary ........................................................................................................96
6.3 Subcontractor Quotes and License Agreements ........................................................145
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2. TECHNICAL SECTION
2.1
Acronyms, Abbreviations, and Symbols
ACB Accession Cell Bank

ATCC American Type Culture Collection
BAA Broad Agency Announcement
C Capsid
CHO Chinese Hamster Ovary
CBRN Chemical, Biological, Radiological, and Nuclear
cDNA complementary Deoxyribonucleic Acid
cGMP current Good Manufacturing Practices
C Capsid
CPE Cytopathic Effect (assay)
CWBS Contract Work Breakdown Structure
DOE Design of Experiment
DMF Drug Master File (FDA)
DMEM Dulbeccos Modified Eagle Medium
DMSO Dimethyl Sulfoxide
EEE Eastern Equine Encephalitis
ELISA Enzyme Linked Immunosorbent Assay
FCS Fetal Calf Serum
FBS Fetal Bovine Serum
FDA Food & Drug Administration
FFU Focus Forming Units
GOI Gene of Interest
GP Glycoprotein
ICH International Committee on Harmonization
IFA Immunofluorescence Assay
IRES Internal Ribosome Entry Site
MCB Master Cell Bank
NLS Nuclear Localization Sequence
PBS Phosphate Buffered Saline
PFD Process Flow Diagram
REN Restriction Endonucleases
RNA Ribonucleic Acid
RSV Rous Sarcoma Virus
SOP Standard Operating Procedure
TFF Tangential Flow Filtration
TK - Thymidine Kinase
VEE Venezuelan Equine Encephalitis
VEEV Venezuelan Equine Encephalitis Virus
VLP Virus-Like Particle
VRP - Virus Replicon Particle
WCB Working Cell Bank
WEE Western Equine Encephalitis
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2.2
Project Objectives
BioFactura has designed an improved scalable cell culture bioprocess for the production of
virus-like replicon particle (VRP) vaccines based on the attenuated strain of the replication
defective Venezuelan Equine Encephalitis (VEE) virus, V3014. If funded the proposed project
will fulfill the Area of Interest, Category 3 (Medical CBRN Countermeasures and Enabling
Technologies), Item 5: Evaluate/develop manufacturing processes which may improve the
production, shelf life, or stability of candidate or FDA-approved medical CBRN
countermeasures. BioFacturas proposed production methods will not only speed up the
advanced development process leading to FDA approval for a broad range of VRP vaccines, but
also offer a significant reduction in cost and time over the current manufacturing process.
Although the VEE VRP platform has proven to yield protective vaccines for the range of
filoviruses (Ebola, Marburg) and alphaviruses (WEE, VEE, and EEE), the current process for
production of VRPs is low yielding and poorly scalable to cGMP manufacture. BioFacturas
process will replace the currently used adherent Vero cell line with a stable suspension Vero
(sVero) cell line (Zelltek) or stable suspension EB66 cell line (Vivalis) that expresses the VRP
structural proteins using a tightly controlled inducible promoter. Furthermore, BioFacturas
production process will replace the current bottleneck of electroporation with a simple, scalable
VRP transduction step to transport the replicon coding for the pathogen genes of interest into the
stable sVero or EB66 cell line. Upon development and optimization, this process will provide a
universal scalable production method for any VEE VRP vaccine using a common stable helper
cell line and modular replicon induction step. Elements of this process may also be applicable to
other VRP- and VLP-based vaccines and platforms.
Figure 1. Vero helper cell line-based VEE VRP

production process flow diagram.
Figure 1. Stable helper cell line-based VEE VRP production Process Flow Diagram (PFD).
Preparation of replicon
delivery vector
(VEE VRP)
Stable suspension helper cell

line thaw and expansion to
production reactor
14 days
Induction and transduction
with replicon delivery vector
(VEE VRP)
1 day
VRP harvest
Recycling of VEE VRPs

VRP purification
Bulk formulation
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2.3
Background Data
2.3.1 Replicon-Helper System from Attenuated Venezuelan Equine Encephalitis Virus

A VEE VRP vaccine platform was developed from an attenuated strain of VEE, V3014,
derived by mutagenesis of pV3000, a cDNA clone of the Trinidad donkey strain of VEE (Davis
et al.,1989, 1991, 1995; Grieder et al., 1995). The replicon RNA consists of the cis-acting 5 and
3 ends of the VEE genome, the complete nonstructural protein gene region, and the subgenomic
26S promoter. The genes encoding the VEE structural proteins are replaced with a gene of
interest (GOI) coding for a vaccine antigen. In one improvement, an internal ribosome entry site
(IRES EV71) preceded by a spacer sequence was cloned upstream of the GOI to better control
expression of the GOI (Kamrud et al., 2007). Upon transfection into eukaryotic cells by
electroporation, versions of these replicon RNAs directed the efficient, high-level synthesis of
multiple heterologous proteins such as influenza virus hemagglutinin (Hubby, et. al., 2007),
cytomegalovirus (Reap, et. al., 2007), and VEE glycoprotein (manuscript in preparation). For
packaging of replicon RNAs into VEE replicon particles (VRP), the VEE capsid and
glycoproteins were supplied in trans by expression from helper RNA(s) co-electroporated with
the replicon. A number of different helper constructs, expressing the VEE structural proteins
from a single or two separate helper RNAs, were derived from attenuated VEE strains. In a
preferred example, a bipartite helper system consisting of separate Capsid (C)- and glycoprotein
(GP)-helper RNAs was constructed from V3014D5207505 (Pushko, et. al., 1997).
Regeneration of infectious virus was not detected when replicons were packaged using a
bipartite helper system encoding the VEE capsid protein and glycoproteins on two separate
RNAs.
2.3.2 Current VRP Vaccine Production Process
Although several improvements have been made to the original VEE VRP platform, these
vaccines are currently produced using a scaled-up research protocol that has multiple
deficiencies in process scalability, vaccine yield, and economic feasibility. For example, a
current manufacturing process developed by AlphaVax for the production of filovirus vaccines
demonstrates production yields of 2-6x1011 Focus Forming Units (FFU) per batch. Assuming the
human dose of 1010 FFU required to generate a protective immune response, the current process
yields 20-60 vaccine doses per batch. This level of productivity is orders of magnitude below
what would be considered acceptable and economically feasible in the drug industry. BioFactura
has identified several key bottlenecks in the current manufacturing process including the use of
adherent Vero cells, the requirement of three plasmid co-transfection, and the use of
electroporation for the co-transfection. The most significant bottleneck in the current AlphaVaxdeveloped manufacturing process is the requirement for the electroporation of the production
Vero cell lines to transport replicon and helper RNAs into the cells and initiate VRP generation.
For large-scale cGMP manufacture (>2000-2500 doses/batch), this step carries high risks of
contamination and process variability, and is prohibitively cost and labor intensive. Other
alternative methods utilizing liposome- and/or chemical-mediated transfection approaches also
carry significant disadvantages and risks such as low efficiency, high cost, and introduction of
unwanted contaminants to the process.
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2.3.3 sVero Parental Cell Line Origin

The sVero cell line will be obtained from Zelltek, S.A. Vero cells from the line VERO E6
(passage 26, Banco Argentino de Clulas, ABAC, http://www.abac.org.ar/) were used as the
starting material for suspension adaptation process. VERO E6 cells available at Banco Argentino
de Clulas come from ATCC (ATCC number CRL-1586). VERO E6 from ABAC was acquired
on February 2004.
Cells were cultured in a monolayer in a 25 cm2 culture flask containing MEM (GIBCO)
medium supplemented with 10% fetal calf serum (FCS). Incubation was at 37C in a 5% CO2
atmosphere. After sufficient expansion of the cells, the cells were then cultured in the above
medium containing 20% serum-free medium and subcultured upon confirming no abnormality in
cells. After subculture and sufficient expansion of the cells, the culture medium was replaced
with medium containing 40% serum-free medium and sub-cultured upon confirming no
abnormality in cells. The procedure was repeated until the content of serum-free medium was
80% (2% FCS). At this point cells were trypsinized and inoculated (2.5 x 105 cells/ml) in a
spinner flask (Techne) containing the same medium. Agitation was at 50 rpm and incubation was
at 37C in a 5% CO2 atmosphere. The cells were transferred to fresh medium according to the
evolution of the pH of the culture. After 90 days of the initiation of the adaptation procedure,
cells were seeded in a medium containing half a volume of MEM supplemented with 0.2% FCS
and half a volume of ExCell 302 CHO serum-free medium (JRH Biosciences) supplemented
with 2 mM glutamine. Doubling time in this medium was about 24 hours and viability 98-100%
at one week after transfer. Cells were grouped in clusters of less than ten cells when the cell
concentration was above 1.5 x 106 cells/ml. At this point, the half volume of FCS supplemented
MEM was replaced with the protein free SMIF-6 medium (GIBCO). After this, the proportion of
ExCellTM 302 CHO serum-free medium was diminished and 120 days after the initiation of the
adaptation procedure, Vero cells were growing in suspension in 100% protein free SMIF-6
medium. These cells were named VERO E6 AGS or sVero for VERO E6 adapted to grow in
suspension. For storage, sVero cells in exponential growth period were centrifuge at 200g and
the cell pellet was suspended in a solution containing 45% SMIF-6 conditioned medium, 45%
fresh SMIF-6 medium, and 10% dimethylsulfoxide (DMSO). This cell suspension was
fractionated in cryotubes containing 1ml of the suspension each and frozen in steps: 1h at 4C, 1h
at -20C in nitrogen atmosphere, and finally in liquid nitrogen at -196C.
2.3.4 EB66 Parental Cell Line Origin
The EB66 cell line, obtained from Vivalis, S.A., is a proprietary and fully documented nongenetically modified cell line displaying industrial friendly characteristics. Building on the
exceptional biological properties of avian embryonic stem cells, Vivalis has undertaken the
development of a series of avian cell lines that fulfill current industrial specifications. The
EB66 cell line was selected based on its remarkable features. EB66 cell line maintains
desirable features of avian embryonic stem (ES) cells and display industrial-friendly
characteristics such as:
Genetic stability
Diploid karyotype
No adventitious agents (ALV, avian viruses)
No RT activity
Indefinite cell proliferation
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High cell densities as suspension cells (>20 millions cells/mL)

Animal serum-free culture conditions
2.3.5 BioFactura Quality System

BioFactura has implemented a series of quality controls based on the FDAs Guidance for
Industry - Phase 1 GMP and ICH Q5D, Derivation and Characterization of Cell Substrates Used
for Production of Biotechnological/Biological Products. Our technical and scientific activities
are governed by SOP and fully documented. We have full traceability of cell substrates, media,
buffers, reagents, and critical supplies used in the development of client products. Our equipment
and instruments are routinely calibrated by qualified service providers and calibration, cleaning
and preventive maintenance are documented. Employee training is conducted regularly, in group
or individual settings, and is fully documented.
2.4
Proposed Technical Approach
2.4.1 Technical Approach Introduction

BioFactura will develop a novel process for the scalable manufacture of VEE VRPs in a
stable suspension helper cell line. In collaboration with Dr. Pamela Glass (Chief, Viral Biology
Department, USAMRIID), we will use a VRP vaccine candidate that expresses the VEE E1 and
E2 glycoprotein antigens as a model for these manufacturing process changes. To mitigate risk,
two cell lines and two inducible promoter systems (Tet-On 3G and Lac Switch II) will be
evaluated. Subsequent down-selection decision points will advance the best performing system
for scale-up and initial process development. Vero in addition to MRC-5 are the only FDA
approved cell lines for the commercial manufacture of live virus and virally-vectored vaccines
principally due to the absence of endogenous retroviruses. BioFactura proposes to use a
suspension-adapted Vero cell line because MRC-5 has been demonstrated to produce lower titers
of VEE virus (VEEV). Vivalis maintains a Drug Master File (DMF) with the FDA for the EB66
cell line, and vaccine candidates produced in EB66 cells have been approved by the US FDA
and Japanese MHW for use in human clinical studies. BioFactura does not recommend using any
other currently available manufacturing cells lines due to complex downstream process
development requirements, significantly increased manufacturing cost, and higher risk of failure.
BioFacturas stable cell line process development approach will be phased and milestone
gated to reduce risk and allow for go/no-go decisions by CBMS. The proposed phase milestones
are as follows:
1. Demonstration of baseline VEE VRP productivity and bioactivity in the suspension Vero
and EB66 cell lines using the current electroporation process.
2. Generation of scalable stable sVero and EB66 helper cell lines capable of inducible
expression of the VEE structural subunits creating universal helper cell lines.
3. Determination of optimal induction and transduction conditions using the target vaccine
product (VEE VRP candidate) as the replicon delivery vector.
4. Initial optimization of process and demonstration of process scalability in bioreactors.
At the end of each successive phase and corresponding upstream process changes, a test lot
of VEE VRP vaccine product will be generated utilizing the current downstream protocols and
compared to a reference lot of the same vaccine produced using the current upstream and
downstream processes. Assays will include indirect immunofluorescence assay (IFA) yield
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determination (FFU), in vitro reactivity (epitope retention based on monoclonal antibody

reactivity in an enzyme linked immunosorbant assay [ELISA]), and in vivo immunogenicity and
protective efficacy in a mouse aerosol challenge model. In addition, we propose to conduct a full
panel of cell line release tests for both the sVero parental cell line and the final stable helper cell
line to comply with cGMP requirements for Master Cell Banks and clinical manufacturing of
live-virus vaccine products. The technical approach of the proposed 25-month effort is outlined
below and consists of all supporting activities and studies leading to a commercially scalable and
economic process for the manufacture of VEE-based VRP vaccines.
2.4.2
Project Technical Phases
2.4.2.1
Phase I: Suspension Parental Cell Lines (CWBS 1.1)
Phase I will establish a key Master Cell Bank (MCB) for the sVero parental cell line as well
as working banks for both sVero and EB66 lines to be used throughout the project. A reference
lot of VEE VRP vaccine will be manufactured using the current adherent Vero cell line and
production processes (triple RNA electroporation and established downstream harvest and
purification methods). This reference material will be used in this and all subsequent phases in
VRP tests as a benchmark for vaccine yield, quality, activity, and protective efficacy. Finally in
Phase I, lots of VRP vaccine will be produced in the two suspension parental cell lines, sVero
and EB66 using the identical process used to manufacture the reference lot. These test lots will
be compared with the benchmark reference using a panel of in vitro assays and in vivo
immunogenicity and protection studies. This VRP testing will be repeated at the end of each
phase to evaluate the impact of key changes in the upstream production process. Advancement of
new cell lines and process changes to the next project phase will be gated by the achievement of
comparable results in these tests by the new VRP vaccine lots as compared to the reference lot.
An additional gate for Phase I will be the successful creation of an MCB for the parental sVero
cell line which, to date, has not been fully tested for use in clinical and commercial
manufacturing.
o CWBS 1.1.1 Working Cell Banks
CWBS 1.1.1.1 EB66 Cell Bank
A cGMP Master Cell Bank (MCB) of EB66 cells will be received from Vivalis and
stored in liquid nitrogen. The cells will be thawed and cultured in the vendor recommended
ExCell EBx GRO-I medium (SAFC). After 3-4 passages to ensure recovery, growth rate and
viability will be determined by manual cell counts using a hemacytometer and Trypan blue
exclusion. Morphology will be observed and all cell line properties compared to the normal
reference information provided by the vendor. To create a Working Cell Bank (WCB),
expanded EB66 cells in exponential growth period will be centrifuged at 200g and the cell
pellet suspended in a solution containing 90% fresh ExCell EBx GRO-I medium, and 10%
DMSO. This cell suspension will be aliquoted in cryotubes containing 1ml of the suspension
each, frozen in chambers at the rate of 1C/minute, and stored in liquid nitrogen vapor phase.
CWBS 1.1.1.2 sVero Cell Bank
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CWBS 1.1.1.2.1-.4 sVero Parental Cell Line Thaw, Expansion, and Creation of an
Accession Cell Bank (ACB)
sVero cells will be received from Zelltek and stored in liquid nitrogen. The cells will
be thawed and cultured in the vendor recommended SMIF-6 medium (GIBCO). After 34 passages to ensure recovery, growth rate and viability will be determined by manual
cell counts using a hemacytometer and Trypan blue exclusion. Morphology will be
observed and all cell line properties compared to the normal reference information
provided by the vendor. To create an accession cell bank (ACB), expanded sVero cells in
exponential growth period will be centrifuged at 200g and the cell pellet suspended in a
solution containing 45% SMIF-6 conditioned medium, 45% fresh SMIF-6 medium, and
10% DMSO. This cell suspension will be aliquoted in cryotubes containing 1ml of the
suspension each, frozen in chambers at the rate of 1C/minute, and stored in liquid
nitrogen vapor phase.
CWBS 1.1.1.2.5-.10 sVero ACB Testing, cGMP Master Cell Bank (MCB), and
Creation of a Working Cell Bank (WCB)
The sVero ACB will be tested for an initial panel of pre-bank qualifying test
including sterility and absence of mycoplasma. Upon successful pre-bank testing, a
cGMP Master Cell Bank (MCB) will be created at a subcontractor (Bioreliance). The
MCB will be subjected to a full panel of tests required for current Good Manufacturing
Practices (cGMP) manufacturing of clinical and commercial live-virus vaccine products.
The tests include a broad panel of adventitious agent tests (e.g., bovine, simian, porcine,
and human viruses), presence of retroviruses, and tumor formation. Two vials will be
shipped back to BioFactura for generation of a Working Cell Bank (WCB) while the
remaining MCB stored offsite at the subcontractor.
o CWBS 1.1.2 Reference VRP Production (Upstream, BSL-3)
CWBS 1.1.2.1 VRP RNA Constructs Generation
Based on established protocols, replicon and helper DNA plasmids will be transformed
into competent E. coli cells using the appropriate methods. Five (5) clones each will be
picked, expanded in suspension culture, and glycerol stocks prepared and stored at -80C. A
portion of the suspension culture will be used to make small-scale (mini) purified plasmid
DNA preparations using a commercially available kit. Purified DNAs will be analyzed by
appropriate restriction endonucleases (REN) and by DNA sequencing (outsourced to
Macrogen). Upon REN and sequence confirmation, a single clone of each plasmid DNA will
be scaled up for large (giga) purified plasmid DNA preparations. These preparations will be
stored at -20C and used for the entire project (DNA Construct Working Banks). For
electroporation of producer cells, purified DNA plasmids will be linearized by NotI
endonuclease digestion and used as templates for in vitro transcription of capped RNA using
RNA Express T7 kits (Promega). After transcription, RNA will be treated with DNase,
purified by anion exchange chromatography followed by desalting, and stored at80C until
use.
CWBS 1.1.2.2-.3 Vero Cell Line Expansion and Electroporation (BSL-3)
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Reference VRP vaccine will be produced using the current adherent cell based process.
Briefly, a Vero working cell bank derived from VERO E6 cells (ATCC number CRL-1586),
will be thawed and cultured in 40-50 mL of Eagles minimum essential medium (EMEM)
with 5% fetal bovine serum (FBS) in 175 cm2 flasks at 37C, 5%CO2. After 24 h, cells will
be detached by treatment with 0.05% trypsin (Gibco) and passaged/expanded daily 3 times.
For VRP production, cells will be harvested, washed and re-suspended in PBS to a
concentration of 1.52.0108 cells/mL, mixed with RNA (30 mg each of replicon, capsid
helper and glycoprotein helper), transferred to 0.4 cm gap cuvettes and electroporated using a
Gene Pulser II electroporation unit (BioRad). Electroporated cells will be resuspended in 100
mL OptiPRO SFM (Invitrogen) with 4 mM glutamine and cultured at 37C and 5% CO2.
CWBS 1.1.2.4 VRP Purification
CWBS 1.1.2.4.1 VRP Harvest

After 24 h the medium and cells will be pooled and drawn into a Sartopore 2 capsule
filter (Sartorius) prewetted with PBS. Cells collected on the filter will be washed with
PBS and VRP recovered by washing with a high salt buffer.
CWBS 1.1.2.4.2-.3 Cytopathic Effect (CPE) Assay

A negative CPE result is the criterion for release of harvested VRP from BSL-3
containment for purification and formulation. A portion of the salt wash material will be
tested in a CPE assay to confirm the absence of detectable replication-competent virus. In
brief, VRP eluted by salt wash will be tested for residual infectivity on BHK-21 cells, a
more sensitive cell line routinely used for detecting infectious alphaviruses. Aliquots of
each test sample (50 L) plus 50 L Dulbeccos Modified Eagle Medium (DMEM) will
be used to inoculate a six-well plate of BHK-21 cells for 1 h at 37C with occasional
plate rocking. Following this incubation, 2.5 mL complete media (DMEM plus 10%, v/v,
FBS) will be added and cells incubated at 37C for 34 days. Following this incubation,
cells will be examined for CPE and an aliquot (50 L) of the supernatant used to
inoculate a fresh six-well monolayer of BHK-21 cells as described above. After each
passage aliquots of the supernatant fluids will be collected and frozen at 70C for virus
titration by plaque assay.
CWBS 1.1.2.4.4-.8 VRP Filtration, Chromatography, and Formulation

The salt wash material will be concentrated on a Hydrosart 100,000 molecular weight
cutoff regenerated cellulose flatsheet tangential flow filtration (TFF) membrane
(Sartorius) and diafiltered against 2M NaCl and then against PBS with 3mM MgCl2.
After treatment with Benzonase to degrade contaminating Vero DNA, VRP will be
diafiltered against 2M NaCl and then 300mM NaCl in 10mM phosphate. The TFF pool
will be filtered through a 0.2 mm filter and loaded on a Cellufine Sulfate column that has
been sequentially washed with 250mM NaCl and 500mM NaCl in 10mM phosphate.
VRP will be eluted with a step gradient to 800mM NaCl in 10mM phosphate. Purified
VRP will be assayed by SDS-PAGE and formulated as bulk vaccine in an excipient mix
that will include normal mouse serum (NMS) to stabilize the VRP during storage at 80C.
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o CWBS 1.1.3 VRP Production: Suspension Parental Cell Lines (Upstream, BSL-3)
VRP vaccine will be produced in both parental sVero and EB66 cell lines using the current
adherent cell based process described above (CWBS 1.1.2.2-.3 Vero Cell Line Expansion and
Electroporation). Cells will be thawed and expanded in their respective media and passaged 3
times to establish robust growth. Cells will be expanded as needed in disposable sterile shaker
flasks to achieve the required 1.52.0108 cells per electroporation reaction. After
electroporation, cells will be resuspended in 100 mL of each cell lines respective growth
medium and cultured in shaker flasks for 24 h. VRP harvest, CPE assay, and VRP purification
and formulation will be performed as per the established protocols described above (CWBS
1.1.2.4 VRP Purification).
o CWBS 1.1.4 VRP Testing
CWBS 1.1.4.1 VRP Titration: Immunofluorescence Assay
To determine transfection efficiencies or the titers of VRP preparations, Vero cells will
be infected with serial dilutions of purified and formulated VRP and incubated in eightchamber slides (Nunc) for 20 h at 37C to allow expression of the VEEV glycoproteins.
Antigen-positive cells will be enumerated for VEEV glycoprotein protein by direct
immunofluorescence using a FITC-conjugated primary reagent or by indirect
immunofluorescence as previously described (Pifat, et al., 1988).
CWBS 1.1.4.2 In-vitro Reactivity

VEEV specific ELISA will be used to measure envelope epitope determinants in the
inactivated virus preparations. The assay is based on a standard sandwich ELISA method
utilizing monoclonal antibodies (Mab 1A4A-1or Mab 1A3A) for the capture of antigen and
detection of antigen by horse anti-VEEV polyclonal serum. Mab 1A4A-1 and Mab 1A3A
recognize the E2c and E2g epitopes, respectively. Wild-type VEE virus and previously
produced VEE VRPs will be included as controls in the assay. Colorimetric determination of
binding will be facilitated through a peroxidase-labeled goat anti-horse antibody followed by
the addition of ABTS substrate (KPL).
CWBS 1.1.4.3 In-vivo Immunogenicity

BALB/c mice will be immunized with two doses of the vaccine candidates by the SC
route on Day 0 and Day 28. Saline and reference VRP inoculated groups will be included to
provide appropriate controls. Mouse sera will be obtained from the periorbital venous sinus
at Day 21 and Day 49 and assayed for VEEV-specific total Ig (G, M and A) by ELISA.
Additionally, the sera will be examined for ability to neutralize virus infectivity by mixing
appropriate amounts of sera with VEEV Trinidad strain (approximately 100 pfu) and
incubating at 4oC overnight. Residual infectious virus will be estimated by plaque assay in
Vero cells.
CWBS 1.1.4.4 In-vivo Protection Assay: Mouse VEE Lethal Aerosol Challenge
BALB/c will be immunized with two doses of the vaccine candidates by the SC route on
Day 0 and Day 28. Saline and reference VRP inoculated groups will be included to provide
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appropriate controls. Mouse sera will be obtained from the periorbital venous sinus at Day 21
and Day 49 and assayed for VEE-specific humoral immune response as described above. At
28 days post-final vaccination, mice will be aerosol challenged with 10000 LD50 VEEV
Trinidad strain. The mice will be challenged with virulent VEEV via the airborne route by
exposure for 10 min to a polydispersed aerosol generated by a Collison nebuliser using the
Henderson Apparatus. Virus dose will be calculated by sampling the air in the box and
assuming a respiratory minute volume for mice of 1.25 mL/g. After challenge, mice will be
observed twice daily for clinical signs of infection (piloerection, hunching, inactivity,
excitability and paralysis) by an observer who is unaware of treatment allocations for 14
days.
2.4.2.2
Phase II: Suspension Helper Cell Lines (CWBS 1.2)
In Phase II, stable helper cell lines will be created using both suspension parental cell lines to
shift the helper function from electroporated RNA constructs to genomically integrated
expression cassettes that will produce the structural VEE C and GP proteins for VRP packaging.
Two inducible expression technologies, LacSwitch II and Tet-On 3G will be evaluated in each
parental cell line resulting in four cell line/expression system combinations. These induction
systems will suppress expression of the potentially cytotoxic VEE structural subunits until cells
are expanded to optimal volumes and densities. Expression of helper functions will be triggered
by the addition of isopropyl -D-thiogalactopyranoside (IPTG) or doxycycline (Dox),
respectively. Coordination of induction and introduction of the self amplifying replicon RNA
into the cells will result in VRP production. As with Phase I, advancement of new stable helper
cell lines to Phase III, will be gated by the achievement of comparable or improved results in the
VRP test panel by the respective VRP vaccine lots as compared to the reference lot.
o CWBS 1.2.1 EB66 Helper Cell Lines
CWBS 1.2.1.1 Lac Induction System
The ability to inducibly turn on the VEE GP and C transgenes is important for the
development of stable helper cell lines as these viral protein subunits are potentially toxic to
the proposed EB66 and sVero parental cell lines. In the Escherichia coli lactose (lac) operon,
the Lac repressor binds as a homotetramer to the lac operator, blocking transcription of the
lacZ gene. Physiological or synthetic inducers, such as allolactose or IPTG respectively, bind
to the Lac repressor causing a conformational change and effectively decrease the affinity of
the repressor for the operator. When the repressor is removed from the operator, transcription
from the lac operon resumes.
The LacSwitch II inducible mammalian expression system utilizes an improved vector
system in which several elements of the lac operon have been modified for use in eukaryotic
cells for the control of gene expression. This method for inducible expression of exogenous
genes in eukaryotic cells consists of a eukaryotic Lac-repressor expressing vector,
pCMVLacI, and a eukaryotic lac-operator containing vector, pOPRSVI/MCS, into which the
gene of interest is inserted by cloning (see Figure 2). These vectors are transfected into a
cultured cell line in which expression of the inserted gene is repressed until an inducer is
added to the media. Upon induction, expression of the inserted gene resumes.
The LacSwitch II inducible mammalian expression system is a versatile and proven
alternative to other systems. The system uses a nontoxic, fast-acting inducer, IPTG, which
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permits induction in 48 hours, partly due to the rapid transportation of IPTG into eukaryotic
cells. The LacSwitch II expression system exhibits low basal expression of a luciferase
reporter gene (~1020 molecules/cell) when in the repressed state.
Figure 2. Map of the eukaryotic Lac-repressor-expressing vector, pCMVLacI, and
pOPRSVI/MCS vector. Expression of the Lac repressor protein is driven by the CMV promoter
and the protein is targeted to the nucleus by the SV40 nuclear localization sequence (NLS).
Hygromycin is used for selection in mammalian cells. For the pOPRSVI/MCS vector, the Rous
sarcoma virus (RSV) promoter drives expression of the gene of interest inserted into the MCS.
Ideal operator sequences for Lac repressor binding are present in the RSV promoter and in the
intron. G418 resistance is provided by the neomycin gene.
CWBS 1.2.1.1.1-.8 EB66 Stable Helper Cell Line Generation

For the proposed EB66 stable helper cell line, the pOPRSVI/MCS vector will be
modified such that it contains two independent expression cassettes beginning at the RSV
promoter and ending after the HSV-thymidine kinase (TK) polyA signal. This bicistronic
vector will permit the cloning of both the VEE C and GP open reading frames (ORFs)
allowing for IPTG inducible expression of all VRP helper functions. VEE structural
genes will be optimized for expression in EB66 and synthesized (GeneArt) with
appropriate flanking sequences to permit restriction and cloning into the expression
vector. VEE C and GP genes will be cloned into the vector and sequence confirmed.
Transient co-transfections will be performed using both the pCMVLacI and expression
vectors to confirm inducible expression of VEE subunits by ELISA and Western blot in
CHO-S suspension culture.
EB66 will be tested for sensitivity to both hygromycin and G418 to establish
optimum selection conditions. Parental cells will be expanded and co-transfected with
both the pCMVLacI and expression vectors. After a 24-hour recovery, the transfection
pool will be resuspended in selection medium with hygromycin and G418. We anticipate
emergence of a stable pool in 2-3 weeks and will perform an initial induction study to
confirm expression of VEE subunits. Following expression confirmation, stable pools
will be cloned by limiting dilution and best performing clones will be selected and
banked.
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CWBS 1.2.1.2 Tet Induction System

The Tet-On 3G System (Clontech) will be used as an alternate inducible system for the
stable expression of VEE GP and C helper functions in the EB66 cell line. Target cells that
express the Tet-On 3G transactivator protein and contain a gene of interest (GOI) under the
control of a TRE3G promoter (PTRE3G) will express high levels of the GOI, but only when
cultured in the presence of Dox. Doxycycline is a synthetic tetracycline derivative that is the
effector molecule for the Tet-On 3G System. When bound by Dox, the Tet-On 3G protein
undergoes a conformational change that allows it to bind to tet operator sequences located in
the PTRE3G promoter (Figure 3). The Dox concentrations required for induction of the TetOn 3G System are far below cytotoxic levels for cell culture.
Figure 3. The Tet-On 3G Systems allow inducible gene expression in the presence of Dox.

For the proposed EB66 stable helper cell line, the pTRE3G-IRES vector will be used
as it has been engineered with an internal ribosome entry site (IRES) to permit the
translation of both VEE C and GP from a single mRNA transcript (see Figure 4). VEE
structural genes will be optimized for expression in EB66 and synthesized (GeneArt)
with appropriate flanking sequences to permit restriction and cloning into the expression
vector. VEE C and GP genes will be cloned into the vector and sequence confirmed.
Transient co-transfections will be performed using both the pCMV-Tet3G regulator and
pTRE3G-IRES response vectors to confirm inducible expression of VEE subunits by
ELISA and Western blot in CHO-S suspension culture.
Figure 4. The pCMV-Tet3G (regulator) and pTRE3G-IRES (response) vector maps.
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Parental cells will be expanded and transfected with the pCMV-Tet3G vector.
Parental cells will be expanded and co-transfected with both the pCMV-Tet3G vector and
the pTRE3G-IRES vector containing the VEE VRP structural genes. After a 24-hour
recovery, the transfection pool will be resuspended in selection medium with hygromycin
and G418. We anticipate emergence of a stable pool in 2-3 weeks and will perform an
initial induction study to confirm expression of VEE subunits. Following expression
confirmation, stable pools will be cloned by limiting dilution and best performing clones
will be selected and banked.
o CWBS 1.2.2 sVero Helper Cell Lines
Stable sVero helper cell lines will be generated using the Lac and Tet inducible systems as
described above for the EB66 lines. If necessary, VEE VRP structural genes will be optimized
for expression in the sVero cell line.
o CWBS 1.2.3 VRP Production (Upstream, BSL-3)
VRP vaccine will be produced in the best performing clones of each EB66-Lac, EB66-Tet,
sVero-Lac, sVero-Tet stable helper cell lines using the current adherent cell based process
described above (CWBS 1.1.2.2-.3 Vero Cell Line Expansion and Electroporation). Cells will be
thawed and expanded in their respective media and passaged 3 times to establish robust growth.
Cells will be expanded as needed in disposable sterile shaker flasks to achieve the required 1.5
2.0108 cells per electroporation reaction. Prior to electroporation, cells will be induced with
either IPTG or Dox as appropriate to initiate helper function expression. After electroporation
with the replicon RNA, cells will be resuspended in 100 mL of each cell lines respective growth
medium and cultured in shaker flasks for 24 h. VRP harvest, CPE assay, and VRP purification
and formulation will be performed as per the established protocols described above (CWBS
1.1.2.4 VRP Purification).
VRP produced with stable helper cell lines will be tested and compared to reference
materials. These assays include indirect immunofluorescence assay (yield), ELISA (identity and
activity) and immunogenicity and protection using murine models. These are described above
(CWBS 1.1.4 VRP Testing)
2.4.2.3 Phase III: Induction/Transduction Optimization (CWBS 1.3)
Phase III potentially brings the most valuable VRP production process change proposed in
the project: The replacement of electroporation with VRP vaccine product transduction as the
means for replicon introduction. The first study in this phase will confirm the feasibility of this
approach be measuring VEE VRP transduction efficiency in the suspension parental cell lines as
compared with adherent Vero controls. Parental cell lines with comparable transduction
efficiencies will be advanced to induction and transduction process optimization. Finally, the
best two performing production systems will be scaled to manufacture test lots of VRP vaccine.
The best performing system will be advanced to Phase IV: Process Development.
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o CWBS 1.3.1 Preliminary Transduction Study

A preliminary study will be performed using EB66, sVero, and adherent Vero (control) to
determine efficiency of VRP transduction and delivery of replicon RNA. Each parental cell line
will be thawed and expanded in their respective media and passaged 3 times to establish robust
growth. Cultures will be transduced at a range of multiplicities of infection (MOIs) using
reference VRP material (CWBS 1.1.2 Reference VRP Production) and allowed to incubate 24
hours. In addition, an electroporation reaction will be used as a control with adherent Vero cells.
Efficiency of transduction and replicon amplification will be determined by ELISA and Western
blot in vitro reactivity assays. Direct measurement of RNA replicon copies will be determined by
quantitative PCR (qPCR). Cells with comparable efficiencies to the adherent Vero controls will
be advanced to Induction/Transduction Optimization.
o CWBS 1.3.2 Induction/Transduction Optimization (BSL-3)
Stable helper cell lines suitable for transduction as determined above (EB66 and/or sVero),
will be evaluated for VRP yield and reactivity at different induction concentrations and times and
at range of MOIs. Utilization of Design of Experiment (DOE) software (JMP) will allow for
testing of multiple variable simultaneously compressing the timeline and reducing the number of
experiments and labor. This set of experiments will be split into Lac cell lines and Tet cell lines
to simplify the induction steps. Briefly, for each experiment, cells will be thawed and expanded
in their respective media and passaged 3 times to establish robust growth. Cells will be expanded
as needed in disposable sterile shaker flasks to achieve the required 1.52.0108 cells per
electroporation reaction. Prior to electroporation, cells will be induced with either IPTG or Dox
as appropriate to initiate helper function expression. After the prescribed induction times,
cultures will be transduced at a range of multiplicities of infection (MOIs) using reference VRP
material (CWBS 1.1.2 Reference VRP Production) and allowed to incubate 24 hours. VRPs will
be harvested at small scale using the high salt wash. This material will be analyzed for CPE and
by indirect immunofluorescence assay (IFA, yield) and ELISA (identity and activity). The two
best performing conditions (System #1 and #2) will be advanced to VRP Production.
VRP vaccine will be produced in the two best performing systems (Systems #1 and #2) as
described above (CWBS 1.3.2 Induction/Transduction Optimization) at production scale (100
mL). VRP harvest, CPE assay, and VRP purification and formulation will be performed as per
the established protocols described above (CWBS 1.1.2.4 VRP Purification).
VRP produced with Systems #1 and #2 will be tested and compared to reference materials.
These assays include indirect immunofluorescence assay (yield), ELISA (identity and activity)
and immunogenicity and protection using murine models. These are described above (CWBS
1.1.4 VRP Testing). The best performing system will be advanced to Process Development.
2.4.2.4
Phase IV: Process Development (CWBS 1.4)
The activities of Phase IV will build upon the foundation established thus far leading to a
scalable, reproducible, and significantly improved VEE VRP vaccine production process. The
top performing system identified in Phase III will be optimized for batch medium and feed
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supplements. These optimization steps are expected to result in significant increases in cell
density and sustained cell viability. These increases in cell culture performance are expected to
concomitantly improve VRP yields. A pilot production run of the optimized process will be
performed prior to bioreactor scale-up and engineering runs at the benchtop scale (5L). As with
the previous phases, test lots of VRP vaccine generated in the three engineering runs will be
compared to the reference lot in the standard VRP test panel. The expected outcome of Phase IV
is the development of a considerably improved VRP production process ready for transfer to
vaccine manufacturing.
o CWBS 1.4.1 Batch Medium Optimization
The best performing clonal helper cell line will be selected for bioreactor process
optimization. The basal growth medium and recommended supplements will be supplied by the
appropriate vendor (Zelltek or Vivalis). Often, due the metabolic uniqueness of mammalian cell
lines following stable transfection, it is imperative to perform an initial series of medium and
feed optimization experiments in order to achieve increased cell densities. An increase in
maximum cell density is often concomitant with significant increases in the yields of vaccine
product. Without these initial studies and appropriate reformulation of the basal growth medium
and the addition of feed supplements, the culture is often deprived of essential metabolites,
particularly primary carbons sources and crucial amino acids, within the first 3 days postinoculation. These studies will be designed using DOE approaches to allow for the testing of
multiple factors in each medium or feed study resulting in a richer data set in a shorter timeline.
The initial optimization studies will focus on the analysis of fresh versus spent medium for
consumption rates of essential metabolites, such as primary carbon sources and amino-acids, by
high performance liquid chromatography (HPLC) and biochemical analytical methods,
respectively. These studies are aimed at identifying specific rate limiting metabolites that will be
rapidly depleted in high-density cultures in stirred tank bioreactors. A list and adjusted
concentrations of each metabolite will be compiled at the completion of CWBS 1.4.1.1
Timecourse Evaluation of Spent Medium-No Induction. The resulting reformulations will be
prepared in-house from high quality media supplements. The reformulated serum-free media will
be used in shaker and spinner flasks to determine adaptability of cultures to growth at increasing
cell densities (CWBS 1.4.1.2 Reformulation and Testing of Initial Carbon Source
Concentrations-No Induction). Finally, the best batch medium formulation will be used in CWBS
1.4.1.3 Reformulation and Testing of Optimized Batch Medium-With Induction to demonstrate
improvements in VRP structural protein expression levels as compared with the original
medium.
o CWBS 1.4.2 Feed Supplement Optimization
In general, reformulations of basal media with optimal carbon source concentration and
specific amino acids result in significant improvements in cell growth and density and
concomitant protein expression. In CWBS 1.4.2 Feed Supplement Optimization, the optimized
batch medium will be supplemented with timed feeds consisting of primary carbon source(s),
amino acids, and other growth and protein expression enhancement supplements. In CWBS
1.4.2.1 Primary Carbon Feed Study-No Induction, the batch culture will be initially
supplemented with primary carbon sources at regular intervals such as day 3, 5, and 7 postinoculation in order to maintain optimum concentrations. In addition, data obtained from batch
culture analysis during medium optimization will be used to formulate an amino acid supplement
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for concomitant addition with the carbon feeds in CWBS 1.4.2.2 Primary Carbon Plus Amino
Acids Feed Study-No Induction. Finally, in CWBS 1.4.2.2 Primary Carbon Plus Amino Acids
Feed Study-No Induction the commercially-available supplements MEM vitamins, yeast extracts,
sodium pyruvate, and selenium will be evaluated as well to create a semi-custom feed
supplement.
During each of the studies, samples will be collected for metabolite analysis 24 hours
following the addition of each bolus feed. Of particular importance will be the monitoring of
lactic acid and ammonia production. Spikes in the production of these metabolites following a
feed containing significant levels of carbon source(s) is indicative of a shift in metabolic
pathways used by the cell for generation of energy. Often, such spikes are indicative of a shift
from aerobic to anaerobic metabolism. Thus, a balance must be achieved to maintain the highest
sustainable levels of aerobic metabolism, which is critical for the production of VRPs. The
concentrations and requirements for other metabolites in each feeding bolus, as outlined above,
will be determined experimentally throughout these studies. It is conceivable that optimal feed
supplements may differ between timed points, but efforts will focus on generating a single
universal feed supplement.
o CWBS 1.4.3 Pilot Production (BSL-3)
Following medium and feed optimization, the best performing stable helper cell line will be
used with the new batch and feed strategies at the 500-mL spinner flask scale to produce VRPs
for preliminary yield and activity testing. After production, VRPs will be harvested at small scale
using the high salt wash. This material will be analyzed for CPE and by indirect IFA (yield) and
ELISA (identity and activity). Success in this pilot production run will advance the process to 5L
Process Scale-up studies to demonstrate scalability and reproducibility.
o CWBS 1.4.4 5L Process Scale-up (Upstream, BSL-3)
Following the successful pilot production run, the process will be adapted for bioreactor
scale-up in two stages: S1 stage, from vial thaw and primary seed expansion stage in flask
culture, and S2 stage, the secondary seed expansion in a 5-L bioreactor. A frozen vial will be
thawed under controlled conditions and used to inoculate a shaker flask to a seeding density in an
appropriate volume of the custom basal medium, usually 30-40 mL (S1 stage). The S1 culture
will be incubated in standard growth conditions until the cell density is in late exponential
growth phase. Cells will then be used to inoculate a 250-mL spinner flask (100 mL working
volume). Cells from the 250-mL spinner flask at the target final density will be used to inoculate
a sterile 1-L spinner flask containing 500-mL of custom basal medium. This culture will be
grown to late exponential growth phase and transferred to the next seed stage, S2. The S2 stage
will be performed in a 5-L bioreactor. Cells from the S1 stage will be used to inoculate a 5-L
bioreactor to in a working volume 3-4 L. Scheduled feeds will be added as determined by
previous development studies. Culture samples will be collected daily, for determination of
viable cell count and for analysis of spent media. Coordinated induction and transduction will be
performed at the optimal timing and conditions as indicated by previous development studies.
VRP harvest, CPE assay, and VRP purification and formulation will be performed as per the
established protocols described above (CWBS 1.1.2.4 VRP Purification). To demonstrate process
reproducibility, three identical engineering runs will be performed.
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VRPs produced in Engineering Runs #1-3 will be tested and compared to reference materials.
These assays include indirect immunofluorescence assay (yield), ELISA (identity and activity)
and immunogenicity and protection using murine models. These are described above (CWBS
1.1.4 VRP Testing).
2.5
References Cited
Davis, N.L., Brown, K.W., Greenwald, G.F., Zajac, A.J., Zacny, V.L., Smith, J.F., and
Johnston, R.E. (1995). Attenuated mutants of Venezuelan equine encephalitis virus containing
lethal mutations in the PE2 cleavage signal combined with a second-site suppressor mutation in
E1. Virology 212, 102110.
Davis, N.L., Powell, N., Greenwald, G.F., Willis, L.V., Johnson, B.J.B., Smith, J.F., and
Johnston, R.E. (1991). Attenuating mutations in the E2 glycoprotein gene of Venezuelan equine
encephalitis virus: Construction of single and multiple mutants in a full-length cDNA clone.
Virology 183, 2031.
Davis, N.L., Willis, L.V., Smith, J.F., and Johnston, R.E. (1989). In vitro synthesis of
infectious Venezuelan Equine Encephalitis virus RNA from a cDNA clone: Analysis of a viable
deletion mutant. Virology 171, 189204.
Grieder, F.B., Davis, N.L., Aronson, J.F., Charles, P.C., Sellon, D.C., Suzuki, K., and
Johnston, R.E. (1995). Specific restrictions in the progression of Venezuelan equine encephalitis
virus-induced disease resulting from single amino acid changes in the glycoproteins. Virology
206, 9941006.
Hubby, B, Talarico, T, Maughan, M, Reap, E.A., Berglund, P., Kamrud, K.I., Copp, L.,
Lewis, W., Cecil, C., Norberg, P., Wagner, J., Watson, A., Negri, S., Burnett, B.K., Graham, A.,
Smith, J.F., and Chulay, J.D. (2007). Development and preclinical evaluation of an alphavirus
replicon vaccine for influenza. Vaccine 25, 81808189.
Kamrud, K.I., Custer, M, Dudek, J.M., Owens, G., Alterson, K.D., Lee, J.S., Groebner, J.L.,
and Smith, J.F. (2007). Alphavirus replicon approach to promoterless analysis of IRES elements.
Virology 360, 376387.
Pifat, D.Y., Osterling, M.C., and Smith, J.F. (1988). Antigenic analysis of Punta Toro virus
and identification of protective determinants with monoclonal antibodies. Virology 167, 442
450.
Pushko P., Parker M., Ludwig G.V., Davis N.L., Johnston R.E., Smith J.F. (1997). Repliconhelper systems from attenuated Venezuelan equine encephalitis virus: expression of heterologous
genes in vitro and immunization against heterologous pathogens in vivo. Virology 239(2), 389
401.
Reap, R.A, Morris, J., Dryga, S.A., Maughana, M., Talarico, T., Esch, R.E., Negri, S.,
Burnett, B., Grahama, A., Olmsted, R.A., and Chulay, J.D. (2007). Development and preclinical
evaluation of an alphavirus replicon particle vaccine for cytomegalovirus
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3. PROJECT MANAGEMENT SECTION

3.1
Statement of Work
3.1.1
Phase I: Suspension Parental Cell Lines (CWBS 1.1)
o CWBS 1.1.1 Working Cell Banks

CWBS 1.1.1.1 EB66 Cell Bank
A cGMP Master Cell Bank (MCB) of EB66 cells will be received from Vivalis. A
Working Cell Bank (WCB) will be created for use in all project phases.
CWBS 1.1.1.2 sVero Cell Bank
CWBS 1.1.1.2.1-.4 sVero Parental Cell Line Thaw, Expansion, and Creation of an
Accession Cell Bank (ACB)
sVero cells will be received from Zelltek. An accession cell bank (ACB) will be
created for use in all project phases.
CWBS 1.1.1.2.5-.10
sVero ACB Testing, cGMP Master Cell Bank (MCB), and
Creation of a Working Cell Bank (WCB)
The sVero ACB will be tested for an initial panel of pre-bank qualifying test
including sterility and absence of mycoplasma by a subcontractor (Bioreliance). Upon
successful pre-bank testing, a cGMP Master Cell Bank (MCB) will be created at a the
subcontractor. The MCB will be subjected to a full panel of tests required for current
Good Manufacturing Practices (cGMP) manufacturing of clinical and commercial livevirus vaccine products. Two vials will be shipped back to BioFactura for generation of a
Working Cell Bank (WCB) while the remaining MCB stored offsite at the subcontractor.
o CWBS 1.1.2 Reference VRP Production (Upstream, BSL-3)
CWBS 1.1.2.1 VRP RNA Constructs Generation
Large-scale (giga) purified plasmid DNA preparations of replicon and helper DNA
plasmids will be made. These preparations will be stored at -20C and used for the entire
project (DNA Construct Working Banks). For electroporation of producer cells, purified
DNA plasmids will be linearized by NotI endonuclease digestion and used as templates for in
vitro transcription of capped RNA using RNA Express T7 kits (Promega). After
transcription, RNA will be treated with DNase, purified by anion exchange chromatography
followed by desalting, and stored at80C until use.
CWBS 1.1.2.2-.3 Vero Cell Line Expansion and Electroporation (BSL-3)

Reference VRP vaccine will be produced using the current adherent cell based process. A
Vero working cell bank will be thawed and expanded. For VRP production, cells will be
electroporated with RNA (30 mg each of replicon, capsid helper, and glycoprotein helper) for
VRP production.
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CWBS 1.1.2.4 VRP Purification
CWBS 1.1.2.4.1 VRP Harvest

After 24 h the medium and cells will be pooled and VRP recovered with a high salt
buffer treatment.
CWBS 1.1.2.4.2-.3 Cytopathic Effect (CPE) Assay

A portion of the salt wash material will be tested in a CPE assay to confirm the
absence of detectable replication-competent virus.
CWBS 1.1.2.4.4-.8 VRP Filtration, Chromatography, and Formulation

The salt wash material will be concentrated and diafiltered. The VRP will be purified
on a Cellufine Sulfate column. Purified VRP will be assayed by SDS-PAGE and
formulated as bulk vaccine in an excipient mix that will include normal mouse serum
(NMS) to stabilize the VRP during storage at -80C.
o CWBS 1.1.3 VRP Production: Suspension Parental Cell Lines (Upstream, BSL-3)
VRP vaccine will be produced in both parental sVero and EB66 cell lines using the current
adherent cell based process described above (CWBS 1.1.2.2-.3 Vero Cell Line Expansion and
Electroporation). VRP harvest, CPE assay, and VRP purification and formulation will be
performed as per the established protocols described above (CWBS 1.1.2.4 VRP Purification).
CWBS 1.1.4.1 VRP Titration: Immunofluorescence Assay
To determine transfection efficiencies or the titers of VRP preparations, Vero cells will
be infected with serial dilutions of purified and formulated VRP and incubated in eightchamber slides (Nunc) to allow expression of the VEEV glycoproteins. Antigen-positive
cells will be enumerated for VEEV glycoprotein protein by direct immunofluorescence.
CWBS 1.1.4.2 In-vitro Reactivity

VEEV specific ELISA will be used to measure envelope epitope determinants in the
inactivated virus preparations. The assay is based on a standard sandwich ELISA method
utilizing monoclonal antibodies.
CWBS 1.1.4.3 In-vivo Immunogenicity

BALB/c mice will be immunized with two doses of the vaccine candidates by the SC
route on Day 0 and Day 28. Saline and reference VRP inoculated groups will be included to
provide appropriate controls. Mouse sera will be obtained at Day 21 and Day 49 and assayed
for VEEV-specific total Ig (G, M and A) by ELISA. Additionally, the sera will be examined
for ability to neutralize virus infectivity by plaque assay in Vero cells.
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CWBS 1.1.4.4 In-vivo Protection Assay: Mouse VEE Lethal Aerosol Challenge
BALB/c will be immunized with two doses of the vaccine candidates by the SC route on
Day 0 and Day 28. Saline and reference VRP inoculated groups will be included to provide
appropriate controls. Mouse sera will be obtained at Day 21 and Day 49 and assayed for
VEE-specific humoral immune response as described above. At 28 days post-final
vaccination, mice will be aerosol challenged with VEEV Trinidad strain. After challenge,
mice will be observed twice daily for clinical signs of infection (piloerection, hunching,
inactivity, excitability and paralysis) by an observer who is unaware of treatment allocations
for 14 days.
o CWBS 1.1.5 Phase I Scientific and Technical Report (CDRL A003)

A Phase I Scientific and Technical Report will be generated.
3.1.2
Phase II: Suspension Helper Cell Lines (CWBS 1.2)
o CWBS 1.2.1 EB66 Helper Cell Lines
CWBS 1.2.1.1 Lac Induction System

For EB66 stable helper cell line, the pOPRSVI/MCS vector will be modified such
that it contains two independent expression cassettes to permit the cloning of both the
VEE C and GP open reading frames (ORFs). VEE structural genes will be optimized for
expression in EB66 and synthesized (GeneArt). VEE C and GP genes will be cloned into
the vector and sequence confirmed. Transient co-transfections will be performed using
both the pCMVLacI and expression vectors to confirm inducible expression of VEE
subunits. EB66 will be tested for sensitivity to both hygromycin and G418 to establish
optimum selection conditions. Parental cells will be expanded and co-transfected with
both the pCMVLacI and expression vectors. We anticipate emergence of a stable pool in
2-3 weeks and will perform an initial induction study to confirm expression of VEE
subunits. Following expression confirmation, stable pools will be cloned by limiting
dilution and best performing clones will be selected and banked.
CWBS 1.2.1.2 Tet Induction System

For the proposed EB66 stable helper cell line, the pTRE3G-IRES vector will be used.
VEE structural genes will be optimized for expression in EB66, synthesized (GeneArt),
cloned into the vector, and sequence confirmed. Transient co-transfections will be
performed using both the pCMV-Tet3G regulator and pTRE3G-IRES response vectors to
confirm inducible expression of VEE subunits. Parental cells will be expanded and
transfected with the pCMV-Tet3G vector. Parental cells will be expanded and cotransfected with both the pCMV-Tet3G vector and the pTRE3G-IRES vector containing
the VEE VRP structural genes. We anticipate emergence of a stable pool in 2-3 weeks
and will perform an initial induction study to confirm expression of VEE subunits.
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Following expression confirmation, stable pools will be cloned by limiting dilution and
best performing clones will be selected and banked.
o CWBS 1.2.2 sVero Helper Cell Lines
Stable sVero helper cell lines will be generated using the Lac and Tet inducible systems as
described above for the EB66 lines. If necessary, VEE VRP structural genes will be optimized
for expression in the sVero cell line.
VRP vaccine will be produced in the best performing clones of each EB66-Lac, EB66-Tet,
sVero-Lac, sVero-Tet stable helper cell lines using the current adherent cell based process
described above (CWBS 1.1.2.2-.3 Vero Cell Line Expansion and Electroporation). VRP harvest,
CPE assay, and VRP purification and formulation will be performed as per the established
protocols described above (CWBS 1.1.2.4 VRP Purification).
VRP produced with stable helper cell lines will be tested and compared to reference materials
as described in CWBS 1.1.4 VRP Testing.
o CWBS 1.2.5 Phase II Scientific and Technical Report (CDRL A003)
A Phase II Scientific and Technical Report will be generated.
3.1.3
Phase III: Induction/Transduction Optimization (CWBS 1.3)
o CWBS 1.3.1 Preliminary Transduction Study

A preliminary study will be performed using EB66, sVero, and adherent Vero (control) to
determine efficiency of VRP transduction and delivery of replicon RNA. Each parental cell line
will be transduced at a range of multiplicities of infection (MOIs) using reference VRP material
(CWBS 1.1.2 Reference VRP Production) and allowed to incubate 24 hours. In addition, an
electroporation reaction will be used as a control with adherent Vero cells. Efficiency of
transduction and replicon amplification will be determined by ELISA, Western blot, and
quantitative PCR (qPCR).
o CWBS 1.3.2 Induction/Transduction Optimization (BSL-3)
Stable helper cell lines suitable for transduction as determined above (EB66 and/or sVero),
will be evaluated for VRP yield and reactivity at different induction concentrations and times and
at range of MOIs. This set of experiments will be split into Lac cell lines and Tet cell lines to
simplify the induction steps. VRPs will be harvested at small scale using the high salt wash. This
material will be analyzed for CPE and by indirect immunofluorescence assay (IFA, yield) and
ELISA (identity and activity).
VRP vaccine will be produced in the two best performing systems (Systems #1 and #2) as
described above (CWBS 1.3.2 Induction/Transduction Optimization) at production scale (100
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mL). VRP harvest, CPE assay, and VRP purification and formulation will be performed as per
the established protocols described above (CWBS 1.1.2.4 VRP Purification).
CWBS 1.3.4 VRP Testing
VRP produced with Systems #1 and #2 will be tested and compared to reference materials as
described in CWBS 1.1.4 VRP Testing.
CWBS 1.3.5 Phase III Scientific and Technical Report (CDRL A003)
A Phase III Scientific and Technical Report will be generated.
3.1.4
Phase IV: Process Development (CWBS 1.4)
o CWBS 1.4.1 Batch Medium Optimization

The initial optimization studies will be performed on the analysis of fresh versus spent
medium for consumption rates of essential metabolites, such as primary carbon sources and
amino-acids, by high performance liquid chromatography (HPLC) and biochemical analytical
methods, respectively. A list and adjusted concentrations of each metabolite will be compiled at
the completion of CWBS 1.4.1.1 Timecourse Evaluation of Spent Medium-No Induction. A
reformulated serum-free media will be used in shaker and spinner flasks to determine
adaptability of cultures to growth at increasing cell densities (CWBS 1.4.1.2 Reformulation and
Testing of Initial Carbon Source Concentrations-No Induction). The best batch medium
formulation will be used in CWBS 1.4.1.3 Reformulation and Testing of Optimized Batch
Medium-With Induction to demonstrate improvements in VRP structural protein expression
levels as compared with the original medium.
o CWBS 1.4.2 Feed Supplement Optimization
In CWBS 1.4.2.1 Primary Carbon Feed Study-No Induction, the batch culture will be initially
supplemented with primary carbon sources at regular intervals. Data obtained from batch culture
analysis during medium optimization will be used to formulate an amino acid supplement for
concomitant addition with the carbon feeds in CWBS 1.4.2.2 Primary Carbon Plus Amino Acids
Feed Study-No Induction. Finally, in CWBS 1.4.2.2 Primary Carbon Plus Amino Acids Feed
Study-No Induction the commercially-available supplements MEM vitamins, yeast extracts,
sodium pyruvate, and selenium will be evaluated as well to create a semi-custom feed
supplement.
o CWBS 1.4.3 Pilot Production (BSL-3)
The best performing stable helper cell line will be used with the new batch and feed
strategies at the 500-mL spinner flask scale to produce VRP that will be tested for yield and
activity.
o CWBS 1.4.4 5L Process Scale-up (Upstream, BSL-3)
Following the successful pilot production run, the process will be adapted for bioreactor
scale-up in two stages: S1 stage, from vial thaw and primary seed expansion stage in flask
culture, and S2 stage, the secondary seed expansion in a 5-L bioreactor. A frozen cell bank vial
will be used to inoculate a shaker flask (S1 stage). The S1 culture will be successively expanded
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in spinner flasks culture up to 500-mL. Cells from the S1 stage will be used to inoculate a 5-L
bioreactor (S2) to in a working volume 3-4 L. Scheduled feeds will be added as determined by
previous development studies. Culture samples will be collected daily, for determination of
viable cell count and for analysis of spent media. Coordinated induction and transduction will be
performed at the optimal timing and conditions as indicated by previous development studies.
VRP harvest, CPE assay, and VRP purification and formulation will be performed as per the
established protocols described above (CWBS 1.1.2.4 VRP Purification). To demonstrate process
reproducibility, three identical engineering runs will be performed.
VRPs produced in Engineering Runs #1-3 will be tested and compared to reference materials
as described in CWBS 1.1.4 VRP Testing.
o CWBS 1.4.5 Phase IV Scientific and Technical Report (CDRL A003)
A Phase IV Scientific and Technical Report will be generated.
3.1.5
Project Management (CWBS 1.5)
o CWBS 1.5.2 Program Reporting & Meetings

CWBS 1.5.2.1 Project Kick-off Meeting
A meeting will be held with all stakeholders (BioFactura, USAMRIID subcontractor,
Government representative) to review project schedule, tasks, and deliverables as well as to
discuss risk drivers and communication procedures.
CWBS 1.5.2.2 Contractor Progress, Status, and Management Report & IMS
Monthly written reports (24 total) will be submitted electronically, which will provide
program status/progress, cost updates, review of problems and proposed resolutions.
CWBS 1.5.2.3 Quarterly Program Review

Quarterly program reviews will be held (8 total) to review task completion, results,
projected tasks, updates, risks, and issues.
3.2
CWBS and CWBS Dictionary
3.2.1 Acronyms, Abbreviations, and Symbols

CWBS Contract Work Breakdown structure
IMS Integrated Master Schedule
3.2.2 Overview
The CWBS and CWBS dictionary have been prepared using the MIL-HDBK-881 guidance
document. In order to obtain the depth and breadth required to define the contract scope and to
accurately describe the proposed effort, the CWBS diagram is shown to level 5 while the CWBS
dictionary lists all IMS elements to level 6. The lists all summary and work package tasks,
milestones and decision points. In addition, the CWBS numbering scheme is maintained
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throughout all documents to ensure complete alignment and integration of the SOW and
Technical Approach sections with the IMS.
In order to satisfy the level of detail requested (to level 4 and beyond), but due to the page
size constraints of Microsoft Word, the CWBS diagram is provided separately in both electronic
files (Microsoft PowerPoint and PDF) and on a large format paper hard copy. The full CWBS
dictionary is provided in Section 5.2 of the Appendix.
3.3
IMS
The IMS documents all critical paths, major milestones, tasks/activities, durations, lag times,
and task relationships (predecessor/successor) in sufficient detail to account for the entire
program. Furthermore, the IMS was used to generate the CWBS and CWBS dictionary and is
directly traceable to the SOW and technical approach sections. The IMS has been prepared to
level 6 but tasks roll-up to increasingly higher summary levels. Due to the page size constraints
of Microsoft Word, the IMS is provided separately in electronic files (Microsoft Project and
PDF) to level 6 and on a large format paper hard copy to level 4.
3.4
Project Management Approach

BSL Bio-Safety Level
CBMS-JVAP-JPM Chemical Biological Medical Systems-Joint Vaccine Acquisition ProgramJoint Program Manager
CDRL Contract Data Requirements List
IMS Integrated Master Schedule
PM Project Management
POC Point of Contact
sVero stable suspension Vero
USAMRIID US Army Medical Research Institute of Infectious Diseases
VEE Venezuelan Equine Encephalitis
VLP Virus-Like Particle
VRP Virus Replicon Particle
3.4.2 Overview
Due to the highly sequential nature of the tasks and milestones leading up to the contracts
project goal to develop a novel VRP production process, BioFacturas management team has
adopted a traditional phased project management approach, also referred to as a waterfall model.
As illustrated in the Figure 5 below, the overall project has been divided into four sequential
technical phases, each of which addresses one of the scientific or technical aspects necessary to
achieve the project goal. This approach has the added benefit that the completion of each stage
offers a logical, natural break without introducing undue work disruptions or delays mid-effort.
At the completion of each stage the company plans to submit interim Scientific and Technical
Reports (per CDRL A0003) to the Government for review, which will serve as go/no-go decision
drivers before proceeding to the next phase of the project.
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Figure 5: Project Technical Phases
3.4.3 Program Status and Progress Tracking

BioFacturas stable helper cell line process development approach will be a phased and
milestone gated effort to reduce risk and allow for go/no-go decisions by the Government. Upon
project completion, this process will provide a universal scalable production method for any
VEE VRP-based vaccine using a common stable helper cell line and modular replicon
transduction step. Elements of this process may also be applicable to other VRP- and VLP-based
vaccines and platforms. The proposed milestones are as follows:
Phase I
Demonstration of baseline VEE VRP productivity and bioactivity in the
suspension Vero and EB66 cell lines using the current electroporation
process.
Phase II
Generation of scalable stable sVero and EB66 helper cell lines capable of
inducible expression of the VEE structural subunits creating universal
helper cell lines.
Phase III
Determination of optimal induction and transduction conditions using the
target vaccine product (VEE VRP candidate) as the replicon
delivery vector.
Phase IV
Integration of unit operations and demonstration of process scalability and
reproducibility in benchtop bioreactors.
The Company has further subdivided each technical phase in the IMS to capture all critical
paths, major and minor milestones, tasks, duration and lag times, decision points, and task
relationships down to level 6. The IMS (in Microsoft Project) will be used to track the progress
and status of all tasks, milestones, and decision points, and will be reviewed and revised, if
necessary, on a monthly basis.
The Project Manager will arrange for weekly meetings with BioFactura project personnel and
the USAMRIID Principal Collaborator as a forum to discuss and update the schedule and review
progress and to dicuss issues and risk drivers. Based on these weekly meetings, the PM will use
the IMS to track the progress and status of all tasks, milestones, and decision points. This will be
accomplished by tracking and updating all active tasks percent completion on a weekly basis in
the IMS.
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3.4.4 Functional Oversight

As PM and Technical Project Manager, BioFacturas CEO, Darryl Sampey will be
responsible for all aspects of the projects scientific and technical efforts. As such he will manage
both in-house and subcontracted tasks, track task status and progress vis--vis the IMS, and
monitor and update risk drivers. A key function of Mr. Sampey will be to ensure a smooth
integration of the highly interdependent tasks to be performed at USAMRIID and BioFactura. As
such he will serve as the man on site at USAMRIID to oversee and assist with tasks and track
USAMRIIDs task progress and status.
The companys COO and CFO, Alexander Matschiner, will serve as Operational Project
Manager. He primarily will responsible for the management of the project budget, G&A support,
and procurement. He will also assist Mr. Sampey with maintaining and updating the IMS
schedule and tracking percent completion. Mr. Matschiner also will serve as interim Project
Manager in the event that Mr. Sampey is absent.
3.4.5
Communications with Government and Stakeholders
3.4.5.1
Government (CBMS-JVAP JPM )
Darryl Sampey will serve as Point of Contact (POC) for all communications with the
Government and the Companys subcontractors. In addition, he will responsible for assembling
and filing periodic status reports per the Contract Data Requirements List items below and for
the scheduling of any meetings with the project stakeholders (BioFactura personnel, government
contracting officer, subcontractor POCs). The Company will follow the reporting requirements
per the CDRL items below to communicate status and progress on the project .
Table 1: Company Reports and Communications
CDRL & Description
Communications
Frequency
Contractor Progress, Status and Management

Report (CDRL A001)
Program status/progress, cost updates, review
of problems and proposed resolutions
Report in MS Office or
PDF via email
Monthly
(2nd Wed)
Integrated Master Schedule (CDRL A002)

Task progress an status, schedule slippage
Report in MS Office or
PDF via email
Initial within 30 days

of Award, thereafter,
Monthly
(2nd Wed)
Quarterly Program Review (CDRL A004)

Review of task completed and results, projected
tasks, schedule updates, review of risks and
issues.
MS Power Point or PDF

file submitted 10 days
prior to briefing;
CBMS-JVAP JPM
briefing
Quarterly following
award date
Scientific and Technical Reports Summary (CDRL

A003)
Study objectives, methodology, data, discussion
of results, conclusions, and any amendments.
MS Office or PDF file

via email
Within 30 days of
completion of a project
phase
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3.4.5.2
Subcontractors
3.4.5.2.1 Minor Subcontractors

Upon a contract award, the PM will contact subcontractors that will be required on an asneeded basis at an appropriate period prior to a subcontractors scheduled start-date to ensure no
scheduling conflicts will occur and that the tasks can be completed as scheduled. The size of the
period will depend on the scope and duration of the task. For instance, sequence analysis and
synthesis requires at most two weeks of notice while cell banking and testing will require at least
one month. As the deadline for engaging a subcontractors services approaches, the PM may
periodically contact his POC at the subcontractor to ensure that there are no changes to the
schedule and to confirm the required turnaround time.
3.4.5.2.2 Major Subcontractor - USAMRIID
USAMRIID will conduct a significant portion of the proposed project tasks for the duration
of the project due to the biosafety level-3 (BSL-3) requirements of the upstream VRP process.
All the tasks performed at USAMRIID represent a critical path towards meeting key project
objectives. As such, the Principal Collaborator at USAMRIID will be an integral member of
BioFacturas project team, who will be present in person or via conference call at all of the
Companys internal weekly project meetings and all government briefings. (See Section 5.1 Key
Personnel Qualifications of the Appendix for more information about the USAMRIID Principal
Collaborator, Dr. Pamela Glass). Dr. Glass will also contribute towards the monthly, quarterly,
and final study reports to be filed with the Government. BioFactura has allotted a significant
portion of the PMs time (including travel to and from the subcontractor and on-site supervision)
to ensure constant communications and oversight of USAMRIIDs progress and schedule.
3.4.5.3
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At the onset of the contract award the PM will hold a Project Kick-Off meeting with the
project stakeholders to review project schedule, tasks, and deliverables as well as to discuss risk
drivers and communication procedures. Thereafter, the PM will arrange for weekly meetings
with BioFactura project personnel and the USAMRIID Principal Collaborator as a forum to
discuss and update the schedule and task progress and to review issues and risk drivers.
3.5
Risk Management Plan

RMS - Risk Management System
3.5.2 Introduction
BioFactura will implement an integrated and proactive Risk Management Plan for the
proposed project. This Plan will be part of an overall management scheme consisting of
Clearly defined stakeholder roles and responsibilities
Methods for effectively identifying, assessing and prioritizing, and planning for risk
Management procedures in terms of tracking, monitoring, and responding to risk triggers
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3.5.3 Roles and Responsibilities

The Company has defined the following roles and responsibilities for the Companys project
stakeholders.
Table 2: Stakeholder Responsibilities
Role
Roles &
Responsibilities
Assignment
Technical
Project Manager
- Initial risk identification, assessment & planning (proposal)

- Plan implementation
- Risk management coordination and oversight
- Review and update RMS
- Provide RMS updates in monthly CBMS reports
Operational
Project Manager
- Monitor risk watch list and communicate triggers

- Identify, communicate, and help assess new risks
A. Matschiner
Cell Culture
Scientist
- Monitor risk watch list and communicate triggers

- Identify, communicate, and help assess new risks
D. Onyabe
3.5.4
D. Sampey
Risk Management Tools and Methodologies
3.5.4.1
Risk Identification
BioFactura has sought to find any potential risks by identifying all events that, when
triggered, could cause problems. There are numerous methods of risk identification. One basic
approach is to seek any potential sources of problems (source analysis) while another is to
identify the problem itself (problem analysis). While source analysis involves finding potential
internal or external risk sources, problem analysis simply identifies any threats. Alternatively,
any event that may endanger achieving an objective partly or completely is identified as a risk
(objectives-based risk identification). The company conducted a risk analysis using the above
risk identification approaches but limited this initial effort to reviewing the proposed project
schedule and looking for the following risk drivers:
Any events that may endanger key project milestones.
Tasks with aggressive timelines and/or cost estimates.
Tasks for which there are a limited number of resources that can do particular tasks and
where those resources are fully allocated, over-allocated, or may become unavailable.
Tasks with several predecessors.
Tasks with long durations and/or a lot of resources.
Tasks with which the team has limited experience; hence a greater risk of predicting the
outcome and planning accordingly.
3.5.4.2
Risk Assessment and Prioritization
Once risks were identified, each risk was assessed as to its potential severity of negative
impact, and to the probability of its occurrence. Each was qualified in terms of Low,
Medium, and High. Based on the Companys and projects risk sensitivities, the priority
Table 3 below was developed, which was then used to prioritize all identified risks. Due to page
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limit constraints, only risks with level 1 4 priorities, (1 being the highest priority) have been
identified in Table 4.
Table 3: Risk Prioritization Table
IMPACT
P
R
O
B
A
B
I
L
I
T
Y
High
Medium
Low
High
Medium
Low
3.5.4.3
Risk Planning
Risks with level 1-3 priorities were defined as High Priority. For each of the high priority
risks in Table 4, a risk trigger was identified and a risk plan formulated (see Table 5). The risks
plans are grouped into three approaches: risk avoidance, risk mitigation, and risk acceptance
(includes a contingency plan[s]). All risk plans were evaluated for their potential impact on the
project and any new resulting risks identified and assessed. Only new risks with priority levels 13 priorities are shown.
3.5.4.4
Risk Management
Upon contract award, the Project Manager (PM) will meet with project personnel (resources)
on a weekly basis to review schedules and progress and to go over the projects high-priority risk
watch list. At the meeting, the project team will make an assessment on risk drivers to determine
if risk trigger events have occurred or are about to occur and formulate an action or contingency
plan accordingly. The meetings will also serve identify and assess any new risks as well as to
determine if the Risk Management Plan needs to revised or updated. Changes to the Risk
Management Plan will be communicated to CBMS in the monthly Contractor Progress, Status
and Management Report (CDRL A0001).
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Table 4: Risk Identification, Assessment and Prioritization Tables (Priority Levels 1 - 4 only)
Risk
ID
A
A.1
B
Risk
Description
Impact
Probability
Risk
Priority
Budget
USAMRIID Subcontractor costs increase due to
scope creep or unanticipated issues
Schedule
B.1
Insufficient time allotted in IMS for tasks
B.2
CBMS go/no-go decision delays
Staffing Resources
C.1
Inadequate staffing resources to meet milestones
C.2
Staffing absence (vacation, illness, emergency)
Contractors
D.1
USAMRIID scheduling and or resource conflicts
D.2
Bioreliance/GeneArt turn-around longer than

projected
Technical
E.1
sVero cell line fails Master Cell Bank testing
E.2
VRP yield and/or quality (activity, efficacy)

significantly lower in suspension cell line
E.3
Stable helper cell lines with low productivity
E.4
Poor VRP transduction of suspension cell lines
F
F.1
Administrative
Delays in procurement
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Table 5: High-Priority Risk Watch List and Risk Plans

Risk
ID
A
A.1
Risk
Trigger
Risk
Plan
Type
Risk Plan
Description
New
Risk
Budget
USAMRIID cost
revisions
Accept
Discuss with CBMS and determine if contract Mod

No
warranted/acceptable or decide on contract scope and/or
schedule adjustment
Duration/Schedule
B.1
Schedule slippage
Mitgate
Increase resource allocation (effort)
B.1.1 Resources fully

allocated (I/P/P: H/L/3)
Resources fully
allocated
Accept
Develop contingency plan with COR and determine if

contract Mod warranted/acceptable or contractor can
secure additional resources to make-up time
No
B.1.1
B.2
Go/no-go decisions
delayed
Staffing Resources
C.1
Schedule slippage
Avoid
Increase resource allocation (effort)
No
C.2
Staff absence
Accept
Company has allocated two people per task as

contingency plan to allow for remaining person to fill-in
C.2.1 - Remaining personnel

may lack info or know-how
(I/P/P: H/L/3)
Mitigate
Assess schedule impact and increase resource allocation

for training and/or make-up time (over-time)
Project delay but risk priority

>3
Mitigate
Assess schedule impact, determine if time can be made up No

or outsource to alternate subcontractor
C.2.1
D
D.1
Personnel lack of info

or know-how
Mitigate
Discuss with COR and determine if contract Mod

No
warranted/acceptable or decide on contract scope and/or
schedule adjustment
Contractors
Subcontractor
milestone delay
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D.2
Accept
Develop contingency plan with COR and USAMRIID

Prinicipal Collaborator
Project delay (depends on

contingency plan)
Accept
Re-adapt cGMP adherent cell line to suspension culture
Schedule delay
Mitigate
Continue with EB66 cell line development per IMS
No backup cell line
VRP yield and/or

quality (activity,
efficacy) significantly
lower in suspension
cell line
Mitigate
Continue with backup cell line development per IMS
No backup cell line
E.3
Stable helper cell lines

with low productivity
Mitigate
Continue with alternate cell lines development per IMS
Reduced alternate cell lines
E.4
Poor VRP transduction

of suspension cell lines
Mitigate
Continue with backup cell line development per IMS
No backup cell line
Mitigate
Using known vendors with known turn-around times;

could use alternative vendors.
Project delay but risk priority

>3
E
E.1
E.2
F
F.1
USAMRIID milestone
delay
Technical
sVero cell line fails
Master Cell Bank
testing
Administrative
Delays in procurement
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4. PAST PERFORMANCE SECTION

4.1
Contract Title: Generation of Stable Eukaryotic Cell Lines Expressing High Yields
of Therapeutic Human Antibodies Against Biowarfare Viral Threat Agents
4.1.1
Contract Agency or Customer: US Army Medical Research Acquisition Activity
4.1.2
Contract Number: W81XWH-06-C-0029
4.1.3
Contract Type: Firm-Fixed Price
4.1.4
Period of Performance: 14 November 2005 15 January 2011
4.1.5
Original Contract $ Value: $69,950
4.1.6
Current/Final Contract $ Value: $3,090,847.00
4.1.7 If Amounts for .5 and .6 above are different, provide a brief description of the reason:
This contract began as a Small Business Innovative Research (SBIR) Phase I award.
Successes in the Phase I effort and the follow-on efforts led to additional funding that was added
to this contract as follows:
Phase I $69,950
Phase I Option $49,671
Phase II $729,766 (Yr 1 $380,523; Yr 2 $349,243)
Phase II Enhancement $500,000
Phase IIIa $966,280
Phase IIIb $775,180
4.1.8 Brief Description of Effort as _X___Prime or ____Subcontractor
Since 2004, BioFactura has been an active collaborator with the US Army Medical Research
Institute of Infectious Diseases (USAMRIID) through various Cooperative Research and
Development Agreements (CRADAs). Activities supporting contract W81XWH-06-C-0029
(USAMRAA) included design and construction of mammalian expression vectors for the
generation of human IgG1 monoclonal antibodies, testing of those vectors in transient
transfection experiments, generation of stable CHO and NS0 cell lines, scale-up and manufacture
of monoclonal antibodies in cell culture bioreactors, development of in-process, release, and
bioactivity assays, and demonstration of efficacy of a monoclonal antibody cocktail against
orthopoxviruses in animal models. BioFactura successfully managed multiple subcontractors
during this contract including several that are proposed in the current submission such as
USAMRIID and Bioreliance. The focus of this work centered around development of stable
production cell lines, process development, scale-up, and activity and efficacy testing, all highly
related to the proposed work in the current submission.
4.1.9
Completion Date: 15 January 2011
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4.1.10 Primary Customer Points of Contact:

Program Manager:
Name:
Office:
Address:
Telephone:
Email:
Contracting Officer: Name:

Office:
Address:
Telephone:
Email:
COTR:
Name:
Office:
Address:
Telephone:
Email:
Jay Hooper, Ph.D., ChiefMolecular Virology Branch

USAMRIID, Virology Division
1301 Ditto Stree
Fort Detrick, MD 21702
301-619-4101
jay.hooper@amedd.army.mil
Joseph Little
USAMRAA
820 Chandler Street
Fort Detrick, MD 21702-5014
301-619-2546
joseph.little@amedd.army.mil
Pamela J. Glass, Ph.D., ChiefViral Biology Department
USAMRIID, Virology Division
1425 Porter Street
301-619-4742
pamela.glass@amedd.army.mil
4.2
Contract Title: Generation of Stable Cell Lines and Monoclonal Antibodies Against
B. anthracis Capsule Protein
4.2.1
Contract Agency or Customer: US Army Medical Research Acquisition Activity
4.2.2
Contract Number: W81XWH-08-P-0097
4.2.3
Contract Type: Firm-Fixed Price
4.2.4
Period of Performance: 15 February 2008 06 January 2009
4.2.5
4.2.6
Current/Final Contract $ Value: $72,125
4.2.7
If Amounts for .5 and .6 above are different, provide a brief description of the reason:
N/A
In 2008, BioFactura was awarded contract W81XWH-08-P-0097 (USAMRAA). This
contract supported requirements for Joint Science and Technology Chemical and Biological
Defense Research Program Project Plan Bacillus Anthracis And Francisella Tularensis As
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Models For The Identification Of Virulence Factors/Biochemical Pathways Common To

Category A And B Bacterial Biowarfare Agents. This contract augmented existing resources
with experience and capability (medical and non-medical) which is not normally available.
Clones were developed with human anti-Bacillus anthracis capsule constructs which were
optimized 25-fold for capsule binding affinity. Once sufficient quantities of these antibodies are
produced, they will be evaluated for their ability to protect laboratory animals against anthrax.
The statement of work included large-scale transient transfections to produce 15 mg of three
monoclonals, chromatography purification of the three antibodies, and generation of clonal
stable CHO cell lines for expression of two monoclonals. The focus of this work centered around
development of stable production cell lines for therapeutic antibody manufacture, highly related
to the proposed work in the current submission.
4.2.9
Completion Date: 06 January 2009

Program Manager:
Name:
Office:
Address:
Telephone:
Email:
Contracting Officer: Name:

Office:
Address:
Telephone:
Email:
COTR:
Name:
Office:
Address:
Telephone:
Email:
Arthur M. Friedlander, M.D., Senior Scientist

USAMRIID
1425 Porter Street
301-619-7343
arthur.friedlander@amedd.army.mil
Cheryl Miles
USAMRAA
820 Chandler Street
301-619-7148
cheryl.miles@amedd.army.mil
Arthur M. Friedlander, M.D., Senior Scientist
USAMRIID
1425 Porter Street
301-619-7343
4.3
Contract Title: Recombinant Antigen Multiagent Diagnostic Assays for Lassa and
Other Arenaviruses
4.1.1
Contract Agency or Customer: NIH -National Institute of Allergy and Infectious Diseases
4.1.2
Contract Number: 1 UC1 AI067188-01
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4.1.3 Contract Type: Subaward to prime (Tulane University Health Sciences Center), Firm
Fixed Price
4.1.4
Period of Performance: 21 September 2005 30 September 2008
4.1.5
4.1.6
4.1.7
N/A
4.1.8 Brief Description of Effort as ____Prime or _ X___Subcontractor
In collaboration with Tulane University, USAMRIID, Corgenix Medical Corp., Autoimmune
Technologies, LLC, and various partners in West Africa, BioFactura developed recombinant
reagents (viral antigens and monoclonal antibodies) for test kits for hemorrhagic fever diagnosis
under a $3.8 million grant awarded by the National Institutes of Health (NIH). Under the NIH
grant, Tulane led a three-year study designed to develop rapid diagnostic tests for viral
hemorrhagic fevers, some of which are caused by arenaviruses that are potential bioterrorism
agents due to their high fatality rate and ease of transmission from person-to-person. BioFactura
designed novel versions of viral protein subunits, created expression vectors, and manufactured
these subunits in mammalian cell culture for ELISA diagnostic kits. These kits were field
deployed in Sierra Leone and were demonstrated to accurately diagnose and monitor Lassa virus
infection. These virus subunit design and expression efforts are highly related to the proposed
work in the current submission.
4.1.9
Completion Date: 30 September 2008

Program Manager:
Name:
Office:
Address:
Telephone:
Email:
BioFactura, Inc.
Robert F. Garry, Ph.D., Professor

Tulane University School of Medicine, Department
of Microbiology and Immunology
1430 Tulane Avenue, SL-38
New Orleans, LA 70112-2699
504-988-2027
Page 38 of 218
Contracting Officer:
Name:
Office:
Address:
Telephone:
Email:
Kathleen M. Kozar, Director, Research Admin.

Tulane University Health Sciences Center Office of
Research Administration
1430 Tulane Avenue, EP-15
New Orleans, LA 70112-2699
504-988-5613
kkozar@tulane.edu
4.4
Contract Title: Optimization and Development of Transfection Methodology for

YB2/0 Rat Myeloma Cell Line
4.4.1
Contract Agency or Customer: Invitrogen Corporation
4.4.2
Contract Number: A1084601
4.4.3
Contract Type: Firm Fixed Price
4.4.4
Period of Performance: 21 May 2008 15 April 2009
4.4.5
4.4.6
4.4.7
N/A
In 2008, BioFactura was awarded a contract with Invitrogen to determine the optimal
experimental conditions for the transfection of serum free medium adapted YB2/0 myeloma cell
lines. Once optimal conditions were identified, these were used to transfect and select the
parental cell line to create a pool of recombinant Y2B/0 expressing an Invitrogen customers
(LFB Biotechnologies) monoclonal antibody. These stable cell line generation activities are
highly related to the proposed work in the current submission.
4.4.9
Completion Date: 15 April 2009

Program Manager:
Name:
Office:
Address:
Telephone:
Email:
BioFactura, Inc.
Graziella Piras, Ph.D., Senior Project Manager

Invitrogen CorporationPD-Direct
7335 Executive Way
Frederick, Maryland 21704
240-793-1216
graziella.piras@invitrogen.com
Page 39 of 218
Contracting Officer:
Name:
Office:
Address:
Telephone:
Email:
BioFactura, Inc.
Trent Carrier, Ph.D.

Invitrogen Corporation
1600 Faraday Avenue
Carlsbad, CA 92008
240-370-4333
trent.carrier@invitrogen.com
Page 40 of 218
5. COST SECTION
5.1
Overview
The following cost proposal provides a comprehensive budget estimate of the all the direct
and indirect project costs along with descriptions of the estimating techniques and allocation
methods employed. All individual costs elements have CWBS numbers that correlate directly to
the SOW, CWBS, and IMS. The summary cost proposal as well as the supporting detailed cost
center break-downs are shown by U.S. Government Fiscal Year (1 Oct-30 Sep). The Cost
Proposal was prepared using Microsoft Excel and an electronic cope is being provided with the
submission in a MS Excel 97-2004 compatible format.
5.2
Cost Proposal
Table 6 below shows the cost summary for the overall project. Direct and indirect costs are
shown by Government fiscal year. The project start date was set tentatively to June 1, 2012 for
budgeting purposes. The project duration is estimated at about 25 months with projection
completion on or about June 27, 2014. It should be noted, however, that the Company is
proposing to divide the project into four technical phases as each phase represents a key
technical milestone and a go/no-go decision point to proceed to the next phase.
Table 6: Project Cost Summary
FY12
FY13
FY14
Total
Direct Costs
Direct Labor Hours
755
2,928
2,043
5,726
$59,775
$204,831
$157,272
$421,878
USAMRIID
$116,089
$55,378
$55,378
$226,845
Bioreliance
$153,976
$217,189
$15,598
$386,763
$1,500
$1,500
$3,000
$64
$64
$128
$15,114
$32,812
$13,143
$61,070
$7,837
$1,557
$1,227
$10,621
$104,800
$104,800
$11,250
$11,250
$22,500
$459,911
$527,510
$255,910
$1,243,331
Direct Labor Dollars (incl. Fringe)

Subcontractors
Geneart
Macrogen
Consultants
Material and Supplies
Material Handling
Travel
Equipment
Other Direct Costs
EB66 License
Tet License
Sub-Total Direct Costs
Indirect Costs
BioFactura, Inc.
Page 41 of 218
Overhead
$10,341
$35,436
$27,208
$72,985
G&A - Internal
$22,272
$70,675
$50,681
$143,629
G&A - Subcontractors
$19,213
$14,347
$4,173
$37,733
$51,826
$120,458
$82,062
$254,346
Total Estimated Target Cost
$511,737
$647,968
$337,972
$1,497,677
Target Fee
$102,347
$129,594
$67,594
$299,535
Total Target Cost Plus Fee
$614,084
$777,561
$405,567
$1,797,213
FCCOM
Sub-Total Indirect Costs
5.3
Cost Elements
The following sections provide a cost-breakdown by CWBS number and by fiscal year as
well as the estimating and allocation techniques employed.
5.3.1 Direct Labor
Table 7 below provides a breakdown of direct base labor by fiscal year and CWBS number
down to level 6. In addition, the table has been divided into the four technical project phases (I IV) to provide estimated labor costs and man-hours for each phase.
The man-hours for each IMS element or work package (task/activity) were derived directly
from the IMS to ensure complete correlation between the IMS and the projects labor cost
estimate. Man-hours were generated in the IMS by assigning task durations and the individual
effort levels for all personnel involved in the task. The raw data from the Microsoft Project-based
IMS file was then extracted and transferred to a Microsoft Excel file to generate Table 3.5.4.1.
For the purposes of these labor calculations, one year was defined as 2,080 man-hours. The
hourly rates supplied in the following table are for base salaries, i.e. do not include fringe
benefits. A 25.5% fringe benefit rate was applied to obtain the loaded direct labor cost shown in
the Table 3.5.3.1 above. Base labor rates were based on historic rates except for the two manager
positions for which projected salary rates were used. A labor escalation factor was applied to
base labor rates on the first month of each new calendar year starting with January 2013. The
escalation factor is based on the U.S. Bureau of Labor Statistics 2012 Consumer Price Index for
All Urban Consumers (CPI-U) of 2.9%.
BioFactura, Inc.
Page 42 of 218
Table 7: Direct Labor Cost Breakdown

CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
1.1.1.1.2
1.1.1.1.2
1.1.1.1.2
1.1.1.1.3
1.1.1.1.3
1.1.1.1.3
1.1.1.2.2
1.1.1.2.2
1.1.1.2.2
1.1.1.2.3
1.1.1.2.3
1.1.1.2.3
1.1.1.2.9
1.1.1.2.9
1.1.2.1.1.1
1.1.2.1.1.2
1.1.2.1.1.3
1.1.2.1.1.5
1.1.2.1.1.6
1.1.2.1.2.1
1.1.2.1.2.2
1.1.2.1.2.3
1.1.2.1.2.5
1.1.2.1.2.6
1.1.2.1.3.1
1.1.2.1.3.2
1.1.2.1.3.3
1.1.2.1.3.5
1.1.2.1.3.6
1.1.2.2
1.1.2.3
1.1.2.4.1
1.1.2.4.2
1.1.2.4.4
1.1.2.4.4
1.1.2.4.4
1.1.2.4.5
1.1.2.4.5
1.1.2.4.5
1.1.2.4.6
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
4
4
5
5
5
5
5
5
5
5
5
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Te
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
20
12
4
20
12
4
20
12
4
20
12
4
2
1
1
1
1
2
1
1
1
1
2
1
1
1
1
16
3
3
3
10
16
3
10
16
2
2
BioFactura, Inc.
FY12
Rate
$48
$29
$82
$48
$29
$82
$48
$29
$82
$48
$29
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$48
$82
$82
$48
$82
$82
FY12
Total
$962
$346
$327
$962
$346
$327
$962
$346
$327
$962
$346
$327
$182
$47
$92
$47
$92
$182
$47
$92
$47
$92
$182
$47
$92
$47
$92
$1,308
$262
$262
$262
$785
$769
$262
$785
$769
$131
$196
FY13
Hrs
FY13
Rate
24
8
-
$30.0
$84.9
-
FY14
Total
$692
$654
-
FY14
Hrs
-
FY14
Rate
FY14
Total
Page 43 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
1.1.2.4.6
1.1.2.4.6
1.1.2.4.7
1.1.2.4.7
1.1.2.4.7
1.1.3.1.1.1
1.1.3.1.1.2
1.1.3.1.2.1
1.1.3.1.2.2
1.1.3.1.3.1
1.1.3.1.3.2
1.1.3.2.1
1.1.3.2.2
1.1.3.2.3.1
1.1.3.2.3.2
1.1.3.2.3.4
1.1.3.2.3.4
1.1.3.2.3.4
1.1.3.2.3.5
1.1.3.2.3.5
1.1.3.2.3.5
1.1.3.2.3.6
1.1.3.2.3.6
1.1.3.2.3.6
1.1.3.2.3.7
1.1.3.2.3.7
1.1.3.3.1
1.1.3.3.2
1.1.3.3.3.1
1.1.3.3.3.2
1.1.3.3.3.4
1.1.3.3.3.4
1.1.3.3.3.4
1.1.3.3.3.5
1.1.3.3.3.5
1.1.3.3.3.5
1.1.3.3.3.6
1.1.3.3.3.6
1.1.3.3.3.6
1.1.3.3.3.7
1.1.3.3.3.7
1.1.3.3.3.7
5
5
5
5
5
6
6
6
6
6
6
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
4
1
2
4
1
1
1
1
1
1
1
16
3
3
3
10
16
3
10
16
2
2
4
1
2
1
16
3
3
3
10
16
3
10
16
2
2
4
1
2
4
1
BioFactura, Inc.
FY12
Rate
$48
$82
$82
$48
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$82
$48
$82
$82
$48
$82
$82
$48
$82
$82
$82
$82
$82
$82
$82
$82
$48
$82
$82
$48
$82
$82
$48
$82
$82
$48
$82
FY12
Total
$192
$65
$196
$192
$65
$47
$92
$47
$92
$47
$92
$1,308
$262
$262
$262
$785
$769
$262
$785
$769
$131
$196
$192
$65
$196
$65
$1,308
$262
$262
$262
$785
$769
$262
$785
$769
$131
$196
$192
$65
$196
$192
$65
FY13
Hrs
-
FY13
Rate
-
FY14
Total
FY14
Hrs
-
FY14
Rate
FY14
Total
Page 44 of 218
CWBS
No.
Job
Categ.
FY12
Hrs
1.1.4.1
4
1.1.4.2
4
1.1.4.3
4
1.1.4.4
4
1.1.4.5
4
1.1.5.1
4
1.1.5.1
4
1.1.5.1
4
Phase I Sub-Totals
PM
PM
PM
PM
PM
CC Sc
Pu/Op
PM
2
2
6
10
2
40
40
8
560
$82
$82
$82
$82
$82
$48
$82
$82
$1,923
$3,270
$654
1.2.1.1.1.1
1.2.1.1.1.1
1.2.1.1.1.1
1.2.1.1.1.3
1.2.1.1.1.3
1.2.1.1.1.3
1.2.1.1.1.4
1.2.1.1.1.4
1.2.1.1.1.4
1.2.1.1.2
1.2.1.1.2
1.2.1.1.2
1.2.1.1.3
1.2.1.1.3
1.2.1.1.3
1.2.1.1.4
1.2.1.1.4
1.2.1.1.4
1.2.1.1.6
1.2.1.1.6
1.2.1.1.6
1.2.1.1.8.1
1.2.1.1.8.1
1.2.1.1.8.1
1.2.1.2.1.1
1.2.1.2.1.1
1.2.1.2.1.1
1.2.1.2.1.3
1.2.1.2.1.3
1.2.1.2.1.3
1.2.1.2.1.4
1.2.1.2.1.4
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
20
12
3
20
12
3
-
$48
$29
$82
$48
$29
$82
-
$35,31
6
$962
$346
$262
$962
$346
$262
-
Hrs
BioFactura, Inc.
6
6
6
6
6
6
6
6
6
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
FY12
Rate
FY12
Total
$163
$163
$490
$817
$196
FY13
Hrs
FY13
Rate
32
40
24
8
20
12
4
8
5
2
44
26
9
12
7
2
96
58
19
20
12
4
40
24
8
20
12
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
FY14
Total
FY14
Hrs
FY14
Rate
FY14
Total
$1,923
$692
$654
$962
$346
$327
$385
$138
$131
$2,116
$762
$719
$577
$208
$196
$4,616
$1,662
$1,569
$962
$346
$327
$1,923
$692
$654
$962
$346
$1,346
Page 45 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
1.2.1.2.1.4
1.2.1.2.2
1.2.1.2.2
1.2.1.2.2
1.2.1.2.3
1.2.1.2.3
1.2.1.2.4
1.2.1.2.4
1.2.1.2.4
1.2.1.2.6
1.2.1.2.6
1.2.1.2.6
1.2.1.2.8.1
1.2.1.2.8.1
1.2.1.2.8.1
1.2.2.1.1.1
1.2.2.1.1.1
1.2.2.1.1.1
1.2.2.1.1.3
1.2.2.1.1.3
1.2.2.1.1.3
1.2.2.1.1.4
1.2.2.1.1.4
1.2.2.1.1.4
1.2.2.1.2
1.2.2.1.2
1.2.2.1.2
1.2.2.1.3
1.2.2.1.3
1.2.2.1.3
1.2.2.1.4
1.2.2.1.4
1.2.2.1.4
1.2.2.1.6
1.2.2.1.6
1.2.2.1.6
1.2.2.1.8.1
1.2.2.1.8.1
1.2.2.1.8.1
1.2.2.2.1.1
1.2.2.2.1.1
1.2.2.2.1.1
6
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
PM
CC Sc
CC Te
PM
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
BioFactura, Inc.
FY12
Rate
FY12
Total
-
FY13
Hrs
FY13
Rate
4
8
5
2
26
9
12
7
2
96
58
19
20
12
4
20
12
4
40
24
8
20
12
4
8
5
2
44
26
9
12
7
2
96
58
19
16
10
3
20
12
4
$84.9
$50.0
$30.0
$84.9
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
FY14
Total
$327
$385
$138
$131
$762
$719
$577
$208
$196
$4,616
$1,662
$1,569
$962
$346
$327
$999
$360
$340
$1,998
$719
$679
$999
$360
$340
$400
$144
$136
$2,198
$791
$747
$599
$216
$204
$4,796
$1,727
$1,631
$799
$288
$272
$999
$360
$340
FY14
Hrs
-
FY14
Rate
FY14
Total
Page 46 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
1.2.2.2.1.3
1.2.2.2.1.3
1.2.2.2.1.3
1.2.2.2.1.4
1.2.2.2.1.4
1.2.2.2.1.4
1.2.2.2.2
1.2.2.2.2
1.2.2.2.2
1.2.2.2.3
1.2.2.2.3
1.2.2.2.3
1.2.2.2.4
1.2.2.2.4
1.2.2.2.4
1.2.2.2.6
1.2.2.2.6
1.2.2.2.6
1.2.2.2.8.1
1.2.2.2.8.1
1.2.2.2.8.1
1.2.3.1.1
1.2.3.1.2
1.2.3.2.1
1.2.3.2.2.1
1.2.3.2.2.2
1.2.3.2.3.1
1.2.3.2.3.2
1.2.3.2.3.4
1.2.3.2.3.4
1.2.3.2.3.4
1.2.3.2.3.5
1.2.3.2.3.5
1.2.3.2.3.5
1.2.3.2.3.6
1.2.3.2.3.6
1.2.3.2.3.6
1.2.3.2.3.7
1.2.3.2.3.7
1.2.3.2.3.7
1.2.3.3.1
1.2.3.3.2.1
6
6
6
6
6
6
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
5
6
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
PM
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
BioFactura, Inc.
FY12
Rate
FY12
Total
-
FY13
Hrs
FY13
Rate
40
24
8
20
12
4
8
5
2
44
26
9
12
7
2
96
58
19
16
10
3
1
2
8
1
1
2
2
10
16
3
10
16
2
2
4
1
2
4
1
8
1
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$84.9
FY14
Total
$1,998
$719
$679
$999
$360
$340
$400
$144
$136
$2,198
$791
$747
$599
$216
$204
$4,796
$1,727
$1,631
$799
$288
$272
$68
$136
$679
$68
$68
$136
$136
$815
$799
$272
$815
$799
$136
$204
$200
$68
$204
$200
$68
$679
$68
FY14
Hrs
-
FY14
Rate
FY14
Total
Page 47 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
1.2.3.3.2.2
1.2.3.3.3.1
1.2.3.3.3.2
1.2.3.3.3.4
1.2.3.3.3.4
1.2.3.3.3.4
1.2.3.3.3.5
1.2.3.3.3.5
1.2.3.3.3.5
1.2.3.3.3.6
1.2.3.3.3.6
1.2.3.3.3.6
1.2.3.3.3.7
1.2.3.3.3.7
1.2.3.3.3.7
1.2.3.4.1
1.2.3.4.2.1
1.2.3.4.2.2
1.2.3.4.3.1
1.2.3.4.3.2
1.2.3.4.3.4
1.2.3.4.3.4
1.2.3.4.3.4
1.2.3.4.3.5
1.2.3.4.3.5
1.2.3.4.3.5
1.2.3.4.3.6
1.2.3.4.3.6
1.2.3.4.3.6
1.2.3.4.3.7
1.2.3.4.3.7
1.2.3.4.3.7
1.2.3.5.1
1.2.3.5.2.1
1.2.3.5.2.2
1.2.3.5.4.1
1.2.3.5.4.2
1.2.3.5.4.4
1.2.3.5.4.4
1.2.3.5.4.4
1.2.3.5.4.5
1.2.3.5.4.5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
5
6
6
6
6
6
6
6
6
6
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
BioFactura, Inc.
FY12
Rate
FY12
Total
-
FY13
Hrs
FY13
Rate
1
2
2
10
16
3
10
16
2
2
4
1
2
4
1
8
1
1
2
2
9
16
3
10
16
3
2
4
1
2
4
1
8
1
1
2
2
10
16
3
10
16
$84.9
$84.9
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
FY14
Total
$68
$136
$136
$815
$799
$272
$815
$799
$136
$204
$200
$68
$204
$200
$68
$679
$68
$68
$136
$136
$747
$799
$272
$815
$799
$272
$204
$200
$68
$204
$200
$68
$679
$68
$68
$136
$136
$815
$799
$272
$815
$799
FY14
Hrs
-
FY14
Rate
FY14
Total
Page 48 of 218
CWBS
No.
Hrs
Job
Categ.
1.2.3.5.4.5
6
PM
1.2.3.5.4.6
6
Pu/Op
1.2.3.5.4.6
6
Pu Sc
1.2.3.5.4.6
6
PM
1.2.3.5.4.7
6
Pu/Op
1.2.3.5.4.7
6
Pu Sc
1.2.3.5.4.7
6
PM
1.2.4.1
4
PM
1.2.4.2
4
PM
1.2.4.3
4
PM
1.2.4.4
4
PM
1.2.4.5
4
PM
1.2.5.1
4
CC Sc
1.2.5.1
4
Pu/Op
1.2.5.1
4
PM
Phase II Sub-Total
1.3.1.1.1
1.3.1.1.1
1.3.1.1.1
1.3.1.1.2
1.3.1.1.2
1.3.1.1.2
1.3.1.1.3
1.3.1.1.3
1.3.1.1.3
1.3.1.2.1
1.3.1.2.1
1.3.1.2.1
1.3.1.2.2
1.3.1.2.2
1.3.1.2.2
1.3.2.1.1.1
1.3.2.1.1.2
1.3.2.1.2
1.3.2.1.3
1.3.2.1.4
1.3.2.2.1.1
1.3.2.2.1.2
1.3.2.2.2
1.3.2.2.3
1.3.2.2.4
BioFactura, Inc.
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
5
5
5
6
6
5
5
5
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
PM
FY12
Hrs
FY12
Rate
FY12
Total
70
$3,139
-
FY13
Hrs
FY13
Rate
FY14
Total
FY14
Hrs
FY14
Rate
FY14
Total
3
2
4
1
2
4
1
2
2
6
10
2
40
40
8
2,190
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$50.0
$84.9
$84.9
$272
$204
$200
$68
$204
$200
$68
$170
$170
$510
$849
$204
$1,998
$3,397
$679
$111,654
26
16
6
26
16
6
26
16
6
16
10
3
16
10
3
8
8
3
2
2
8
8
3
2
2
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$50.0
$30.0
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$1,319
$480
$476
$1,319
$480
$476
$1,319
$480
$476
$799
$288
$272
$799
$288
$272
$679
$679
$272
$136
$136
$679
$679
$272
$136
$136
Page 49 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
1.3.2.3.1
1.3.2.3.2
1.3.2.3.3
1.3.3.1.1
1.3.3.1.2
1.3.3.1.3
1.3.3.1.4.1
1.3.3.1.4.2
1.3.3.1.4.4
1.3.3.1.4.4
1.3.3.1.4.4
1.3.3.1.4.5
1.3.3.1.4.5
1.3.3.1.4.5
1.3.3.1.4.6
1.3.3.1.4.6
1.3.3.1.4.6
1.3.3.1.4.7
1.3.3.1.4.7
1.3.3.1.4.7
1.3.3.2.1
1.3.3.2.2
1.3.3.2.3
1.3.3.2.4.1
1.3.3.2.4.2
1.3.3.2.4.4
1.3.3.2.4.4
1.3.3.2.4.4
1.3.3.2.4.5
1.3.3.2.4.5
1.3.3.2.4.5
1.3.3.2.4.6
1.3.3.2.4.6
1.3.3.2.4.6
1.3.3.2.4.7
1.3.3.2.4.7
1.3.3.2.4.7
1.3.4.1
1.3.4.2
1.3.4.3
1.3.4.4
1.3.4.5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
4
4
4
4
4
PM
PM
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
BioFactura, Inc.
FY12
Rate
FY12
Total
-
FY13
Hrs
FY13
Rate
1
3
3
8
3
2
3
3
10
16
3
10
16
2
2
4
1
2
4
1
8
3
2
3
3
10
16
3
-
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$50.0
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$50.0
$84.9
-
FY14
Total
$95
$238
$238
$679
$272
$136
$272
$272
$815
$799
$272
$815
$799
$136
$204
$200
$68
$204
$200
$68
$679
$272
$136
$272
$272
$815
$799
$272
-
FY14
Hrs
10
16
3
2
4
1
2
4
1
2
2
6
10
2
FY14
Rate
$88
$52
$88
$88
$52
$88
$88
$52
$88
$88
$88
$88
$88
$88
FY14
Total
$815
$799
$272
$204
$200
$68
$204
$200
$68
$170
$170
$510
$849
$204
Page 50 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
FY12
Rate
FY12
Total
1.3.5.1
4
CC Te
1.3.5.1
4
PM
1.3.6.1
4
CC Sc
1.3.6.1
4
Pu/Op
1.3.6.1
4
PM
Phase III Sub-Total
1.4.1.1.1
1.4.1.1.1
1.4.1.1.1
1.4.1.1.2
1.4.1.1.2
1.4.1.1.2
1.4.1.1.3
1.4.1.1.3
1.4.1.1.3
1.4.1.1.4
1.4.1.1.4
1.4.1.1.4
1.4.1.2.1
1.4.1.2.1
1.4.1.2.1
1.4.1.2.2
1.4.1.2.2
1.4.1.2.2
1.4.1.2.3
1.4.1.2.3
1.4.1.2.3
1.4.1.3.1
1.4.1.3.1
1.4.1.3.1
1.4.1.3.2
1.4.1.3.2
1.4.1.3.2
1.4.1.3.3
1.4.1.3.3
1.4.1.3.3
1.4.1.3.4
1.4.1.3.4
1.4.1.3.4
1.4.2.1.1
1.4.2.1.1
BioFactura, Inc.
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
Pu/Op
Pu Sc
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
Pu/Op
Pu Sc
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
Pu/Op
Pu Sc
PM
CC Sc
CC Te
PM
CC Sc
CC Te
FY13
Hrs
FY13
Rate
391
FY14
Total
FY14
Hrs
FY14
Rate
FY14
Total
24
8
40
22
8
168
$31
$88
$52
$88
$88
$719
$679
$1,998
$1,902
$679
$10,711
80
48
16
56
34
11
8
5
2
14
24
2
56
34
11
16
10
2
14
24
2
56
34
11
5
3
1
14
24
2
8
5
2
56
34
$52
$31
$88
$52
$31
$88
$52
$31
$88
$88
$52
$88
$52
$31
$88
$52
$31
$88
$88
$52
$88
$52
$31
$88
$52
$31
$88
$88
$52
$88
$52
$31
$88
$52
$31
$3,996
$1,439
$1,359
$2,797
$1,007
$951
$400
$144
$136
$1,223
$1,199
$204
$2,797
$1,007
$951
$830
$299
$141
$1,271
$1,246
$212
$2,907
$1,046
$988
$274
$100
$99
$1,271
$1,246
$148
$411
$149
$148
$2,907
$1,046
$23,643
Page 51 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
4
4
4
5
5
4
4
4
PM
CC Sc
CC Te
PM
Pu/Op
Pu Sc
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
Pu/Op
Pu Sc
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
CC Sc
CC Te
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
CC Sc
CC Te
PM
1.4.2.1.1
1.4.2.1.2
1.4.2.1.2
1.4.2.1.2
1.4.2.1.3
1.4.2.1.3
1.4.2.1.3
1.4.2.2.1
1.4.2.2.1
1.4.2.2.1
1.4.2.2.2
1.4.2.2.2
1.4.2.2.2
1.4.2.2.3
1.4.2.2.3
1.4.2.2.3
1.4.2.3.1
1.4.2.3.1
1.4.2.3.1
1.4.2.3.2
1.4.2.3.2
1.4.2.3.2
1.4.2.3.3
1.4.2.3.3
1.4.2.3.3
1.4.2.3.4
1.4.2.3.4
1.4.2.3.4
1.4.2.3.5
1.4.2.3.5
1.4.2.3.5
1.4.2.3.6
1.4.2.3.6
1.4.2.3.6
1.4.3.1
1.4.3.2
1.4.3.3
1.4.3.4.1
1.4.3.4.2
1.4.3.5
1.4.3.5
1.4.3.5
BioFactura, Inc.
FY12
Rate
FY12
Total
-
FY13
Hrs
-
FY13
Rate
-
FY14
Total
FY14
Hrs
-
11
16
10
2
14
24
2
56
34
11
16
10
2
14
24
2
20
12
4
20
12
4
20
12
4
20
12
4
16
10
2
24
40
4
24
2
2
3
3
16
10
3
FY14
Rate
$88
$52
$31
$88
$88
$52
$88
$52
$31
$88
$52
$31
$88
$88
$52
$88
$52
$31
$88
$52
$31
$88
$52
$31
$88
$52
$31
$88
$52
$31
$88
$88
$52
$88
$88
$88
$88
$88
$88
$52
$31
$88
FY14
Total
$988
$830
$299
$141
$1,271
$1,246
$212
$2,907
$1,046
$988
$830
$299
$141
$1,271
$1,246
$212
$1,038
$374
$353
$1,038
$374
$353
$1,038
$374
$353
$1,038
$374
$353
$830
$299
$141
$2,118
$2,076
$353
$2,118
$141
$141
$282
$282
$830
$299
$282
Page 52 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
1.4.3.6
1.4.3.6
1.4.3.6
1.4.3.7.1
1.4.3.7.2
1.4.4.1.1
1.4.4.1.2
1.4.4.1.3
1.4.4.1.4.1
1.4.4.1.4.2
1.4.4.1.4.4
1.4.4.1.4.4
1.4.4.1.4.4
1.4.4.1.4.5
1.4.4.1.4.5
1.4.4.1.4.5
1.4.4.1.4.6
1.4.4.1.4.6
1.4.4.1.4.6
1.4.4.1.4.7
1.4.4.1.4.7
1.4.4.1.4.7
1.4.4.2.1
1.4.4.2.2
1.4.4.2.3
1.4.4.2.4.1
1.4.4.2.4.2
1.4.4.2.4.4
1.4.4.2.4.4
1.4.4.2.4.4
1.4.4.2.4.5
1.4.4.2.4.5
1.4.4.2.4.5
1.4.4.2.4.6
1.4.4.2.4.6
1.4.4.2.4.6
1.4.4.3.1
1.4.4.3.2
1.4.4.3.3
1.4.4.3.4
1.4.4.3.4.1
1.4.4.3.4.4
4
4
4
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
5
5
5
6
6
6
6
6
6
6
6
6
6
6
5
5
5
5
6
6
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
Pu/Op
BioFactura, Inc.
FY12
Rate
FY12
Total
-
FY13
Hrs
-
FY13
Rate
-
FY14
Total
FY14
Hrs
-
14
24
2
4
4
8
2
2
3
3
10
16
3
10
16
2
2
4
1
2
4
1
8
2
2
3
3
10
16
2
5
8
2
2
4
1
8
2
2
13
3
10
FY14
Rate
$88
$52
$88
$88
$88
$88
$88
$88
$88
$88
$88
$52
$88
$88
$52
$88
$88
$52
$88
$88
$52
$88
$88
$88
$88
$88
$88
$88
$52
$88
$88
$52
$88
$88
$52
$88
$88
$88
$88
$88
$88
$88
FY14
Total
$1,271
$1,246
$212
$353
$353
$691
$141
$141
$282
$282
$847
$830
$282
$847
$830
$141
$212
$208
$71
$212
$208
$71
$741
$141
$141
$282
$282
$847
$830
$141
$424
$415
$141
$212
$208
$71
$741
$141
$141
$1,129
$282
$847
Page 53 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
6
6
6
6
6
6
6
6
4
4
4
4
4
4
4
4
4
4
4
4
4
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Pu Sc
PM
Pu/Op
Pu Sc
PM
Pu/Op
Pu Sc
PM
PM
PM
PM
PM
PM
CC Sc
Pu/Op
PM
CC Sc
CC Te
Pu/Op
Pu Sc
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
8
8
8
8
8
4
8
4
8
4
8
-
1.4.4.3.4.4
1.4.4.3.4.4
1.4.4.3.4.5
1.4.4.3.4.5
1.4.4.3.4.5
1.4.4.3.4.6
1.4.4.3.4.6
1.4.4.3.4.6
1.4.5.1
1.4.5.2
1.4.5.3
1.4.5.4
1.4.5.5
1.4.6.1
1.4.6.1
1.4.6.1
1.5.2.1
1.5.2.1
1.5.2.1
1.5.2.1
1.5.2.1
1.5.2.2.1.1
1.5.2.2.1.1
1.5.2.2.2.1
1.5.2.2.2.1
1.5.2.2.3.1
1.5.2.2.3.1
1.5.2.2.4.1
1.5.2.2.4.1
1.5.2.2.5.1
1.5.2.2.5.1
1.5.2.2.6.1
1.5.2.2.6.1
1.5.2.2.7.1
1.5.2.2.7.1
1.5.2.2.8.1
1.5.2.2.8.1
1.5.2.2.9.1
1.5.2.2.9.1
1.5.2.2.10.
1
1.5.2.2.10.
1
1.5.2.2.11.
1
BioFactura, Inc.
FY12
Rate
$48
$29
$82
$48
$82
$82
$82
$82
$82
$82
$82
-
FY12
Total
$385
$231
$654
$385
$654
$327
$654
$327
$654
$327
$654
-
FY13
Hrs
FY13
Rate
4
8
4
8
4
8
4
8
4
8
4
8
4
8
4
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
FY14
Total
$327
$654
$327
$654
$327
$654
$340
$679
$340
$679
$340
$679
$340
$679
$340
FY14
Hrs
16
2
5
8
2
2
4
1
2
2
6
10
2
40
40
8
-
FY14
Rate
$52
$88
$88
$52
$88
$88
$52
$88
$88
$88
$88
$88
$88
$52
$88
$88
-
FY14
Total
$830
$141
$424
$415
$141
$212
$208
$71
$176
$176
$529
$882
$212
$2,076
$3,530
$706
-
Page 54 of 218
CWBS
No.
Hrs
Job
Categ.
FY12
Hrs
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
PM
Pu/Op
PM
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
PM
Pu/Op
20
20
4
4
-
1.5.2.2.11.
1
1.5.2.2.12.
1
1.5.2.2.12.
1
1.5.2.2.13.
1
1.5.2.2.14.
1
1.5.2.2.14.
1
1.5.2.2.15.
1
1.5.2.2.15.
1
1.5.2.2.16.
1
1.5.2.2.16.
1
1.5.2.2.17.
1
1.5.2.2.17.
1
1.5.2.2.18.
1
1.5.2.2.18.
1
1.5.2.2.19.
1
1.5.2.2.19.
1
1.5.2.2.20.
1
1.5.2.2.20.
1
1.5.2.2.21.
1
1.5.2.2.21.
1
1.5.2.2.22.
1
1.5.2.2.22.
1
1.5.2.2.23.
1
1.5.2.2.23.
1
1.5.2.2.24.
1
1.5.2.3.1.1
1.5.2.3.1.1
1.5.2.3.1.3
1.5.2.3.1.3
1.5.2.3.2.1
1.5.2.3.2.1
1.5.2.3.2.3
1.5.2.3.2.3
1.5.2.3.3.1
1.5.2.3.3.1
1.5.2.3.3.3
1.5.2.3.3.3
1.5.2.3.4.1
1.5.2.3.4.1
1.5.2.3.4.3
1.5.2.3.4.3
1.5.2.3.5.1
BioFactura, Inc.
FY12
Rate
$82
$82
$82
$82
-
FY12
Total
$1,635
$1,635
$327
$327
-
FY13
Hrs
FY13
Rate
8
4
8
8
4
8
4
8
20
20
4
4
16
16
4
4
16
16
4
4
20
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
$84.9
FY14
Total
$679
$340
$679
$679
$340
$679
$340
$679
$1,635
$1,635
$327
$327
$1,359
$1,359
$340
$340
$1,359
$1,359
$340
$340
$1,699
FY14
Hrs
4
8
4
8
4
8
4
8
4
8
4
8
4
8
4
8
8
-
FY14
Rate
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
$88
-
FY14
Total
$340
$679
$340
$679
$340
$679
$353
$706
$353
$706
$353
$706
$353
$706
$353
$706
$706
-
Page 55 of 218
CWBS
No.
Hrs
Job
Categ.
1.5.2.3.5.1
6
PM
1.5.2.3.5.3
6
Pu/Op
1.5.2.3.5.3
6
PM
1.5.2.3.6.1
6
Pu/Op
1.5.2.3.6.1
6
PM
1.5.2.3.6.3
6
Pu/Op
1.5.2.3.6.3
6
PM
1.5.2.3.7.1
6
PM
1.5.2.3.8.1
6
Pu/Op
1.5.2.3.8.1
6
PM
1.5.2.3.8.3
6
Pu/Op
1.5.2.3.8.3
6
PM
Phase IV Sub-Totals
Project Total by FY
Total Hours
Total Base Labor Cost
FY12
Hrs
124
755
5,726
$336,158
FY12
Rate
FY12
Total
-
$9,174
$47,62
9
FY13
Hrs
FY13
Rate
FY14
Total
FY14
Hrs
FY14
Rate
20
4
4
316
2,928
$84.9
$84.9
$84.9
-
$1,699
$340
$340
$26,569
$163,212
16
16
4
4
20
20
20
4
4
1,875
2,043
$88
$88
$88
$88
$88
$88
$88
$88
$88
FY14
Total
$1,359
$1,359
$340
$340
$1,765
$1,765
$1,765
$353
$353
$114,60
5$125,31
6
Table Abbreviations:
CC Sc Cell Culture Scientist
CC Te Cell Culture Tech
Pu Sc Purification Scientist
PM Technical Project Manager
Pu/Op Purification Manager & Operational Project Manager
5.3.2 Subcontractor Costs

Table 8 below provides a breakdown of subcontractor costs by fiscal year and CWBS
number down to level 6. As before, the table also has been divided into the four technical project
phases (I - IV). For any subcontractor estimates exceeding $50,000, copies of the proposals and
agreements have been included the Appendices section.
No price reasonableness was performed for USAMRIID as we believe this is the only U.S.
federal lab with both the necessary biosafety level 3 resources and capabilities and the VRP
expertise to support this project. A cost breakdown by phase (level 2) for USAMRIID is
provided in Table 9. Although USAMRIID has issued a CRADA it has not yet been finalized so
the projected costs are subject to revision. However, every effort will be made to ensure that any
changes are reasonable and do not result in a substantial cost revision.
The Company also obtained quotations from both Bioreliance and Charles River for the cell
banking and testing, but removed the latter from further consideration after the service group did
not exhibit sufficient knowledge of the testing requirements for the Vero and EB66 cell lines. It
should be noted that ultimately either sVero or EB66 could be used for the generation of the
Helper Cell Line Master Cell Bank (depends on the cell line selection process outcome).
However, for budgetary purposes the larger EB66 cell banking and testing cost estimate was
used.
BioFactura, Inc.
Page 56 of 218
Table 8: Subcontractor Costs Breakdown

CWBS
Number
Work Description
Contracto
r
FY12
USAMRII
D
Biorelianc
e
$60,711
$60,711
$10,563
$10,563
$142,72
6
$142,72
6
$687
$687
$214,68
8
$214,68
8
$55,378
$55,378
Geneart
$575
$575
Macrogen
$32
$32
Geneart
$925
$925
Macrogen
$32
$32
Geneart
$575
$575
Macrogen
$32
$32
Geneart
$925
$925
Macrogen
$32
$32
$3,538
$3,538
$12,690
$12,690
$3,039
$3,039
$3,039
$3,039
$1,628
$1,628
$1,628
$1,628
$56,942
$27,126
$84,068
1.1
Phase I USAMRIID cost summary
1.1.1.2.5
sVero pre-MCB testing & pilot study
1.1.1.2.7
sVero cGMP MCB generation & testing
Biorelianc
e
1.1.6.1
sVero MCB off-site storage
Biorelianc
e
1.1
Phase I Sub-Total
1.2
Phase II USAMRIID cost summary
1.2.1.1.1.
2
1.2.1.1.1.
3
1.2.1.2.1.
2
1.2.1.2.1.
3
1.2.2.1.1.
2
1.2.2.1.1.
3
1.2.2.2.1.
2
1.2.2.2.1.
3
1.2.6.1
1.2.6.2
1.2.6.2.1
1.2.6.2.2
1.2.6.2.3
1.2.6.2.4
1.2
Gene Synthesis
Sequence confirmation post-vectro
contruction
Gene Synthesis
contruction
Gene Synthesis
contruction
Gene Synthesis
contruction
Stable HCL pools (4) release testing prestorage
EB66-Lac helper cell line pools off-site
storage
EB66-Tet helper cell line pools off-site
storage
sVero-Lac helper cell line pools off-site
storage
sVero-Tet helper cell line pools off-site
storage
Phase II Sub-Total
BioFactura, Inc.
USAMRII
D
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
FY13
FY14
Total
Page 57 of 218
CWBS
Number
Work Description
Contracto
r
1.3
Phase III USAMRIID cost summary
1.3.5.3
EB66 HCL pre-MCB testing*
1.3.5.5
EB66 HCL cGMP MCB generation &

testing*
1.3.7.1
1.3.7.2.1
1.3.7.2.2
1.3.7.2.3
1.3.7.2.4

storage
storage
storage
storage
1.3.7.3
Helper cell line MCB off-site storage
1.3
Phase III Sub-Total
1.4
Phase IV USAMRIID cost summary
1.4.7.1
1.4.7.2.1
1.4.7.2.2
1.4.7.2.3
1.4.7.2.4

storage
storage
storage
storage
1.4.7.3
Helper cell line MCB off-site storage
1.4
Phase IV Sub-Total
FY12
USAMRII
D
Biorelianc
e
FY14
Total
$55,378
$55,378
$10,563
$10,563
$175,08
0
$175,08
0
$2,768
$2,768
$740
$2,589
$3,329
$740
$2,589
$3,329
$740
$2,589
$3,329
$740
$2,589
$3,329
$257
$900
$1,158
$247,00
5
$11,25
6
$258,26
1
$55,37
8
$55,378
$724
$724
$724
$724
$724
$724
$724
$724
$724
$724
$724
$724
$271,62
9
$274,13
1
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
USAMRII
D
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
Biorelianc
e
TOTAL
FY13
$59,71
9
$70,97
5
$59,719
$616,73
6
Table 9: USAMRIID Subcontractor Cost Breakdown Estimate

Cost Category
Labor
Contract Personnel
Supplies
Direct Cost
BioFactura, Inc.
Phase I
$14,368.15
$6,583.78
$6,360.03
$27,311.96
Phase II
$13,105.95
$6,005.41
$5,801.32
$24,912.68
Phase III
$13,105.95
$6,005.41
$5,801.32
$24,912.68
Phase IV
$13,105.95
$6,005.41
$5,801.32
$24,912.68
Total
$53,686.00
$24,600.00
$23,764.00
$102,050.00
Page 58 of 218
Vet Med
Aerosol Services
Cell Culture
Hybridoma
SIP
Facility Infrastructure
Other Direct Cost
Indirect
Total
BioFactura, Inc.
$4,356.85
$4,847.51
$4,748.35
$2,149.18
$2,629.04
$9,149.16
$27,880.09
$5,519.13
$60,711.19
$3,974.11
$4,421.66
$4,331.22
$1,960.38
$2,398.09
$8,345.43
$25,430.89
$5,034.29
$55,377.86
$3,974.12
$4,421.67
$4,331.22
$1,960.38
$2,398.09
$8,345.43
$25,430.90
$5,034.29
$55,377.87
$3,974.12
$4,421.67
$4,331.22
$1,960.38
$2,398.09
$8,345.43
$25,430.90
$5,034.29
$55,377.87
$16,279.20
$18,112.50
$17,742.01
$8,030.31
$9,823.30
$34,185.45
$104,172.77
$20,622.00
$226,844.77
Page 59 of 218
5.3.3
Consultants n/a
5.3.4 Materials and Supplies

Table 10 provides a breakdown of supplies and material costs by fiscal year and CWBS
number down to level 4. In addition, the table has been divided into the four technical project
phases (I - IV) to provide estimated supplies and material costs for each phase.
The list was assembled by reviewing the available scientific literature on the current VRP
process and determining material and supplies requirements for each step of the current VRP
production process. The requirements for the remaining novel elements proposed by the
Company were generated based on the R&D personnels extensive experience. The Company
has accounts with multiple vendors, which offer web based pricing. This was used to generate
unit and price information for the materials and supplies. A 10% surcharge was added to all item
costs to account for handling, shipping, and fuel surcharge fees.
BioFactura, Inc.
Page 60 of 218
Table 10: Materials and Supplies Breakdown

CWBS
No.
1.1.1.1
Description
Basis of
Estimate
Source
Unit
Unit
Cost
Quat
.
DPBS-Gibco: 14190-136
Trypan Blue Stain, 0.4%Gibco: 15250-061
ExCell
EBx GRO-I mediumSAFC:
Dimethyl14530C
Sulphoxide
(DMSO)-Sigma:
D2650356520
1 mL Ser Pipettes-BD:
Inv.
Inv.
SAFC
Sigma
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
1L
100 mL
1L
5x10
mL
Cs/1000
Latex Gloves, Small-KC:

HC220Gloves, Medium-KC:
Latex
HC330
Kimwipes-KC: 34120
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Cs/1000
Cs/200
Cs/200
Cs/200
Cs/100
Cs/5 pk
Cs/5 pk
Cs/5 pk
Cs/5 pk
Cs/5 pk
Cs/100
Cs/500
Cs/500
Cs/500
Cs/12
Each
Cs/10
pk
Cs/10
pk
Cs/8400
$32.50
$16.20
$84.00
$96.00
$314.00
$156.00
$38.00
$39.00
$115.00
$105.00
$500.00
$313.00
$313.00
$313.00
$680.00
$162.00
$200.00
$110.00
$106.00
$160.00
$40.00
$331.00
$331.00
$150.00
1
1
3
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
2
1
1
1
$32.50
$16.20
$252.00
$96.00
$314.00
$156.00
$38.00
$39.00
$115.00
$105.00
$500.00
$313.00
$313.00
$313.00
$680.00
$162.00
$400.00
$110.00
$106.00
$160.00
$80.00
$331.00
$331.00
$150.00
SMIF-6 Medium-Gibco
Web
est
Inv.
Inv.
1L
1L
$32.50
$60.00
1
3
pH 4 Buffer: SB101-500
Web
Fisher
500 ml
$18.00
$32.50
$180.00
$9,789.18
$18.00
2 mL Ser Pipettes-BD: 356507

5 mL Ser Pipettes-BD: 356543
356551
356525
356550
1000E Pipette Tips-ART:
2079E
200 Pipette Tips-ART: 2069
100E Pipette Tips-ART:
2065E
20E Pipette Tips-ART: 2149P
10E Pipette Tips-ART: 2139F05
T-75 Flasks-Corning: 430641
1.5 mL Cryovials-Nalgene:
5000-1020
50 mL Tubes-Corning: 430828
15 mL Tubes-Corning: 430790
1000 mL Filter CupsMillipore:
LaboratorySCGPU11RE
Notebook: S40527
FY12
Cost
$5,112.70
1.1.1.2
1.1.2.4
BioFactura, Inc.
Page 61 of 218
FY13
Cost -
FY14
Cost -
Total
$32.50
$16.20
$252.00
$96.00
$314.00
$156.00
$38.00
$39.00
$115.00
$105.00
$500.00
$313.00
$313.00
$313.00
$680.00
$162.00
$400.00
$110.00
$106.00
$160.00
$80.00
$331.00
$331.00
$150.00
$32.50
$180.00
$18.00
pH 10 Buffer : SB115-500
Ethanol: 61509-0020
NaCl : AC327300025
PBS (10X): BP449
MgCl2 :AC22321-1000
Benzonase 500 U/ml:
1.01695.0002
Sodium
phosphate monobasic:
4011-01
Sodium phosphate dibasic:
4062-1
NaOH: SS255-4
Sodium azide: AC19038-1000
Normal mouse serum:PI31881
Cellufine
SO4 affinity resin 5
ml
column:
19845-15
Sartorius hydrosart
100k
membrane
:14668-47D
Sartopore capsule
filter:5445307H9-00-A
0.2 um Steriflip: SCGP00525
Millex GV syringe
filter:SLGVM33R
Stericup 0.2um: SCGVU05RE
serological pipets 10ml bulk:
357534
serological pipets 25 ml bulk:
357535
357550
Sterile media bottles: 20190250
Parafilm: PM-992
Parafilm: PM-996
Cryovial 1ml: 430487
Microcentrifuge tubes: 02681-320
Autoclave tape: 15-901-104
Regular tape: 15-078-206
15 ml polypropylene tube:
352096
352070
Gloves: EV2050-M
BioFactura, Inc.
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Invoice
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
amsbio
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
500 ml
500 ml
2L
1kg
4L
100g
100k
units
500g
500g
4L
100g
5 ml
1 x 5ml
10/pk
4/pk
25/PK
50/pk
12/pk
500/Cs
200/Cs
100/Cs
48/Cs
24/Cs
12/Cs
500/Cs
500/Cs
250/pk
6/pk
4/pk
500/Cs
500/Cs
10/Cs
$20.00
$18.00
$115.00
$135.09
$111.81
$25.00
$600.00
$143.00
$131.00
$60.00
$50.00
$73.00
$400.00
$100.00
$797.94
$100.00
$133.11
$115.00
$60.00
$90.00
$130.00
$150.00
$570.00
$265.00
$177.00
$370.00
$21.00
$27.00
$10.00
$100.00
$110.00
$147.00
1
1
1
1
1
1
4
1
1
1
1
6
4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
$20.00
$18.00
$115.00
$135.09
$111.81
$25.00
$2,400.00
$143.00
$131.00
$60.00
$50.00
$438.00
$1,600.00
$100.00
$797.94
$100.00
$133.11
$115.00
$60.00
$90.00
$130.00
$150.00
$570.00
$265.00
$177.00
$370.00
$21.00
$27.00
$10.00
$100.00
$110.00
$147.00
Page 62 of 218
$20.00
$18.00
$115.00
$135.09
$111.81
$25.00
$2,400.00
$143.00
$131.00
$60.00
$50.00
$438.00
$1,600.00
$100.00
$797.94
$100.00
$133.11
$115.00
$60.00
$90.00
$130.00
$150.00
$570.00
$265.00
$177.00
$370.00
$21.00
$27.00
$10.00
$100.00
$110.00
$147.00
20 ul pipet tips: 02-707-432

200 ul pipet tips: 02-707-430
1000 ul pipet tips:02-707-404
Kimwipes: 71600
SimplyBlue Safestain: LC6060
4-12% BisTris gel
MES
Antioxidant
Load buffer
Red Agent
Novex unstained protein
standard
BCA protein assay kit: 23227
Disposable UV cuvettes:
759150
Phase I Sub-Total
Web
Web
Web
Web
Web
Fisher
Fisher
Fisher
Fisher
Inv.
Web
Inv.
Web
Inv.
Web
Web
Web
Inv.
Fisher
Fisher
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Agilent
Inv.
Inv.
Inv.
Inv.
Fisher
Inv.
Fisher
Fisher
Fisher
Fisher
Fisher
Inv.
Qiagen
Inv.
New
England
Fisher
Biolabs
960/pk
960/pk
960/pk
12
pk/Cs
1L
10/box
Each
Each
Each
Each
500 ul
500 ml
100/pk
$80.00
$85.00
$90.00
$57.00
$142.00
$131.66
$63.82
$23.00
$12.02
$49.14
$117.59
$120.00
$80.00
1
1
1
1
1
1
1
1
1
1
1
1
1
$80.00
$85.00
$90.00
$57.00
$142.00
$131.66
$63.82
$23.00
$12.02
$49.14
$117.59
$120.00
$80.00
$80.00
$85.00
$90.00
$57.00
$142.00
$131.66
$63.82
$23.00
$12.02
$49.14
$117.59
$120.00
$80.00
$15,114.38
$670.00
$110.00
$79.00
$95.00
$63.00
$41.00
$765.00
$160.00
$81.00
$83.00
$21.00
$107.00
$150.00
$402.00
$150.00
$68.00
$41.00
1
1
1
1
2
1
1
1
7
1
4
1
1
1
1
12
1
$15,304.8
$689.43
6
$113.19
$81.29
$97.76
$129.65
$42.19
$787.19
$164.64
$583.44
$85.41
$86.44
$110.10
$154.35
$413.66
$154.35
$839.66
$42.19
$689.43
$113.19
$81.29
$97.76
$129.65
$42.19
$787.19
$164.64
$583.44
$85.41
$86.44
$110.10
$154.35
$413.66
$154.35
$839.66
$42.19
1.2.1.1
LacSwitch II Mammalian
Expression
System-Agilent:
LB Agar, Lennox
L217450
Invitrogen:
22700-025
LB
Broth Base-Invitrogen:
12795-027
S.O.C. Medium-Invitrogen:
15544-034
DEPC Treated WaterInvitrogen:
750024PM-992
Parafilm 2"x250':
OneShot TOP10 E. coliInvitrogen:
C4040-06
Culture
Tubes,
17x100 mmFisher:
14-956-6B
100 mm Plates-Fisher: 08-75712
10 uL Steriloops-Fisher: 22363-607
1.5 mL Microcentrifuge
Tubes-Fisher:
02-681-320
10x TAE Buffer-Fisher:
BP1335-4
Agarose-Invitrogen:
16500100
QIAPrep Spin MiniprepQiagen:
27106
Agarose-Invitrogen:
16500100
Various Restriction
Endonucleases-NEB:
XXX
Ethiduim Bromide: BP102-1
BioFactura, Inc.
Each
Each
Each
10x10
mL
4x100
mL
Each
40 rxns
pk/1000
pk/25
pk/960
pk/250
Each
100 g
250
preps
100 g
Each
1g
Page 63 of 218
10x Blue Juice-Invitrogen:

10816-015
TriDye 1kb DNA LadderNEB:
100
bpN3272S
DNA Ladder-NEB:
N3231S
T4 DNA Ligase-NEB:
M0202L
Antarctic Phosphatase-NEB:
M0289S
FreeStyle MAX CHO
Expression
System-Invitrogen:
DPBS-Gibco:
14190-136
K9000-20
ExCell EBx GRO-I mediumSAFC:
14530C
Gene Pulser
Cuvette, 0.4 cmBioRad:
165-2088
Reagent Reservoirs-Corning:
4870
96-Well Plates-Nunc: 161093
125 mL Shaker FlasksCorning:
431143
1 L Shaker
Flasks-Corning:
431147
PURIFICATION - Refills
Benzonase 500 U/ml:
1.01695.0002
Cellufine SO4 affinity resin 5
ml
column:capsule
19845-15
Sartopore
filter:5445307H9-00-A
Gloves: EV2050-M
4-12% BisTris gel
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Inv.
New
England
New
Biolabs
England
New
Biolabs
England
New
Biolabs
England
Inv.
Biolabs
Inv.
SAFC
BioRad
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
3x1 mL
Each
Each
Each
Each
Each
1L
1L
pk/50
Cs/200
Cs/160
Cs/75
Cs/75
Cs/100
Cs/50
Cs/50
Cs/25
Web
Web
Web
Web
Web
Web
Fisher
Fisher
amsbio
Fisher
Fisher
Fisher
100k
units
5 ml
Web
Web
Web
Web
Web
Web
Inv.
Inv.
Inv.
Fisher
Fisher
Fisher
$41.00
$70.00
$60.95
$290.00
$68.00
$1,000.98
$32.50
$84.00
$190.00
$90.00
$325.00
$135.00
$115.00
$162.00
$170.00
$394.00
$481.00
1
1
1
1
1
1
2
6
1
2
1
1
1
1
1
1
1
$42.19
$72.03
$62.72
$298.41
$69.97
$1,030.01
$66.89
$518.62
$195.51
$185.22
$334.43
$138.92
$118.34
$166.70
$174.93
$405.43
$494.95
$42.19
$72.03
$62.72
$298.41
$69.97
$1,030.01
$66.89
$518.62
$195.51
$185.22
$334.43
$138.92
$118.34
$166.70
$174.93
$405.43
$494.95
1 x 5ml
4/pk
12/pk
10/Cs
10/box
$600.00
$73.00
$400.00
$797.94
$115.00
$147.00
$131.66
4
8
5
1
1
1
1
$441.20
$76.22
$18.50
$162.00
$170.00
$394.00
1
2
1
1
1
1
$2,469.60
$600.94
$2,058.00
$821.08
$118.34
$151.26
$135.48
$3,209.70
$453.99
$156.86
$19.04
$166.70
$174.93
$405.43
$2,469.60
$600.94
$2,058.00
$821.08
$118.34
$151.26
$135.48
1 mL
1L
100 mL
Cs/100
Cs/50
Cs/50
1.2.1.2
FreeStyle MAX ReagentInvitrogen:CHO
K9000-20
FreeStyle
Expression
Medium-Invitrogen:
12651OptiPRO SFM-Invitrogen:
014
12309-050
125 mL Shaker FlasksCorning: 431143
BioFactura, Inc.
Page 64 of 218
$453.99
$156.86
$19.04
$166.70
$174.93
$405.43
1 L Shaker Flasks-Corning:
431147
Doxycycline-Clontech:
631311 96-Well PlatesPolySorp
Nunc:
456529
TMB Substrate-Sigma
Web
Web
Web
Web
Fisher
Clontech
Fisher
Sigma
Cs/25
5g
Cs/180
100 mL
$481.00
$144.00
$743.00
$89.70
1
2
1
3
$494.95
$296.35
$764.55
$276.90
$494.95
$296.35
$764.55
$276.90
SMIF-6 Medium-Gibco
FreeStyle MAX ReagentInvitrogen:
K9000-20
FreeStyle CHO
Expression
Medium-Invitrogen:
014
12309-050
431143
1 L Shaker
Flasks-Corning:
431147
IPTG-Sigma: I6758-10G
Web
est
Web
Web
Web
Web
Web
Web
Web
Web
Inv.
Inv.
Inv.
Inv.
Inv.
Fisher
Fisher
Fisher
Fisher
Sigma
1L
1L
1 mL
1L
100 mL
Cs/100
Cs/50
Cs/50
Cs/25
10 g
$32.50
$60.00
$441.20
$76.22
$18.50
$162.00
$170.00
$394.00
$481.00
$403.00
2
6
1
2
1
1
1
1
1
1
$66.89
$370.44
$453.99
$156.86
$19.04
$166.70
$174.93
$405.43
$494.95
$414.69
$66.89
$370.44
$453.99
$156.86
$19.04
$166.70
$174.93
$405.43
$494.95
$414.69
FreeStyle MAX ReagentInvitrogen:CHO

K9000-20
FreeStyle
Expression
Medium-Invitrogen:
014
12309-050
Web
Web
Web
Web
Web
Web
Web
Inv.
Inv.
Inv.
Fisher
Fisher
Fisher
Fisher
1 mL
1L
100 mL
Cs/100
Cs/50
Cs/50
Cs/25
$441.20
$76.22
$18.50
$162.00
$170.00
$394.00
$481.00
1
2
1
1
1
1
1
$453.99
$156.86
$19.04
$166.70
$174.93
$405.43
$494.95
$453.99
$156.86
$19.04
$166.70
$174.93
$405.43
$494.95
$23,110.36
Web
Web
Web
Web
Web
est
Web
Inv.
Inv.
Inv.
Inv.
Inv.
Inv.
SAFC
1L
1L
500 mL
100 mL
1L
1L
1L
$32.50
$38.00
$363.00
$12.00
$70.00
$60.00
$84.00
1
1
1
1
1
1
1
$33.44
$39.10
$373.53
$12.35
$72.03
$61.74
$86.44
$33.44
$39.10
$373.53
$12.35
$72.03
$61.74
$86.44
1.2.2.1
1.2.2.2

431143
1
L Shaker
Flasks-Corning:
431147
Phase II Sub-Total
1.3.1.1
Eagles minimum essential
medium
(EMEM):11095-072
Fetal
Bovine
Serum, CertifiedGibco:
16000-044
0.05% Trypsin-EDTA-Gibco:
25300-054
OptiPRO SFM-Invitrogen:
12309-019
SMIF-6 Medium-Gibco
ExCell EBx GRO-I mediumSAFC: 14530C
BioFactura, Inc.
Page 65 of 218
1.3.3.1

125 mL Shaker FlasksCorning: 431143
Web
Web
Web
Fisher
Fisher
Fisher
Cs/100
Cs/50
Cs/50
$162.00
$170.00
$394.00
1
1
1
$166.70
$174.93
$405.43
$166.70
$174.93
$405.43
pH 10 Buffer : SB115-500
Ethanol: 61509-0020
NaCl : AC327300025
PBS (10X): BP449
MgCl2 :AC22321-1000
Benzonase 500 U/ml:
1.01695.0002
Sodium
phosphate monobasic:
4011-01
Sodium phosphate dibasic:
4062-1
NaOH: SS255-4
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Invoice
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
amsbio
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
500 ml
500 ml
500 ml
2L
1kg
4L
100g
100k
units
500g
$18.00
$20.00
$18.00
$115.00
$135.09
$111.81
$25.00
$600.00
$143.00
$131.00
$60.00
$50.00
$73.00
$400.00
$100.00
$797.94
$100.00
$133.11
$115.00
$60.00
$90.00
$130.00
$150.00
$570.00
$265.00
$177.00
$370.00
$21.00
1
1
1
1
1
1
1
2
1
1
1
1
4
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
$18.52
$20.58
$18.52
$118.34
$139.01
$115.05
$25.73
$1,234.80
$147.15
$134.80
$61.74
$51.45
$300.47
$1,234.80
$102.90
$821.08
$102.90
$136.97
$118.34
$61.74
$92.61
$133.77
$154.35
$586.53
$272.69
$182.13
$380.73
$21.61
$18.52
$20.58
$18.52
$118.34
$139.01
$115.05
$25.73
$1,234.80
$147.15
$134.80
$61.74
$51.45
$300.47
$1,234.80
$102.90
$821.08
$102.90
$136.97
$118.34
$61.74
$92.61
$133.77
$154.35
$586.53
$272.69
$182.13
$380.73
$21.61
Sodium azide: AC19038-1000

Cellufine
SO4 affinity resin 5
ml
column:
19845-15
Sartorius hydrosart
100k
membrane
:14668-47D
Sartopore capsule
filter:5445307H9-00-A
0.2 um Steriflip: SCGP00525
Millex GV syringe
filter:SLGVM33R
serological pipets 10ml bulk:
357534
357535
357550
Sterile media bottles: 20190250
Parafilm: PM-992
Parafilm: PM-996
Microcentrifuge tubes: 02681-320
BioFactura, Inc.
500g
4L
100g
5 ml
1 x 5ml
10/pk
4/pk
25/PK
50/pk
12/pk
500/Cs
200/Cs
100/Cs
48/Cs
24/Cs
12/Cs
500/Cs
500/Cs
250/pk
Page 66 of 218
Autoclave tape: 15-901-104

Regular tape: 15-078-206
352096
352070
Gloves: EV2050-M
20 ul pipet tips: 02-707-432
200 ul pipet tips: 02-707-430
1000 ul pipet tips:02-707-404
Kimwipes: 71600
SimplyBlue Safestain: LC6060
4-12% BisTris gel
MES
Antioxidant
Load buffer
Red Agent
Novex unstained protein
standard
BCA protein assay kit: 23227
Disposable UV cuvettes:
759150
Phase III Sub-Total
Web
Web
Web
Web
Web
Web
Web
Web
Web
Web
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Fisher
Inv.
6/pk
4/pk
500/Cs
500/Cs
10/Cs
960/pk
960/pk
960/pk
12
pk/Cs
1L
Web
Inv.
Web
Inv.
Web
Web
Web
Inv.
Fisher
Fisher
10/box
Each
Each
Each
Each
500 ul
500 ml
100/pk
Web
est
Web
Web
Web
Web
Web
Inv est
Inv est
Inv est
Inv est
Inv.
Inv.
Fisher
Fisher
Fisher
Fisher
Fisher
Agilent
Agilent
Agilent
Agilent
1L
1L
Cs/100
Cs/50
Cs/50
Cs/25
ea
ea
bulk
bulk
ea
$27.00
$10.00
$100.00
$110.00
$147.00
$80.00
$85.00
$90.00
$57.00
$142.00
$131.66
$63.82
$23.00
$12.02
$49.14
$117.59
$120.00
$80.00
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
$27.78
$10.29
$102.90
$113.19
$151.26
$82.32
$87.47
$92.61
$58.65
$146.12
$135.48
$65.67
$23.67
$12.37
$50.57
$121.00
$123.48
$82.32
$27.78
$10.29
$102.90
$113.19
$151.26
$82.32
$87.47
$92.61
$58.65
$146.12
$135.48
$65.67
$23.67
$12.37
$50.57
$121.00
$123.48
$82.32
$9,702.11
$32.50
$60.00
$162.00
$170.00
$394.00
$481.00
$610.00
$414.70
1
1
1
1
1
1
1
1
1
2
1
$34.41
$63.53
$171.53
$180.00
$417.18
$509.30
$645.89
$439.10
$34.41
$63.53
$171.53
$180.00
$417.18
$509.30
$645.89
$439.10
$2,152.41
$324.22
$736.50
1.4.1.1
SMIF-6 Medium-Gibco
431143
1 L Shaker
Flasks-Corning:
431147
Eclipse Plus C18 P/N 959990902
Guard column & holder
AAA reagents
AAA supplies
D2 lamp
$2,032.80
$153.10
$695.57
1.4.1.2
BioFactura, Inc.
Page 67 of 218
$2,152.4
$324.22
1
$736.50
$97.94
SMIF-6 Medium-Gibco
Web
est
Inv.
Inv.
1L
1L
$32.50
$60.00
1
1
$34.41
$63.53
$34.41
$63.53
SMIF-6 Medium-Gibco
Web
est
Inv.
Inv.
1L
1L
$32.50
$60.00
1
1
$34.41
$63.53
$34.41
$63.53
SMIF-6 Medium-Gibco
431143
1 L Shaker
Flasks-Corning:
431147
YSI Reagents-YSI
Web
est
Web
Web
Web
Web
Invoice
Inv.
Inv.
Fisher
Fisher
Fisher
Fisher
RJM Sales
1L
1L
Cs/100
Cs/50
Cs/50
Cs/25
Pack
$32.50
$60.00
$162.00
$170.00
$394.00
$481.00
$372.30
1
1
1
1
1
1
1
$34.41
$63.53
$171.53
$180.00
$417.18
$509.30
$394.21
$34.41
$63.53
$171.53
$180.00
$417.18
$509.30
$394.21
SMIF-6 Medium-Gibco
MEM Vitamin SolutionInvitrogen:
11120-052
Yeast
Extract
SolutionInvitrogen:
18180-059
MEM Sodium Pyruvate
Solution
100 mM-Invitrogen:
Sodium Selenite-Sigma:
11360-070
S5261-10G
Web
est
Web
Web
Web
Web
Inv.
Inv.
Inv.
Inv.
Inv.
Sigma
1L
1L
100 mL
100 mL
100 mL
10 g
$32.50
$60.00
$16.02
$26.87
$8.84
$23.30
1
1
1
1
1
1
$34.41
$63.53
$16.96
$28.45
$9.36
$24.67
$34.41
$63.53
$16.96
$28.45
$9.36
$24.67
Benzonase 500 U/ml:

1.01695.0002
Normal
mouse serum:PI31881
Cellufine SO4 affinity resin 5
ml
column:capsule
19845-15
Sartopore
filter:5445307H9-00-A
Web
Web
Web
Web
Web
Web
Fisher
Fisher
amsbio
Fisher
Fisher
Fisher
100k
units
5 ml
$600.00
$73.00
$400.00
$797.94
$115.00
$147.00
$131.66
3
6
4
1
1
1
1
$5,325.5
5
$1,905.9
$463.77
1
$1,905.91
$463.77
$1,694.15
$844.89
$121.77
$155.65
$139.41
$13,143.08
$61,069.93
1.4.1.3
1.4.2.1
1.4.2.3
1.4.4.1
Gloves: EV2050-M
4-12% BisTris gel
Phase IV Sub-Total
PROJECT TOTAL (includes 10% S&H)
BioFactura, Inc.
1 x 5ml
4/pk
12/pk
10/Cs
10/box
Page 68 of 218
$1,694.1
$844.89
5
$121.77
$155.65
$139.41
5.3.5
Travel
Table 11 provides a breakdown of travel costs by fiscal year and CWBS number down to
level 4. In addition, the table has been divided into the four technical project phases (I - IV) to
provide estimated travel costs for each phase.
The table includes two cost items. The first item is for travel reimbursement for two technical
product specialists from Vivalis (France), who will be travelling to the U.S. to provide hands-on
training on the EB66 cell line generation. The travel expenses consist of airfare, lodging, and car
rental. The training and product support for duration of the license is included in the EB66
license. The second item is for car mileage reimbursement for the Technical Project Manager to
travel from the Company (Rockville, MD) to USAMRIID (Fredrick, MD) to oversee and/or
assist with critical path tasks. The rate is based on the Internal Revenue Services 2012 car
mileage rate of 55.5 cents per mile.
BioFactura, Inc.
Page 69 of 218
Table 11: Travel Cost Breakdown

CWBS
Number
Purpose
Dates
No. of
Persons
Airfare
Hotel
Per
Diem
Car
Rental
Other
FY12
FY13
FY14
Total
1.1
Phase I USAMRIIDBioFactura car travel
Phase I
$1,447
$1,447
$1,447
1.1.1.1
EB66 on-site training

travel reimbursment
6/1/12
$4,000
$900
$300
$5,200
$5,200
1.1
Phase I Sub-Total
$6,647
$6,647
1.2
Phase II USAMRIIDBioFactura car travel
$1,190
$1,190
1.2
Phase II Sub-Total
$1,190
$1,190
1.3
Phase III USAMRIIDBioFactura car travel
$1,557
$1,557
1.3
Phase III Sub-Total
$1,557
$1,557
1.4
Phase IV USAMRIIDBioFactura car travel
$1,227
$1,227
1.4
Phase IV Sub-Total
$1,227
$1,227
$1,557
$1,227
$10,621
Phase II
Phase III
Phase IV
$1,190
$1,557
$1,227
$7,837
TOTAL
BioFactura, Inc.
Page 70 of 218
5.3.6
Equipment n/a
5.3.7 Other Costs

Table 12 provides a breakdown of other costs, which consists of two research license fees.
One is a 25-month license for the EB66 cell line from Vivalis and the other is an annual license
for the Tet expression system from TET Systems.
Table 12: Other Costs
CWBS
Number
1.1.1.1
1.2.1.2
1.1
Description
EB66 license
Tet license
Phase I Sub-Total
Date
Cost
FY12
FY13
FY14
Total
6/1/12
9/3/12
$104,800
$11,250
$104,800
$104,800
$11,250
$11,250
$11,250
$11,250
$104,800
$22,500
$127,300
5.3.8 Indirect Costs

BioFactura does not have DCAA approved rates as, to date, the Company has only had Fixed
Price contracts and no other contracts or grants with this requirement. In lieu, the Company is
providing historical trends for the last three-year period for its G&A, overhead, and fringe
benefit rates to assist in negotiating the final rates to be used (see Table 13 below). For
budgetary purposes the Company has used the 2010 rates (the Companys accounts and records
for 2011 have not been closed out and reviewed by the accountants).
Table 13: Historical Indirect Cost Rates
Rate
2008
2009
2010
Fringe Benefits
28.65%
26.45%
25.50%
Overhead
27.49%
22.35%
17.30%
G&A
40.12%
47.12%
29.74%
5.3.9
Facilities Capital Cost of Money n/a
5.3.10 DCAA n/a

5.3.11 Estimating System
The man-hours for each IMS element or work package (a task or activity) were generated by
selecting a task duration and assigning individual effort levels for all personnel involved in the
task. Task durations and effort levels were estimated based on the Companys extensive
experience in providing contract R&D services to biotechnology companies and academic and
federal research labs. Over the past 7 years, BioFactura has provided services ranging from
molecular biology and cell line generation through process and analytical development to scaleup and GLP pilot production runs. BioFactura has developed a standardized Excel-based
estimation approach to quickly provide labor cost projections. This also allows referencing past
contract worksheets and ensures pricing consistency. The ability to obtain pricing through webBioFactura, Inc.
Page 71 of 218
based accounts, including but not limited to Life Technologies, Fisher Scientific, Sigma, VWR,
New England Biolabs, allows the Company to rapidly obtain price estimates and obtain the best
pricing.
5.3.12 Purchasing System
Based on the Companys and personnels extensive vendor experience in the biotechnology
industry, the Company has developed a core of vendors, which supply over 90% of its supplies
and materials needs. For the large vendors, such as Life Technologies and Fisher Scientific, from
which the Company orders the bulk of its supplies, the Company has negotiated small business
discounts and/or receives reduced shipping and handling fees. Purchasing is handled by the
Companys Chief Operating and Financial Officer (COO/CFO).
5.3.13 Accounting System
As BioFactura is a small business, the Companys COO/CFO also handles all routine
bookkeeping, and accounting using QuickBooks 2011 software. The COO/CFO also is
responsible for generating all client, grant, and contract budget projections. An accountant firm
reviews the Companys accounts on a regular basis and files all the necessary annual federal,
state, and property tax returns. Then Companys accounts in Quickbooks are maintained in
accrual basis (returns are filed on a cash basis).
Although, the Company has not been audited and approved by DCAA, the Company has
developed with its accountants an accounting system that was specifically designed to pass a
government audit and which is, to best of its knowledge, DCAA-acceptable. The accounting
system is divided into five cost pools: Direct Expenses, G&A, Fringe Benefits, Overhead, and
Unallowables. This allows for effective calculation of the G&A, fringe, and overhead rates, but
also ensures clear segregation of costs.
The direct expense account is further divided into contract services and R&D expenses to
distinguish between external and internal R&D projects. In addition, a class, customer and job
designation is assigned to all direct expense entries (accounts payables) and invoices (accounts
receivables). Finally, the Company employs a timesheet system that is broken into G&A and
direct expense sub-categories. The latter include individual R&D projects to enable separate
tracking of employees hours for each R&D project. Overall this accounting system allows for
completing accounting of each projects expenses and enables the Company to rapidly compare
these to budget projections.
5.3.14 Company Financial Statements
The Companys 2008, 2009, and 2010 income statements are attached on the following
pages.
BioFactura, Inc.
Page 72 of 218
5.3.14.1
Income Statements
12:11 PM
BioFactura Inc
05/05/11
Profit & Loss

January through December 2010
Accrual Basis
Jan - Dec 10
Ordinary Income/Expense
Income
40000 Income
41000 Commercial R&D Contract Service
42000 R&D Grants and Contracts
49000 R&D Tax Grant
1,205.18
1,080,274.94
204,793.72
1,286,273.84
Total 40000 Income
1,286,273.84
Total Income
Cost of Goods Sold
50000 Direct Expense
51000 Contract Service Expense
51100 Salary Expense
51900 Miscellaneous
461.54
205.18
666.72
Total 51000 Contract Service Expense

52000 R&D Expenses
52200 Supplies & Materials
52300 Outsourced R&D Services
52320 Patent Cost
52800 Licensing Fees & Legal Costs
52900 Miscellaneous Expenses
Total 52000 R&D Expenses
305,544.25
97,109.71
159,638.53
15,217.70
49,602.00
5,476.18
632,588.37
633,255.09
Total 50000 Direct Expense
633,255.09
Total COGS
653,018.75
Gross Profit
Expense
60000 Fringe Benefit
60100 PTO
60200 Accrued Vacation Expense
60500 Insurance Expenses
60510 Health Insurance
60520 Group Disability Insurance
60530 Worker's Comp Insurance
48,924.63
8,182.85
12,646.22
2,514.83
2,052.33
Total 60500 Insurance Expenses
17,213.38
60600 Retire. Plan Match

60700 Payroll Tax
13,254.39
32,385.59
119,960.84
Total 60000 Fringe Benefit

70000 Overhead
70100 OH Bid & Proposal
70600 Lab Rent
70900 Misc. R&D Overhead
72.83
56,057.60
10,294.07
66,424.50
Total 70000 Overhead

80000 G&A Expense
80100 G&A Salary Expense
80110 General G&A
80120 Business Development
80130 Bid & Proposal
Total 80100 G&A Salary Expense
80200 Office Supplies
80210 Computer Expenses
80230 Shipping and Postage
80300 Professional Services
80400 Meals
80410 Meetings & Dues
80420 Parking , Gas & Tolls
80430 Travel & Lodging
58,043.90
28,337.10
29,015.28
115,396.28
2,826.34
7,313.61
911.41
29,094.28
1,002.45
5,721.40
343.25
1,919.96
Page 1
BioFactura, Inc.
Page 73 of 218
12:11 PM
BioFactura Inc
05/05/11
Profit & Loss

Accrual Basis
Jan - Dec 10
80500 Insurance
80510 Package Policy
80520 Automobile
80530 DO & EPLI
Total 80500 Insurance
80600 Office Rent
80610 Telephone, Fax & Internet
80630 Bank & Misc. Fees
80640 Payroll Expenses
80700 Tax
80800 Government Licenses and Permits
80900 Miscellaneous
89000 Depreciation Expense
2,327.16
935.00
3,826.00
7,088.16
16,770.00
5,490.70
947.23
1,220.74
701.45
250.00
-229.00
8,825.78
205,594.04
Total 80000 G&A Expense

90000 Unallowable Expenses
90200 Bad Debt Expense
90600 Interest Expense
90610 Misc. Interest Expense
90802 MdBio Royalty Payments
Total 90600 Interest Expense
90700 Fines and Penalties
90800 Foreign Exchange Gain/Loss
Total 90000 Unallowable Expenses
Total Expense
Net Ordinary Income
Other Income/Expense
Other Income
91000 Interest Income
49,470.76
7,961.40
367.67
8,329.07
100.00
0.01
57,899.84
449,879.22
203,139.53
147.09
Total Other Income
147.09
Other Expense
92000 Other Expense
200.00
Total Other Expense
200.00
Net Other Income

Net Income
-52.91
203,086.62
Page 2
BioFactura, Inc.
Page 74 of 218
12:16 PM
BioFactura Inc
05/05/11
Profit & Loss

Accrual Basis
Jan - Dec 09
Income
40000 Income
39,650.02
817,980.31
857,630.33
Total 40000 Income
857,630.33
Total Income
Cost of Goods Sold
52000 R&D Expenses
52300 Outsourced R&D Services
52320 Patent Cost
52400 Travel, Meals & Lodging
52800 Licensing Fees & Legal Costs
52900 Miscellaneous Expenses
Total 52000 R&D Expenses
11,745.89
1,427.67
13,173.56
222,399.08
74,353.08
33,622.46
15,871.63
115.71
17,500.00
9,597.71
373,459.67
386,633.23
386,633.23
Total COGS
470,997.10
Gross Profit
Expense
60100 PTO
60500 Insurance Expenses
60510 Health Insurance
60520 Group Disability Insurance
60530 Worker's Comp Insurance
58,425.03
12,822.72
2,399.57
2,056.56
Total 60500 Insurance Expenses
17,278.85
60600 Retire. Plan Match

60700 Payroll Tax
7,585.87
28,103.02
111,392.77

70000 Overhead
70900 Misc. R&D Overhead
66,177.19
66,177.19

80000 G&A Expense
80100 G&A Salary Expense
80110 General G&A
80120 Business Development
88,240.28
24,158.54
15,370.19
Total 80100 G&A Salary Expense
127,769.01
80200 Office Supplies

80220 Printing and Reproduction
80400 Meals
80420 Parking , Gas & Tolls
2,867.56
9,586.56
51.66
788.47
36,359.45
-591.25
4,136.50
132.00
Page 1
BioFactura, Inc.
Page 75 of 218
12:16 PM
BioFactura Inc
05/05/11
Profit & Loss

Accrual Basis
Jan - Dec 09
80500 Insurance
80520 Automobile
80530 DO & EPLI
Total 80500 Insurance
80600 Office Rent
80620 Utilities
80640 Payroll Expenses
80700 Tax
80900 Miscellaneous
3,050.84
906.68
637.67
4,595.19
13,692.60
6,028.26
985.20
562.24
1,063.74
1,563.22
39.68
6,269.52
215,899.61
Total 80000 G&A Expense

90600 Interest Expense
90610 Misc. Interest Expense
90802 MdBio Royalty Payments
Total 90600 Interest Expense
90900 Misc. Unallowable Expenses
Total Expense
Net Ordinary Income
Other Income
Total Other Income
Net Other Income
Net Income
47,921.55
7,451.02
55,372.57
274.48
743.59
56,390.64
449,860.21
21,136.89
640.04
640.04
640.04
21,776.93
Page 2
BioFactura, Inc.
Page 76 of 218
BioFactura, Inc.
12:40 PM
Profit & Loss
05/05/11
Accrual Basis
Jan - Dec 08
Income
716,263.79
168,430.19
884,693.98
Total Income
884,693.98
Gross Profit
Expense
60110 CS - Salary Expense
60120 CS - Supplies & Materials
60130 CS - Shipping & Postage
60150 CS - Miscellaneous
63,102.63
24,999.92
168.52
192.67
88,463.74

60200 R&D Expense
60210 R&D Salary Expense
60220 R&D Miscellaneous Expenses
60230 R&D License & Legal Cost
60240 R&D Outsourced Services
60260 R&D Supplies & Materials
202,749.19
4,953.70
62,315.73
128.00
40,867.18
311,013.80
Total 60200 R&D Expense
464.14
399,941.68

64000 GA Expense
64020 Utilities
64040 Recruiting
64060 Employee Relations
64070 Property & Liability Insurance
64072 Automobile
58,250.92
2,473.44
445.00
9,599.14
800.00
3,015.40
890.06
Total 64070 Property & Liability Insurance
3,905.46

64090 Office Expense
64100 GA Salary Expense
64101 GA Salary Expense
64103 GA Misc. Payroll Expenses
1,025.00
2,479.97
99,982.56
1,434.10
101,416.66
Total 64100 GA Salary Expense
532.81
353.00
640.32
2,069.16
4,666.00
10,313.58
6,189.00
202.13
47.19

64115 Parking & Tolls
64130 Tax
64200 Office Rent
64210 Printing and Reproduction
64900 Miscellaneous
205,408.78
Total 64000 GA Expense

68000 Indirect Expense
68110 FB - Insurance Expenses
68111 FB - Health Insurance
68112 FB - Worker's Comp Insurance
68113 FB - Group Disability Insurance
Total 68110 FB - Insurance Expenses
16,611.73
1,689.33
2,051.27
20,352.33
Page 1
BioFactura, Inc.
Page 77 of 218
BioFactura, Inc.
12:40 PM
Profit & Loss
05/05/11
Accrual Basis
Jan - Dec 08
68120 FB - Retire. Plan Match
68130 FB - Salary Expense
68140 FB - Payroll Tax
68200 Overhead
68210 R&D Overhead
68220 Direct Selling
9,377.84
59,293.94
30,470.51
119,494.62
93,977.81
86.14
94,063.95
213,558.57
Total 68000 Indirect Expense
818,909.03
Total Expense
65,784.95
Net Ordinary Income

Other Income
214.25
214.25
Total Other Income

Other Expense
80100 UA - Meals & Entertainment
80200 UA - Interest Expense
80210 UA - Misc. Interest Expense
80220 UA - MdBio Royalty Payments
Total 80200 UA - Interest Expense
80300 Marketing & Business Dev
80310 UA - Travel, Lodging & Meals
80320 UA - Salary Expense
80330 UA - Meetings & Events
Total 80300 Marketing & Business Dev
Total Other Expense
Net Other Income
Net Income
1,966.58
28,503.41
6,035.66
34,539.07
2,823.35
18,878.39
3,816.10
25,517.84
131.00
62,154.49
62,154.49
-61,940.24
3,844.71
Page 2
BioFactura, Inc.
Page 78 of 218
6. APPENDICES
6.1
Key Personnel Qualifications
6.1.1
Darryl Sampey Project & Technical Project Manager (BioFactura)
Darryl Sampey will serve as Technical Project Manager and will responsible for all aspects
of the projects scientific and technical efforts at BioFactura (prime) and at the key subcontractor
and collaborator the US Army Medical Research Institute of Infectious Diseases (USAMRIID).
A key function of Mr. Sampey will be to ensure a smooth integration of the highly
interdependent tasks to be performed at USAMRIID and BioFactura. As such he will serve as the
man on site at USAMRIID to oversee and assist with tasks and track USAMRIIDs task
progress and status. Overall, he will manage both in-house and subcontracted tasks, track task
status and progress vis--vis the Integrated Master Scheudle (IMS), and monitor and update risk
drivers. Furthermore, he will ensure that all resources are available as required for each IMS
element. Mr. Sampey will be the point of contact (POC) at BioFactura for all contractual and
reporting activities as required and requested by Chemical Biological Medical Systems (CBMS).
He will serve as lead in all presentations and meeting during the course of the project.
6.1.1.1
Biography
Darryl Sampey co-founded BioFactura in 2001 and as President and CEO manages all
strategic and scientific endeavors of the Company including partnership/alliance building,
fundraising, intellectual property maintenance, contract research and development, platform
technology programs, and biopharmaceutical product development. To date, he has raised over
$6M in funding for BioFactura including the award of two Congressional Special Projects
(defense earmarks), and successfully transitioned a novel monoclonal antibody therapeutic
against smallpox from research to the pre-Investigational New Drug application stage. He is the
inventor and developer of BioFacturas VeriCyte Discovery and StableFast Biomanufacturing
Platforms. Before BioFactura, he led both process development and manufacturing teams at
Human Genome Sciences, Inc. (HGS). Mr. Sampey joined the protein development department
of HGS in 1998, and honed his skills developing new biologics processes and control strategies.
During his tenure with HGS, Mr. Sampey played key roles in the start-up, commissioning, and
validation of the companys first cGMP manufacturing facility and associated development
laboratories. Additionally, he performed lead roles in the development, transfer, and evaluation
of novel fermentation processes for cGMP clinical manufacturing. Prior to his work at HGS, Mr.
Sampey gained industrial experience in the commercial research laboratory designing and
optimizing fermentation and product recovery processes for novel vaccines at North American
Vaccine, Inc. His work in vaccine research has since progressed to internationally-approved
vaccines for whooping cough in infants and meningitis in adults. Darryl Sampey began his
career in biotechnology at the University of Maryland. During his undergraduate years, Mr.
Sampey pursued independent research in novel protein analysis technique under the advisement
of Dr. William Bentley. Mr. Sampey graduated first in his class and was awarded a Bachelor of
Science in Chemical Engineering, Magna Cum Laude. In addition to his current responsibilities
at BioFactura, he is also completing his Ph.D. in Bioengineering at the University of Maryland
BioFactura, Inc.
Page 79 of 218
developing an innovative memory B cell capture technology for fully human therapeutic
monoclonal antibody discovery. Mr. Sampey is also a co-founder and Director of the Small
Biotechnology Business Coalition (SBBC), the only Federal advocacy organization dedicated
specifically to advancing the progress of small biotechnology and medical device firms.
6.1.1.2
Education
B.S. in Chemical Engineering, Magna Cum Laude, University of Maryland College Park, 1996
Ph.D. in Bioengineering, University of Maryland College Park, expected 2012
6.1.1.3
Work Experience
President and Chief Executive Officer

(Apr 2004 Present)
Co-Founder
BioFactura, Inc.
9430 Key West Avenue, Suite 125
Rockville, MD 20850
Business and Management:
Conceived and developed core contract services, technology development, and product
development/licensing departments of the emerging venture, BioFactura, Inc. Perform extensive
business development duties; recruiting new customers for contract services and potential
strategic partners for drug product and platform technology development. Serve as principle
liaison between BioFactura and its academic and government collaborators; coordinating product
in-licensing, co-writing joint grant proposals, and directing pre-clinical research. Present
corporate research and development and business topics to potential customers, partners, and
investors. Design, write, and edit proposals and contracts. Managed up to six execs, scientists,
and technicians over multiple simultaneous projects.
Science and Engineering:
Equipped BioFacturas R&D laboratories and lead execution of contract research and
manufacturing. Perform a range of laboratory duties including all Laboratory Techniques
described in Special Skills section above. Led drug development through demonstration of
preclinical efficacy of a trivalent monoclonal antibody therapeutic for the treatment of smallpox
and other human orthopoxvirus pathogens. Co-invented and led development of the StableFast
Biomanufacturing Platform, a novel stable cell line system for the production of monoclonal
antibodies and glycoproteins (US Pat 8,076,102). Invented and lead development of the
VeriCyte Discovery Platform, a novel biological microelectromechanical system (bioMEMS) for
the isolation of antigen-specific memory B cells and cytotoxic T cells for antibody and cell based
therapeutic development, respectively (Pat App PCT/US2010/026624).
Director
(Feb 2010 Present)
Co-Founder
Small Biotechnology Business Coalition
9710 Traville Gateway Drive, #325
Rockville, MD 20850
Created, developed, and incorporated a non-profit advocacy organization. Developed and
maintain website. Lead teams in the direct advocacy for the small biotech business community
BioFactura, Inc.
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including communications with Members and staff of the US Congress and other biotechnology
trade organizations (i.e., Biotechnology Industry Organization [BIO]). Plan and organize
strategic and tactical initiatives. The SBBC is a membership based, grass roots organization
comprising small biotech and medical device firms (Members) as well as other organizations and
individuals (Associate Members) that want to help these firms improve our nations economy
and healthcare system. Top legislative priorities of the Coalition are to bring about an expansion
of, and improvements to, the NIHs Small Business Innovative Research (SBIR) program while
ensuring that these funds remain primarily directed at R&D for which significant amounts of
private capital financing is generally unavailable or insufficient.
Process Engineer III
(Jul 1998 Apr 2004)
Human Genome Sciences, Inc.
Dept. of Fermentation Clinical Development
9410 Key West Ave.
Rockville, MD 20850
Developed, optimized, and scaled-up microbial, yeast, and cell culture processes for transfer
to cGMP clinical manufacturing groups. Performed technology transfer of manufacturing
processes; composed, reviewed, and edited batch records and SOPs; and performed evaluation
and troubleshooting of cGMP processes at both the manufacturing and bench scales. Assisted
with process validation design and executed validation plans. Wrote and edited tech reports for
process development, tech transfer, and process validation. Designed multiple fed-batch control
strategies based on culture oxygen uptake, pH, and carbon dioxide evolution. Performed lead
roles in development, transfer, and evaluation of multiple fermentation processes from
development to cGMP clinical manufacturing. Regularly designed, led, and analyzed
development experiments with little or no supervision. Trained new employees on fermentation
and analysis techniques.
Process Engineer I
(Aug 1996 July 1998)
Div. of Microbiology and Immunology
North American Vaccine, Inc.
12103 Indian Creek Ct.
Beltsville, MD 20705-4223
Designed and optimized fermentation and product recovery processes for research and
development department. Designed and implemented a direct feedback substrate control system
for high-density recombinant E. coli fermentation using New Brunswick Scientific process
control software and a YSI glucose analyzer. Served as liaison for technology transfer of a
Group C N. meningitidis fermentation to the process development group for the cGMP
production of a capsular polysaccharide to be used in conjugate vaccine clinical trials.
Developed a defined medium for Group B Streptococcus fermentation, scaled a recombinant E.
Coli fermentation and recovery process for producing a pili vaccine that protects against urinary
tract infection, and investigated tryptophan auxotroph E. coli strains for recombinant protein
structure elucidation.
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Research Assistant
(May 1995 Aug 1996)
Dept. of Chemical Engineering
University of Maryland at College Park
College Park, MD 20742
Designed and performed experiments for basic and applied biochemical engineering
research. Prepared and ran 1- and 10-liter recombinant E. coli fermentations, quantified protein
content, and developed a novel 3-dimensional polyacrylamide gel electrophoresis technique for
protease activity analysis.
6.1.1.4
Research Support
SBIR W81XWH-06-C-0029
Sampey (PI)
(Nov 2005 Dec 2010)
Generation of Stable Eukaryotic Cell Lines Expressing High Yields of Therapeutic Human
Antibodies Against Biowarfare Viral Threat Agents
The overall goal of this program is to generate a cocktail of protective and therapeutic human
or humanized mAbs to vaccinia virus subunit proteins that will improve upon and/or replace; 1)
vaccinia immune globulin (VIG) for the treatment of adverse smallpox vaccination events, and
2) existing countermeasures against the potential use of smallpox as a biological weapon.
Role: PI
U01 1 UC1 AI067188-01
Garry (PI)
(Sep 2005 Oct 2008)
Recombinant Antigen Multiagent Diagnostic Assays for Lassa and Other Arenaviruses
The main goals of this project were to develop and validate multiagent diagnostic
immunoassays for arenaviruses using recombinant antigens.
Role: Subcontractor
Fort Detrick Tech Trans Init Grant
Sampey (PI)
(Feb 2006 Jun 2006)
Smallpox Therapy DevelopmentCell Line Characterization, Medium Formulation, and Process
Optimization
The main goals of this project were to characterize stable CHO cell lines expressing human
monoclonal antibodies, evaluate medium formulations for growth and antibody production, and
develop a scalable bioreactor process for antibody production.
Role: PI
Maryland Industrial Partnerships Grant
Sampey/Bentley (PI) (May 2006 Apr 2007)
Novel Antifungal Drug-Expression System Evaluation
The main goal of this project was to evaluate commercially-available approaches to
expression of a novel antifungal peptide.
Role: Co-PI
6.1.1.5
Honors and Activities
Innovator of the Year, The Daily Record, 2009.

Graduate, Montgomery County Business Innovation Network, 2009.
Finalist, Maryland Incubator Company of the Year, 2007.
Mindshare Class of 2007.
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Magna Cum Laude (top 5% of graduating class).

Engineering Honors Program.
Chairman of Chemical Engineering Outstanding Senior Award, 1996.
Sec. and National Delegate (1995-1996), Tau Beta Pi National Engineering Honor Soc.
Member, Omega Chi Epsilon National Chemical Engineering Honor Society.
Member, Phi Kappa Phi National Honor Society.
Member, American Institute of Chemical Engineers.
6.1.1.6
Publications, Presentations, and Patents
Sampey D and Goldman J. (1996). Topic Selection and Idea Development in The Elements of
Academic Research, Ed. By R. McCuen, ASCE Press, New York, pp. 58-73.
Sampey D. (1996). Classification of Stress-Induced Proteases in Recombinant Escherichia coli
Via a Novel Three-Dimensional Polyacrylamide Gel Electrophoresis Technique, Honors
Dissertation, University of Maryland, College Park.
Pulliam T, Sampey D, and Bentley W. (1996). 1, 2, and 3D Substrate Gel Electrophoresis for
Elucidation of Cellular Stress-Related Proteolysis in E. Coli, Poster at 211th American Chemical
Society National Meeting, New Orleans.
Sun W, Sampey D, Blake M, and Fusco P. (1997). High Cell Density Fed-Batch Fermentation
of Recombinant Escherichia coli Producing Neisseria meningitidis Class 3 Porin, Poster at 97th
American Society for Microbiology General Meeting, Miami Beach.
Sampey D, Fusco P, Sun W, Bogdan J, Blake M, Remeta D, and Minetti C. (1998). Structural
Studies of Neisseria meningitidis PorB Proteins: Use of Tryptophan Analogues to Characterize
Porin Topology. Poster at American Society for Biochemistry and Molecular Biology Annual
Meeting, Washington, D. C.
Gwinn W, Zhang M, Mon S, Sampey D, Zukauskas D, Kassebaum C, Zmuda JF, Tsai A, Laird
MW. (2006). Scalable purification of Bacillus anthracis protective antigen from Escherichia
coli. Protein Expression and Purification, 45(1), pp. 30-6.
Branco L, Matschiner A, Fair J, Goba A, Sampey D, Ferro P, Cashman K, Schoepp R, Tesh R,
Bausch D, Garry R and Guttieri M. (2008). Bacterial-based systems for expression and
purification of recombinant Lassa virus proteins of immunological relevance. Virology Journal,
5(74).
Terrell J, Gordonov T, Cheng Y, Wu H-C, Sampey D, Luo X, Tsao C-Y, Ghodssi R, Rubloff G,
Payne G, and Bentley W. (2012). Integrated biofabrication for electro-addressed in-film
bioprocessing. Biotechnology Journal, doi: 10.1002/biot.201100181.
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PatentsPending and Issued

Branco, L and Sampey, D. Compositions and methods for metabolic selection of transfected
cells. US Patent and Trademark Office, Washington D.C., USA. International Application No.:
PCT/US2006/019344; US Patent Issued December 13, 2011 (8,076,102).
Branco, LM, Matschiner, A, Illick, MM, Sampey, DB, Garry, RF, Bausch, DG, Fair, JN,
Guttieri, MC, Cashman, KA, Wilson, RB, Kulakosky, PC, and Geske, FJ. Soluble and
membrane-anchored forms of Lassa virus subunit proteins. US Patent and Trademark Office,
Washington D.C., USA; Pub. No.: WO/2008/124176; International Application No.:
PCT/US2008/004622; Filed April 10, 2007 (60/922,732) (Pending).
Sampey, DB. Separation of antigen-specific memory B cells with a conjugated biopolymer
surface. US Patent and Trademark Office, Washington D.C., USA; Pub. No.: WO/2010/104828;
International Application No.: PCT/US2010/026624; Filed March 9, 2009 (61/158,649)
(Pending).
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6.1.2
Alexander MatschinerOperational Project Manager (BioFactura)
Alexander Matschiner will serve as Operational Project Manager, and will additionally
coordinate all scientific and technical activities related to VRP purification and formulation at
BioFactura and at USAMRIID. His oversight task primarily will be the management of the
project budget but he will also assist Mr. Sampey with maintaining and updating the IMS
schedule and tracking percent completion. Mr. Matschiner will be the alternate POC at
BioFactura for all contractual and reporting activities as required and requested by CBMS. He
will serve in a support role and as alternate lead for all presentations and meetings during the
course of the project. Mr. Matschiner also will serve as interim Project Manager in the event that
Mr. Sampey is absent.
6.1.2.1
Biography
Alex Matschiner brings more than 15 years of industry experience in management, R&D,
manufacturing, and facility design. He is a cofounder of BioFactura and has served as the
companys VP of Operations and then Chief Operating Officer since 2004. At BioFactura, Mr.
Matschiner manages all corporate operations including finances, legal, compliance, and human
resources. In addition, he acts as lead on regulatory matters, downstream process and analytical
development, and formulation and stability. Previously, he served as Senior Manager of
Manufacturing Operations at Human Genome Sciences, Inc. (HGS). At HGS, Mr. Matschiner
led the design of the downstream manufacturing areas in the construction of HGS $180 million
commercial large-scale manufacturing facility, which houses twin 20,000liter bioreactors. Mr.
Matschiner also served in similar lead positions during the conceptual design, construction,
startup and validation of the microbial and mammalian pilot production facilities at HGS. After
the completion of the facilities, he led the Recovery and Purification cGMP manufacturing
teams. Prior to his work in manufacturing and engineering, Mr. Matschiner worked in the
Process Development group at Human Genome Sciences. During that time he developed the
downstream manufacturing process for one of HGS leadproduct candidates and wrote the
manufacturing section in the CMC portion of the companys Investigational New Drug (IND)
application. He received his Master of Science degree in Chemical and Biochemical Engineering
from the University of Iowa. In summary, Mr. Matschiner is a seasoned bioprocess engineer with
extensive downstream bioprocess research, development, scale-up, and manufacturing
experience. His project role as Purification Manager is well supported by his track record at
BioFactura developing the candidate smallpox antiviral mAb drug product and his extensive
experience in industrial biopharmaceutical process engineering and manufacturing at HGS.
6.1.2.2
Education
B.A. in Chemistry, Grinnell College, 1991

M.S. in Biochemical Engineering, 1994, University of Iowa
BioFactura, Inc.
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6.1.2.3 Work Experience

Chief Operating Officer & Chief Financial Officer
(2005 Present)
Vice President, Operations & Co-founder
(2004 2005)
BioFactura, Inc.
Rockville, MD 20850
Built company from $25K seed investment to biodefense business with over $1M annual
revenues in 5 years and secured ~$6M in funding from local and state organizations, private
investors, contract services, and federal R&D grants and contracts. Managed all day-to-day
business operations including corporate strategy, accounting/finance, federal grants and client
R&D contract management; outsourcing to CRO/CMO; human resources, corporate governance,
and legal matters. Lead IND-enabling CMC efforts for companys lead biodefense therapeutic
product including developing preclinical plan and cost forecasts. Wrote and lead multiple federal
grant and contract submissions. Developed antibody purification and analytical methods for
companys monoclonal antibody drug candidates as well as a variety of down-stream processes
for contract clients. Co-wrote companys business plans and business presentations.
Senior Manager, Global Project Management
(2003 2004)
9410 Key West Ave.
Rockville, MD 20850
Provided cost of goods analyses for HGS lead and new drug initiatives in collaboration with
accounting group. Worked in close collaboration with clinical management, process
development, clinical, manufacturing, and marketing groups to synch the needs of ongoing/planned clinical studies and new drug initiatives with clinical manufacturing schedules.
Chaired inter-departmental pharmaceutical operations meeting consisting of senior departmental
managers.
Senior Manufacturing Manager, Purification (20,000L cGMP)
(2001 2004)
Led process engineering team responsible for conceptual, preliminary and detailed design of
the down-stream manufacturing suites for HGS 20,000L cGMP Cell Culture manufacturing
facility. Coordinated with purification process development lead scientists to ensure alignment of
process requirements with facility design. Responsible for developing master hiring plan,
training requirements, operational philosophy, and budget for purification group in large-scale
facility. Presented down-stream facility design at FDA Type C meeting. Stretch goals included
development of cost of good models for lead candidate products in collaboration with accounting
and assisting the VP of Manufacturing Operations with the review and oversight of the
departments $100 million yearly budget and monthly trial balances.
Purification Supervisor (Pilot cGMP Cell Culture Facility)
(2000 2001)
Established hiring plan, training requirements, operational philosophy, and budget for
purification manufacturing group. Managed start-up and validation activities of all down-stream
production equipment and CIP skids (24/7 three-shift operation). Generated, reviewed and
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Page 86 of 218
approved operation, cleaning and preventative maintenance SOPs and IQ/OQ/PQ validation
protocols for all down-stream production equipment. Lead down-stream engineer team from
detailed design through construction and start-up of 1,600L cGMP Cell Culture plant. Generated,
reviewed and approved all down-stream facility and equipment designs and procurement
documents. Collaborated closely with purification process development group to ensure process
fit and smooth tech transfer to new facility.
Process Engineer II (Pilot cGMP Microbial Facility)
(1998 2000)
Successfully transferred downstream process to new facility and completed shake-down and
productions runs of phase II clinical material followed by area process change-over. Responsible
for developing and maintaining production schedules for manufacturing facility. Closely worked
with VP of Operations, manufacturing managers, and process development to coordinate
production activities and develop and maintain production schedules. Lead engineering effort
through all phases of design, construction, and start-up of 600L Microbial Pilot Plant Facility for
the Recovery and Purification manufacturing areas. Developed operation, cleaning and
preventative maintenance SOPs. Responsible for factory- and site-acceptance tests, start-up and
commissioning of process equipment and CIP skids.
Process Engineer I/Research Associate II (Process Development) (1995 1998)
Developed and optimized recovery and purification processes (including analytical RPHPLC method) for HGS lead product. Generated first tox lot material and co-authored
Chemistry, Manufacturing and Controls section for IND filing. Lead technology transfer of
down-stream process to GMP contract manufacturer and acted as on-site company technical lead
during the production of companys first Phase I/II clinical material. Developed purification
methods for various recombinant protein candidates from E. coli, insect cell, and CHO systems.
Hands-on work on 10-100L bacterial bioreactors and recovery for pre-clinical production.
Faculty Research Assistant
(1994 1995)
Center of Marine Biotechnology, University of Maryland
701 E. Pratt St.
Baltimore, Maryland 21202
Isolated and purified recombinant Glutamate Dehydrogenase from hyperthermophilic
bacteria, refined purification methodology, and performed enzyme kinetics and stability assays.
6.1.2.4
Research Support
SBIR W81XWH-06-C-0029
Sampey (PI)
(Nov 2005 Dec 2010)
Generation of Stable Eukaryotic Cell Lines Expressing High Yields of Therapeutic Human
Antibodies Against Biowarfare Viral Threat Agents
The overall goal of this program was to generate a cocktail of protective and therapeutic
human or humanized mAbs to vaccinia virus subunit proteins that will improve upon and/or
replace; 1) vaccinia immune globulin (VIG) for the treatment of adverse smallpox vaccination
events, and 2) existing countermeasures against the potential use of smallpox as a biological
weapon.
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Role: Upstream Process Lead Development of mAb purification process, analytical in-process
and lot release assays, pre-formulation, and preliminary stability studies. Safety/tox studies CRO
lead.
U01 1 UC1 AI067188-01
Garry (PI)
(Sep 2005 Oct 2008)
Recombinant Antigen Multiagent Diagnostic Assays for Lassa and Other Arenaviruses
The main goals of this project were to develop and validate multiagent diagnostic
immunoassays for arenaviruses using recombinant antigens.
Role: subcontractor antigens and antibody purification process development.
Fort Detrick Tech Trans Init Grant
Sampey (PI)
(Feb 2006 Jun 2006)
Smallpox Therapy DevelopmentCell Line Characterization, Medium Formulation, and Process
Optimization
The main goals of this project were to characterize stable CHO cell lines expressing human
monoclonal antibodies, evaluate medium formulations for growth and antibody production, and
develop a scalable bioreactor process for antibody production.
Role: Co-PI antibody purification
Maryland Industrial Partnerships Grant
Sampey/Bentley (PI) (May 2006 Apr 2007)
Novel Antifungal Drug-Expression System Evaluation
The main goal of this project was to evaluate commercially-available approaches to
expression of a novel antifungal peptide.
Role: Investigator expression and purification development
(Jan 1998 Apr 2004)
cGMP Facility Design, Construction, Validation, and Management
Performed lead process engineer role in the design, construction and validation of Human
Genome Sciences downstream manufacturing areas in the 600L Microbial and 1,600L Cell
Culture cGMP Pilot Plant Facilities as well as the design of the large-scale 20,000L cGMP
manufacturing plant. Upon start up of facilities, managed all downstream cGMP clinical
manufacturing operations.
(Aug 1995 Jan 1998)
Downstream Process Development and Optimization
Developed and optimized recovery and purification processes for companys lead
biopharmaceutical candidates including Repifermin, a novel wound-healing therapeutic.
Center for Marine Biotechnology
Robb, Frank (PI)
(Oct 1994 Aug 1995)
Isolation, Purification, and Characterization of Recombinant Glutamate Dehydrogenase from
Hyperthermophilic Bacteria
6.1.2.5
Honors and Activities - N/A
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6.1.2.6
Matschiner A, Dordick JS, and Murhammer DW. (1995). Isolation of virally-infected insect
cells from a population containing infected and uninfected cells. Biotechnology Techniques, 9,
pp. 897-900.
Branco L, Matschiner A, Fair J, Goba A, Sampey D, Ferro P, Cashman K, Schoepp R, Tesh R,
Bausch D, Garry R and Guttieri M. (2008). Bacterial-based systems for expression and
purification of recombinant Lassa virus proteins of immunological relevance. Virology Journal,
5(74).
Illick M, Branco L, Fair J, Illick K, Matschiner A, Schoepp R, Garry R, and Guttieri M. (2008).
Uncoupling GP1 and GP2 expression in the Lassa virus glycoprotein complex: implications for
GP1 ectodomain shedding. Virology Journal, 5(161).
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6.1.3
Pamela J. Glass, Ph.D. Principal Collaborator (USAMRIID)
Dr. Pam Glass will serve as Principal Collaborator and lead all VRP production and analysis
activities at USAMRIID. She will be responsible for coordination of all resources at USAMRIID
as required for each Integrated Master Schedule (IMS) element. Dr. Glass will ensure that all
Biological Safety Level-3 (BSL-3) activities are conducted as per regulations and also manage
all animal studies in accordance with the US Army Medical Research and Materiel Command
(USAMRMC) Animal Care and Use Review Office (ACURO). Dr. Glass will attend
presentations and meetings during the course of the project as required.
6.1.3.1
Biography
Dr. Pamela Glass has over 10 years experience in viral vaccine, therapeutic, and animal
model development. Her scientific research experience includes methodologies in virology and
molecular biology with a focus on preventing disease by highly pathogenic viruses of humans for
the protection or treatment of the warfighter. Dr. Glass is Chief of the Viral Biology Department
and currently funded as Principal Investigator (PI) on three JSTO-DTRA projects, totaling over
$2M (FY12), aimed toward the development of vaccines or broad spectrum therapeutics as well
as animal model development. These projects include studies to examine the effectiveness and
targets of potential therapeutics against viruses in cell culture and animal models as well as
safety and efficacy of vaccines in animal models. In addition to her own projects, she actively
collaborates with several external investigators for vaccine development and therapeutic projects.
6.1.3.2
Education
B.S. in Biology and Microbiology, North Carolina State University, 1990

M.S. in Molecular Biology and Biotechnology, Hood College, 1995
Ph.D. in Virology, Baylor College of Medicine, 2001
6.1.3.3
Work Experience
Chief, Viral Biology Department

Virology Division
U.S. Army Medical Research Institute of Infectious Diseases
(2010 Present)
Research Microbiologist, Viral Biology Department

Virology Division
(2005 2010)
Scientist IV, Viral Biology Branch

Virology Division
Goldbelt Raven, Inc., contractor to USAMRIID
(2004 2005)
Principal Investigator Microbiologist, Viral Biology Branch

Virology Division
Clinical Research Management, Inc., contractor to USAMRIID
(2001 2004)
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Biological Laboratory Technician

Virology Division
(1992 1995)
Biological Laboratory Technician

Toxinology Division
(1991 1992)
Microbiologist
Microbiology Department
Uniformed Services University of the Health Sciences
(1990 1991)
6.1.3.4
Research Support
Completed Research Support

USAMRMC/DOD
Glass (PI)
(Feb 2002 Sep 2004)
USAMRIID-ILIR
Analysis and Alterations in Tropism: Efforts to Enhance Immunogenicity of Western Equine
Encephalitis and Eastern Equine Encephalitis Viruses.
Analysis and alteration of tropisms to enhance the immunogenicity of EEE and WEE viruses
for the production of better vaccines for EEE and WEE that are capable of protecting humans.
Role: PI
CUBRC/Prosetta
Glass (PI, Sub)
Noval Viral Biowarfare Agent ID and Treatement (NOVBAIT)
Role: Contract-PI
(Nov 2006 Present)
DTRA-JSTO, Core funding

Glass (PI)
(Oct 2009 Sep 2011)
Small Molecules with Pan-alphavirus Broad Spectrum Antiviral Activity
Role: PI
Co-PI: Dr. Vishwanatha Lingappa, Prosetta Bioconformatics, Inc.
Ongoing Research Support
Glass (PI)
(2001 Present)
Live, Attenuated Viruses for a Multiagent Equine Encephalitis Vaccine
Role: PI
Glass (PI)
(2001 Present)
Alphavirus Replicon Vaccines against equine encephalitis viruses
Role: PI
Glass (PI)
(Oct 2009 Present)
Development of Animal Models for Alphavirus Vaccine Efficacy Testing against Aerosolized
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EEE and WEE viruses

Role: PI
Glass (Co-PI)
(Oct 2009 Present)
Evaluation of FDA Approved Drugs against the Arenaviridae, Bunyaviridae, Filoviridae,
Flaviviridae, and Togaviridae (Alphaviruses)
Role: Co-PI
6.1.3.5
1993-present Member Phi Kappa Phi National Honor Society, Hood College Chapter
6.1.3.6
Bessaud, M., C.N. Peyrefitte, B.A.M. Pastorino, F. Rock, O. Merle, J. Colpart, J. Dehecq, R.
Girod, M. Jaffar-Bandjee, P.J. Glass, M. Parker, H.J. Tolou, and M. Grandadam. (2006).
Chikungunya Virus Strains, Reunion Island Outbreak. EID 12(10):1604-1606.
Gardner, C.L., C.W. Burke, M.Z. Tesfay, P.J. Glass, W.B. Klimstra, and K.D. Ryman. (2008).
Eastern and Venezuelan Equine Encephalitis Viruses Differ in Their Infectivity for Dendritic
Cells and Macrophages: The Impact of Altered Cell Tropism on Pathogenesis. J. Virol.,
82(21):10634-46.
Fine, D.L., Jenkins, E., Martin, S.S., Glass, P., Parker, M.D., and Grimm, B. (2010). A
multisystem approach for development and evaluation of inactivated vaccines for Venezuelan
Equine Encephalitis Virus (VEEV). J Virol. Methods, 163(2):424-32.
Martin, S.M., Baaken, R., Lind, C., Garcia, P., Jenkins, E., Glass, P.J., Parker, M.D., Hart,
M.K., and Fine, D.L. (2010). Evaluation of formalin inactivated V3526 virus with adjuvant as a
next generation vaccine candidate for Venezuelan equine encephalitis virus. Vaccine,
28(18):3143-51.
Martin, S.M., Bakken, R.R., Lind, C.M., Garcia, P., Jenkins, E., Glass, P.J., Parker, M.D., Hart,
M.K., and Fine, D.L. (2010). Comparison of the Immunological Responses and Efficacy of a
Gamma Irradiated V3526 Vaccines Against Subcutaneous and Aerosol Challenge with
Venezuelan Equine Encephalitis Virus Subtype IAB. Vaccine, 28(4):1031-40.
Parker, M.D., Buckley, M.J., Melanson, V.R., Glass, P.J., Norwood, D., and M.K. Hart. (2010).
Antibody to the E3 glycoprotein protects mice against lethal Venezuelan equine encephalitis.
Journal of Virology, 84(24):12683-90.
Sharma, A., Gupta, P., Glass, P.J., Parker, M.D., and R.K. Maheshwari. (2011). Safety and
Protective Efficacy of INA-inactivated Venezuelan Equine Encephalitis virus: Implications in
Vaccine Development. Vaccine, 29(5):953-959.
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6.1.4
David Onyabe, Ph.D.Cell Culture Scientist (BioFactura)
Dr. David Onyabe will serve as Cell Culture Scientist and will lead all molecular biology and
cell line development activities at BioFactura and assist the Project Manager with coordination
of cell culture activities at USAMRIID. He will also assist with resource planning and serve as a
key person for the monitoring and identification of triggers in the risk management strategy. Dr.
Onyabe will co-author all reports and presentations during the course of the project.
6.1.4.1
Biography
David Onyabe joined BioFactura in 2010 as Senior Scientist and currently leads stable cell
line development. Before joining BioFactura, he was Director of Vaccine Research at Bacilligen,
Inc. where he co-invented replication proficient recombinant dsRNA capsids, a novel RNA
vaccine delivery platform. He was responsible for designing recombinant dsRNA cassettes, for
designing assays for functional evaluation of recombinant dsRNA capsids, and for conducting
small animal studies. David previously held the position of Scientist at AERAS Global TB
Vaccine Foundation, where he was co-inventor of bacterial strains that expressed a prototype
recombinant RNA nucleocapsid system. While at AERAS, he also co-invented webbed HIV
envelope immunogens that display high valency epitopes. As a postdoctoral fellow, he worked
on designing conformationally constrained HIV-1 envelope immunogens and used said
immunogens to optimize vaccination regimen in small animal studies. In short, David is a highly
creative biotechnology professional with broad expertise in virology and molecular and cellular
biology. He has over 10 years experience in expression cassette design, stable cell line
development, pre-clinical animal studies, immune assay development, and a wide range of
molecular and cell culture techniques.
6.1.4.2
Education
B.S. in Zoology, University of Jos (Nigeria), 1989

M.S. in Zoology, Ahmadu Bello University (Nigeria), 1993
M.S. in Pest Management, Simon Fraser University (Canada), 1996
Ph.D. in Biology, University of Vermont, 2001
6.1.4.3
Work Experience
Senior Scientist
(2010 Present)
BioFactura, Inc.
Rockville, MD 20850
Developed formal quality control system in the cell culture laboratory for the generation of
regulatory-compliant production cell lines. Responsible for generation of stable cell lines that
express chimeric monoclonal antibodies. Performed optimization of transfection, selection, and
cloning protocols in NS0 and CHO-DG44 cells.
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Director of Vaccine Research

(2006 2010)
Bacilligen, Inc.
Rockville, MD 20850
Responsible for the development of recombinant BCG for cancer therapy. Completed the
detailed design of genetic inserts in recombinant BCG strains for use as improved bladder cancer
treatment. Performed and supervised the hands-on aspects of recombinant BCG strain
construction. Designed assays for functional evaluation of recombinant BCG strains. Supervised
laboratory team activities in strain screening and characterization assays. Responsible for the
development of recombinant double stranded RNA (dsRNA) capsid vaccines. Co-inventor of
replication proficient recombinant dsRNA capsids. Completed the detailed design of
recombinant dsRNA capsid segments. Performed and supervised the hands-on aspects of
recombinant dsRNA capsid construction. Designed assays for functional evaluation of
recombinant dsRNA capsid. Supervised laboratory team activities in capsid screening and
characterization assays. Responsible for day-to-day laboratory operations and budget
management.
Scientist, Vaccine Discovery
(2003 2006)
AERAS Global TB Vaccine Foundation
1405 Research Blvd # 300
Rockville, MD 20850
Responsible for the development of a recombinant dsRNA capsid system. Co-inventor of
recombinant double-stranded RNA nucleocapsid (rdsRN) system. Designed rdsRN platform and
method to launch and produce rdsRN in bacteria. Performed and directed hands-on aspects of
rdsRN development. Responsible for HIV vaccine development project. Co-inventor of new IP
on development of webbed HIV envelope immunogens that display high-valency epitopes. Coauthored two patents related to above inventions.
Postdoctoral Fellow, Division of Vaccine Research
(2001 2003)
University of Maryland Institute of Human Virology
725 West Lombard Street
Baltimore, MD 21201
Responsible for HIV vaccine development project. Designed conformationally constrained
HIV-1 immunogens. Optimized vaccination regimen using constrained HIV-1 immunogens in
small animal studies. Studied use of attenuated Salmonella as vaccine vector. Investigated
attenuated cholera toxin as a vaccine adjuvant to induce long lasting immune response.
6.1.4.4
Research Support - N/A
6.1.4.5
Honorable Mention, Entomological Society of America, 1999

Sidney Hogg Memorial Graduate Scholarship, Simon Fraser University, 1995
H.R. MacCarthy Graduate Scholarship, Simon Fraser University, 1995
Jos International Breweries Prize, University of Jos, 1989
BioFactura, Inc.
Page 94 of 218
6.1.4.6
Onyabe D.Y., T.R. Fouts, A.L. DeVico, G.K. Lewis, and D.M. Hone. Induction of durable hightiter serum antibodies to HIV-1 in human CD4-transgenic mice through vaccination with DNA
vaccines that express a conformationally constrained gp120. (In preparation).
Matthews SD, L.J Meehan, D.Y. Onyabe, J. Vineis, I. Nock, I. Ndams, and J.E. Conn (2007).
Evidence for late Pleistocene population expansion of the malarial mosquitoes, Anopheles
arabiensis and Anopheles gambiae in Nigeria. Medical and Veterinary Entomology 21:358-369.
Conn. J.E, J.H Vineis, J.P. Bollback, D.Y. Onyabe, R.C. Wilkerson, and M.M. Pvoa (2006).
Population structure of the malaria vector Anopheles darlingi in a malaria-endemic region of
eastern Amazonian Brazil. American Journal of Tropical Medicine and Hygiene 74:798-806.
Onyabe, D.Y., C.G. Vajime, I.H. Nock, I.S. Ndams, A. Akpa, A.A. Alaribe, and J.E. Conn
(2003). The distribution of M and S molecular forms of the malaria mosquito Anopheles
gambiae in Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene.
97:605-608.
Bagley, K.C., M.T. Shata, D.Y. Onyabe, A.L. DeVico, N.H. Carbonetti, T.R. Fouts, G.K. Lewis,
and D.M. Hone (2003) Induction of durable antibody responses by an HIV-1 gp120 DNA
vaccine that co-expresses the enzymatically active A1 domain of cholera toxin as an adjuvant.
Vaccine. 21:3335-3341.
Fouts T.R., A.L. DeVico, D.Y. Onyabe, M.T. Shata, K.C. Bagley, G.K. Lewis, and D.M. Hone
(2003). Progress toward the development of a bacterial vaccine vector that induces high-titer
long-lived broadly neutralizing antibodies against HIV-1. FEMS Immunol Med Microbiol.
37:129-134.
Hone, D.M., A.C. DeVico, T.R. Fouts, D.Y. Onyabe, S.M. Agwale, C.O. Wambebe, W.A.
Blattner, R.C. Gallo, and G.K. Lewis (2002). Development of vaccination strategies that elicit
broadly neutralizing antibodies against human immunodeficiency virus type 1 in both the
mucosal and systemic immune compartments. Journal of Human Virology 5:17-23.
Onyabe, D.Y. and J.E. Conn (2001). The population genetic structure of the malaria mosquito
Anopheles arabiensis across Nigeria suggests range expansion. Molecular Ecology 10: 25772591.
Onyabe, D.Y. and J.E. Conn (2001). Genetic differentiation of the malaria vector Anopheles
gambiae across Nigeria suggests that selection limits gene flow. Heredity 87: 647-658.
Onyabe, D.Y. and J.E. Conn (2001). The distribution of two major malaria vectors, Anopheles
gambiae and Anopheles arabiensis (Diptera: Culicidae), in Nigeria. Memorias do Instituto
Oswaldo Cruz 96: 1081-1084.
BioFactura, Inc.
Page 95 of 218
Conn, J. E., J.P. Bollback, D.Y. Onyabe, T.N. Robinson, R.C. Wilkerson, and M.M. Povoa
(2001). Isolation of polymorphic microsatellite markers from the malaria vector Anopheles
darlingi. Molecular Ecology Notes 1: 223-225.
Onyabe, D.Y. and J.E. Conn (1999). Intragenomic heterogeneity of a ribosomal DNA spacer
(ITS2) varies regionally in the neotropical malaria vector, Anopheles nuneztovari (Diptera:
Culicidae). Insect Molecular Biology 8:435-442.
Onyabe, D.Y., B.D. Roitberg, and W.G. Friend (1997). Feeding and mating strategies in
Anopheles (Diptera: Culicidae): theoretical modeling approach. Journal of Medical Entomology
34: 644-650.
Onyabe, D.Y. and B.D. Roitberg (1997). The effect of conspecifics on oviposition site selection
and oviposition behavior in Aedes togoi (Diptera: Culicidae). The Canadian Entomologist 129:
1173-1176.
PatentsPending and Issued
Hone D.M. and D.Y. Onyabe. US Patent: 7,537,769. Webbed immunogens comprising
recombinant human immunodeficiency virus (HIV) envelope glycoproteins and the M9 scorpion
toxin. Filed June 2, 2006; Awarded May 26, 2009.
Hone D.M., J. Fulkerson, J.C. Sadoff, D.Y Onyabe and M. Stone. US Patent: 8,053,568
Bacterial packaging strains useful for generation and production of recombinant double-stranded
phage nucleocapsids and uses thereof. Filed November 23, 2005; Awarded November 8, 2011.
Hone D.M. and D.Y. Onyabe. Webbed HIV envelope immunogens and methods for production
and use of same. US Patent and Trademark Office, Washington D.C., USA. Publ. No.
20070014814; Filed June 2006 (Pending).
Hone D.M. and D.Y. Onyabe. Replication-proficient dsRNA capsids and uses thereof. US
Patent and Trademark Office, Washington D.C., USA. Publ. No. US 2010/0322951 A1 Filed
Dec. 2007 (Pending).
BioFactura, Inc.
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6.2
CWBS Dictionary
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
VEE VRP Production Process
Development of a novel process for the scalable manufacture of VEE VRPbased vaccines in a stable suspension helper cell line.
1.1
Suspension Parental Cell Lines
Receipt, establishment, banking, and testing of parental sVero and EB66 cell
lines.
1.1.1
Working Cell Banks
Creation of working and, in the case of sVero, master cell banks for
suspension parental cell lines.
1.1.1.1
EB66 Cell Bank
Creation of a working cell bank for the EB66 parental cell line.
1.1.1.1.1
Milestone: Vendor Cell Vial and

Documentation Receipt
Receipt of a master cell bank vial of EB66 from vendor (Vivalis).
1.1.1.1.2
Thaw and Growth Evaluation
Thaw and confirmation of growth characteristics for the EB66 parental cell
line.
1.1.1.1.3
WCB Generation
Generation of a working cell bank for the EB66 parental cell line.
1.1.1.1.4
Milestone: EB66 Working Cell Bank
Completion of an EB66 parental cell line working cell bank.
1.1.1.2
sVero Cell Bank
Creation of accession, master and working cell banks for the EB66 parental
cell line.
1.1.1.2.1
Milestone: Vendor Cell Vial and

Documentation Receipt
Receipt of a cell bank vial of sVero from vendor (Zelltek).
BioFactura, Inc.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.1.2.2
Thaw and Growth Evaluation
Thaw and confirmation of growth characteristics for the sVero parental cell
line.
1.1.1.2.3
Accession Bank Generation
Generation of an accession cell bank for the sVero parental cell line.
1.1.1.2.4
Milestone: sVero ACB
Completion of sVero parental cell line accession cell bank.
1.1.1.2.5
PMCB Testing (Bioreliance)
Pre-master cell bank testing prior to sVero parental cell line master cell bank
generation.
1.1.1.2.6
Decision Point: MCB Generation
Go/no-go decision for sVero parental cell line master cell bank.
1.1.1.2.7
cGMP MCB Generation & Testing

(Bioreliance)
Generation of a master cell bank for the sVero parental cell line.
1.1.1.2.8
Milestone: sVero MCB
Completion of Vero parental cell line master cell bank.
1.1.1.2.9
WCB Generation
Generation of a working cell bank for the sVero parental cell line.
1.1.1.2.10
Milestone: sVero Working Cell Bank
Completion of sVero parental cell line working cell bank.
1.1.2
Reference VRP Production
Production of a reference lot of VEE VRP vaccine using current methods.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.2.1
VRP RNA Constructs Generation
Generation of VRP RNA constructs for electroporation of producer cell

lines.
1.1.2.1.1
Replicon RNA Construct
Generation of VRP replicon RNA construct for electroporation of producer

cell lines.
1.1.2.1.1.1
Bacterial Transformation
Transformation of competent E. coli with VRP replicon DNA plasmid.
1.1.2.1.1.2
Sequence Verification
Sequence verification of VRP replicon DNA plasmid.
1.1.2.1.1.3
Plasmid Preps
Medium-scale (giga) preparation of VRP replicon DNA plasmid.
1.1.2.1.1.4
Milestone: Replicon DNA Construct

Working Bank Prepared
Completion of replicon DNA construct working bank.
1.1.2.1.1.5
Plasmid Linearization/Purification
Restriction enzyme linearization and purification of VRP replicon DNA

plasmid.
1.1.2.1.1.6
RNA Generation
Transcription of linearized VRP replicon DNA plasmid and generation of

capped RNA.
1.1.2.1.2
GP Helper RNA Construct
Generation of VRP GP helper RNA construct for electroporation of producer

cell lines.
1.1.2.1.2.1
Transformation of competent E. coli with VRP GP helper DNA plasmid.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.2.1.2.2
Sequence verification of VRP GP helper DNA plasmid.
1.1.2.1.2.3
Plasmid Preps
Medium-scale (giga) preparation of VRP GP helper DNA plasmid.
1.1.2.1.2.4
Milestone: GP Helper DNA Construct

Completion of GP helper DNA construct working bank.
1.1.2.1.2.5
Restriction enzyme linearization and purification of VRP GP helper DNA

plasmid.
1.1.2.1.2.6
RNA Generation
Transcription of linearized VRP GP helper DNA plasmid and generation of

capped RNA.
1.1.2.1.3
C Helper RNA Construct
Generation of VRP C helper RNA construct for electroporation of producer

cell lines.
1.1.2.1.3.1
Transformation of competent E. coli with VRP C helper DNA plasmid.
1.1.2.1.3.2
Sequence verification of VRP C helper DNA plasmid.
1.1.2.1.3.3
Plasmid Preps
Medium-scale (giga) preparation of VRP C helper DNA plasmid.
1.1.2.1.3.4
Milestone: C Helper DNA Construct

Completion of C helper DNA construct working bank.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.2.1.3.5
Restriction enzyme linearization and purification of VRP C helper DNA

plasmid.
1.1.2.1.3.6
RNA Generation
Transcription of linearized VRP C helper DNA plasmid and generation of

capped RNA.
1.1.2.2
Vero Cell Line Expansion
Thaw and expansion of adherent Vero cell line.
1.1.2.3
Electroporation
Electroporation of adherent Vero cell line with three RNA constructs.
1.1.2.4
VRP Purification
Purification of VRP.
1.1.2.4.1
VRP Harvest
High salt harvest of VRP.
1.1.2.4.2
CPE Assay
Cytopathic effect assay of harvested VRP.
1.1.2.4.3
Decision Point:Absence of CPE

Go/No-Go
Go-no go decision for release of VRP from BSL-3 containment based on

negative results of cytopathic effect assay.
1.1.2.4.4
TFF Concentration/Diafiltration
Tangential flow filtration and diafiltration of VRP.
1.1.2.4.5
Cellufine Chromatography
Chromatography purification of VRP.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.2.4.6
SDS-PAGE Analysis
Sodium dodecyl sufate-polyacrylamide gel electrophoresis analysis of

purified VRP.
1.1.2.4.7
VRP Formulation/Storage
Formulation and storage of VRP.
1.1.2.4.8
Milestone: Purified VRP Reference

Material
Completion of production of purified VRP reference material.
1.1.3
VRP Production
Production of test lots of VEE VRP vaccine using current methods in

suspension parental cell lines.
1.1.3.1
VRP RNA Constructs Generation
Generation of VRP RNA constructs for electroporation of producer cell

lines.
1.1.3.1.1
Replicon RNA Construct
Generation of VRP replicon RNA construct for electroporation of producer

cell lines.
1.1.3.1.1.1

plasmid.
1.1.3.1.1.2
RNA Generation

capped RNA.
1.1.3.1.2
GP Helper RNA Construct
Generation of VRP GP helper RNA construct for electroporation of producer

cell lines.
1.1.3.1.2.1
Restriction enzyme linearization and purification of VRP GP helper DNA

plasmid.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.3.1.2.2
RNA Generation
Transcription of linearized VRP GP helper DNA plasmid and generation of

capped RNA.
1.1.3.1.3
C Helper RNA Construct
Generation of VRP C helper RNA construct for electroporation of producer

cell lines.
1.1.3.1.3.1
Restriction enzyme linearization and purification of VRP C helper DNA

plasmid.
1.1.3.1.3.2
RNA Generation
Transcription of linearized VRP C helper DNA plasmid and generation of

capped RNA.
1.1.3.2
VRP Production in EB66
Production of a test lot of VEE VRP vaccine using current methods in the
EB66 parental cell line.
1.1.3.2.1
Cell Line Expansion
Thaw and expansion of EB66 parental cell line.
1.1.3.2.2
Electroporation
Electroporation of EB66 parental cell line with three RNA constructs.
1.1.3.2.3
VRP Purification
1.1.3.2.3.1
VRP Harvest
1.1.3.2.3.2
CPE Assay
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.3.2.3.3

Go/No-Go

1.1.3.2.3.4
1.1.3.2.3.5
1.1.3.2.3.6
SDS-PAGE Analysis

purified VRP.
1.1.3.2.3.7
1.1.3.2.3.8
Milestone: Purified VRP Test

Material
Completion of production of purified VRP test material.
1.1.3.3
VRP Production in sVero
sVero parental cell line.
1.1.3.3.1
Cell Line Expansion
Thaw and expansion of sVero parental cell line.
1.1.3.3.2
Electroporation
Electroporation of sVero parental cell line with three RNA constructs.
1.1.3.3.3
VRP Purification
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.3.3.3.1
VRP Harvest
1.1.3.3.3.2
CPE Assay
1.1.3.3.3.3

Go/No-Go

1.1.3.3.3.4
1.1.3.3.3.5
1.1.3.3.3.6
SDS-PAGE Analysis

purified VRP.
1.1.3.3.3.7
1.1.3.3.3.8

Material
1.1.4
VRP Testing
VRP testing and comparison of purified VRP test materials with reference
materials.
1.1.4.1
VRP Titration
Determination and comparison of yield of VRP using an indirect

immunofluorescence assay.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.4.2
In-vitro Reactivity
Determination and comparison of identity and activity of VRP generated

antigen using an enzyme linked immunosorbent assay.
1.1.4.3
In-vivo Immunogenicity
Determination and comparison of immunogenicity of VRP using a murine

immunization protocol.
1.1.4.4
In-vivo Protection Assay
Determination and comparison of protective efficacy of VRP using a murine

VEE challenge protocol.
1.1.4.5
VRP Test Report Generation
Generation of a VRP test report.
1.1.4.6
Milestone: VRP Test Report
Completion of VRP test report.
1.1.5
Phase I Scientific and Technical

Report (CDRL A003)
Generation and review of Phase I Scientific and Technical Report.
1.1.5.1
Report Generation
Generation of Phase I Scientific and Technical Report.
1.1.5.2
Milestone: Report
Completion of Phase I Scientific and Technical Report.
1.1.5.3
Report Review
CBMS review of Phase I Scientific and Technical Report.
1.1.5.4
Decision Point: Cell Line Selection
Selection of one or both suspension parental cell lines for advancement to

Phase II (Suspension Helper Cell Lines).
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.1.6
Cell Bank Off-site Storage
Off-site storage of cell banks.
1.1.6.1
sVero MCB (Bioreliance)
Off-site storage of sVero parental cell line master cell bank.
1.2
Suspension Helper Cell Lines
Generation, testing, and banking of stable suspension helper cell lines.
1.2.1
EB66 Helper Cell Lines
Generation, expression testing, and accession cell banking of stable EB66

helper cell lines.
1.2.1.1
Lac Induction System
Generation, expression testing, and accession cell banking of stable EB66Lac helper cell lines.
1.2.1.1.1
Lac Expression Vector Construction
Design, construction, and expression testing of Lac expression vector for

EB66 cell line.
1.2.1.1.1.1
Vector Design
Design of Lac expression vector for EB66 cell line.
1.2.1.1.1.2
Gene Synthesis (Geneart)
Synthesis of VEE VRP structural genes for Lac expression vector for EB66
cell line.
1.2.1.1.1.3
Vector Construction
Construction of Lac expression vector for EB66 cell line.
1.2.1.1.1.4
Transient Transfection
Expression testing of Lac expression vector for EB66 cell line.
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NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.1.1.1.5
Milestone: Expression Confirmation
Confirmation of expression of VEE VRP structural proteins of Lac

expression vector for EB66 cell line.
1.2.1.1.2
Parental Cell Line Transfection
Transfection of EB66 parental cell line with Lac expression vector.
1.2.1.1.3
Stable Cell Line Selection
Selection of stable pools of EB66-Lac helper cell lines.
1.2.1.1.4
Preliminary Induction Study
Preliminary study to confirm inducible expression of VEE VRP structural

proteins in stable pools of EB66-Lac helper cell lines.
1.2.1.1.5
Decision Point: Expression

Confirmation
Confirmation of expression of VEE VRP structural proteins by stable pools

of EB66-Lac helper cell lines.
1.2.1.1.6
Clonal Selection
Selection of best performing clonal stable EB66-Lac helper cell lines by

limiting dilution and testing of VEE VRP structural protein expression upon
induction.
1.2.1.1.7
Milestone: Stable Helper Cell Line
Completion of generation of clonal stable EB66-Lac helper cell lines.
1.2.1.1.8
Generation and testing of accession cell banks for clonal stable EB66-Lac
helper cell lines.
1.2.1.1.8.1
Generation of accession cell banks for clonal stable EB66-Lac helper cell
lines.
1.2.1.1.8.2
ACB Testing (Bioreliance)
Testing of accession cell banks for sterility and mycoplasma for clonal stable
EB66-Lac helper cell lines.
BioFactura, Inc.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.1.1.8.3
Milestone: EB66-Lac ACB
Completion of generation of accession cell banks for clonal stable EB66-Lac

helper cell lines.
1.2.1.2
Tet Induction System
Generation, expression testing, and accession cell banking of stable EB66Tet helper cell lines.
1.2.1.2.1
Tet Expression Vector Construction
Design, construction, and expression testing of Tet expression vector for

EB66 cell line.
1.2.1.2.1.1
Vector Design
Design of Tet expression vector for EB66 cell line.
1.2.1.2.1.2
Synthesis of VEE VRP structural genes for Tet expression vector for EB66
cell line.
1.2.1.2.1.3
Vector Construction
Construction of Tet expression vector for EB66 cell line.
1.2.1.2.1.4
Expression testing of Tet expression vector for EB66 cell line.
1.2.1.2.1.5
Confirmation of expression of VEE VRP structural proteins of Tet

expression vector for EB66 cell line.
1.2.1.2.2
Transfection of EB66 parental cell line with Tet expression vector.
1.2.1.2.3
Selection of stable pools of EB66-Tet helper cell lines.
BioFactura, Inc.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.1.2.4

proteins in stable pools of EB66-Tet helper cell lines.
1.2.1.2.5

Confirmation

of EB66-Tet helper cell lines.
1.2.1.2.6
Clonal Selection
Selection of best performing clonal stable EB66-Tet helper cell lines by

induction.
1.2.1.2.7
Completion of generation of clonal stable EB66-Tet helper cell lines.
1.2.1.2.8
Generation and testing of accession cell banks for clonal stable EB66-Tet
helper cell lines.
1.2.1.2.8.1
Generation of accession cell banks for clonal stable EB66-Tet helper cell
lines.
1.2.1.2.8.2
EB66-Tet helper cell lines.
1.2.1.2.8.3
Milestone: EB66-Tet ACB
Completion of generation of accession cell banks for clonal stable EB66-Tet

helper cell lines.
1.2.2
sVero Helper Cell Lines
Generation, expression testing, and accession cell banking of stable sVero

helper cell lines.
1.2.2.1
Lac Induction System
Generation, expression testing, and accession cell banking of stable sVeroLac helper cell lines.
BioFactura, Inc.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.2.1.1
Lac Expression Vector Construction
Design, construction, and expression testing of Lac expression vector for

sVero cell line.
1.2.2.1.1.1
Vector Design
Design of Lac expression vector for sVero cell line.
1.2.2.1.1.2
Synthesis of VEE VRP structural genes for Lac expression vector for sVero
cell line.
1.2.2.1.1.3
Vector Construction
Construction of Lac expression vector for sVero cell line.
1.2.2.1.1.4
Expression testing of Lac expression vector for sVero cell line.
1.2.2.1.1.5
Confirmation of expression of VEE VRP structural proteins of Lac

expression vector for sVero cell line.
1.2.2.1.2
Transfection of sVero parental cell line with Lac expression vector.
1.2.2.1.3
Selection of stable pools of sVero-Lac helper cell lines.
1.2.2.1.4

proteins in stable pools of sVero-Lac helper cell lines.
1.2.2.1.5

Confirmation

of sVero-Lac helper cell lines.
BioFactura, Inc.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.2.1.6
Clonal Selection
Selection of best performing clonal stable sVero-Lac helper cell lines by

induction.
1.2.2.1.7
Completion of generation of clonal stable sVero-Lac helper cell lines.
1.2.2.1.8
Generation and testing of accession cell banks for clonal stable sVero-Lac
helper cell lines.
1.2.2.1.8.1
Generation of accession cell banks for clonal stable sVero-Lac helper cell
lines.
1.2.2.1.8.2
sVero-Lac helper cell lines.
1.2.2.1.8.3
Milestone: sVero-Lac ACB
Completion of generation of accession cell banks for clonal stable sVero-Lac

helper cell lines.
1.2.2.2
Tet Induction System
Generation, expression testing, and accession cell banking of stable sVeroTet helper cell lines.
1.2.2.2.1
Tet Expression Vector Construction
Design, construction, and expression testing of Tet expression vector for

sVero cell line.
1.2.2.2.1.1
Vector Design
Design of Tet expression vector for sVero cell line.
1.2.2.2.1.2
Synthesis of VEE VRP structural genes for Tet expression vector for sVero
cell line.
BioFactura, Inc.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.2.2.1.3
Vector Construction
Construction of Tet expression vector for sVero cell line.
1.2.2.2.1.4
Expression testing of Tet expression vector for sVero cell line.
1.2.2.2.1.5
Confirmation of expression of VEE VRP structural proteins of Tet

expression vector for sVero cell line.
1.2.2.2.2
Transfection of sVero parental cell line with Tet expression vector.
1.2.2.2.3
Selection of stable pools of sVero-Tet helper cell lines.
1.2.2.2.4

proteins in stable pools of sVero-Tet helper cell lines.
1.2.2.2.5

Confirmation

of sVero-Tet helper cell lines.
1.2.2.2.6
Clonal Selection
Selection of best performing clonal stable sVero-Tet helper cell lines by

induction.
1.2.2.2.7
Completion of generation of clonal stable sVero-Tet helper cell lines.
1.2.2.2.8
Generation and testing of accession cell banks for clonal stable sVero-Tet
helper cell lines.
BioFactura, Inc.
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CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.2.2.8.1
Generation of accession cell banks for clonal stable sVero-Tet helper cell
lines.
1.2.2.2.8.2
sVero-Tet helper cell lines.
1.2.2.2.8.3
Milestone: sVero-Tet ACB
Completion of generation of accession cell banks for clonal stable sVero-Tet

helper cell lines.
1.2.3
VRP Production
Production of test lots of VEE VRP vaccine using current methods in the
stable helper cell lines.
1.2.3.1
Replicon RNA Construct Generation
Generation of VRP replicon RNA construct for electroporation of stable

helper cell lines.
1.2.3.1.1

plasmid.
1.2.3.1.2
RNA Generation

capped RNA.
1.2.3.2
VRP Production in EB66-Lac
EB66-Lac stable helper cell line.
1.2.3.2.1
Cell Line Expansion
Thaw and expansion of EB66-Lac stable helper cell line.
1.2.3.2.2
Transfection
Induction and electroporation of EB66-Lac stable helper cell line.
BioFactura, Inc.
Page 114 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.3.2.2.1
Stable Helper Cell Line Induction
Induction of EB66-Lac stable helper cell line.
1.2.3.2.2.2
Electroporation
Electroporation of EB66-Lac stable helper cell line VRP replicon RNA

construct.
1.2.3.2.3
VRP Purification
1.2.3.2.3.1
VRP Harvest
1.2.3.2.3.2
CPE Assay
1.2.3.2.3.3

Go/No-Go

1.2.3.2.3.4
1.2.3.2.3.5
1.2.3.2.3.6
SDS-PAGE Analysis

purified VRP.
1.2.3.2.3.7
BioFactura, Inc.
Page 115 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.3.2.3.8

Material
1.2.3.3
VRP Production in EB66-Tet
EB66-Tet stable helper cell line.
1.2.3.3.1
Cell Line Expansion
Thaw and expansion of EB66-Tet stable helper cell line.
1.2.3.3.2
Transfection
Induction and electroporation of EB66-Lac stable helper cell line.
1.2.3.3.2.1
Induction of EB66-Tet stable helper cell line.
1.2.3.3.2.2
Electroporation
Electroporation of EB66-Tet stable helper cell line VRP replicon RNA

construct.
1.2.3.3.3
VRP Purification
1.2.3.3.3.1
VRP Harvest
1.2.3.3.3.2
CPE Assay
1.2.3.3.3.3

Go/No-Go

BioFactura, Inc.
Page 116 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.3.3.3.4
1.2.3.3.3.5
1.2.3.3.3.6
SDS-PAGE Analysis

purified VRP.
1.2.3.3.3.7
1.2.3.3.3.8

Material
1.2.3.4
VRP Production in sVero-Lac
sVero-Lac stable helper cell line.
1.2.3.4.1
Cell Line Expansion
Thaw and expansion of sVero-Lac stable helper cell line.
1.2.3.4.2
Transfection
Induction and electroporation of sVero-Lac stable helper cell line.
1.2.3.4.2.1
Induction of sVero-Lac stable helper cell line.
1.2.3.4.2.2
Electroporation
Electroporation of sVero-Lac stable helper cell line VRP replicon RNA

construct.
BioFactura, Inc.
Page 117 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.3.4.3
VRP Purification
1.2.3.4.3.1
VRP Harvest
1.2.3.4.3.2
CPE Assay
1.2.3.4.3.3

Go/No-Go

1.2.3.4.3.4
1.2.3.4.3.5
1.2.3.4.3.6
SDS-PAGE Analysis

purified VRP.
1.2.3.4.3.7
1.2.3.4.3.8

Material
1.2.3.5
VRP Production in sVero-Tet
sVero-Tet stable helper cell line.
BioFactura, Inc.
Page 118 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.3.5.1
Cell Line Expansion
Thaw and expansion of sVero-Tet stable helper cell line.
1.2.3.5.2
Transfection
Induction and electroporation of sVero-Lac stable helper cell line.
1.2.3.5.2.1
Induction of sVero-Tet stable helper cell line.
1.2.3.5.2.2
Electroporation
Electroporation of sVero-Tet stable helper cell line VRP replicon RNA

construct.
1.2.3.5.3
VRP Purification
1.2.3.5.3.1
VRP Harvest
1.2.3.5.3.2
CPE Assay
1.2.3.5.3.3

Go/No-Go

1.2.3.5.3.4
1.2.3.5.3.5
BioFactura, Inc.
Page 119 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.3.5.3.6
SDS-PAGE Analysis

purified VRP.
1.2.3.5.3.7
1.2.3.5.3.8

Material
1.2.4
VRP Testing
materials.
1.2.4.1
VRP Titration

1.2.4.2
In-vitro Reactivity
Determination and comparison of identity and activity of VRP using an

enzyme linked immunosorbent assay.
1.2.4.3

1.2.4.4
In-vivo protection assay

1.2.4.5
1.2.4.6
BioFactura, Inc.
Page 120 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.5
Phase II Scientific and Technical

Report (CDRL A003)
Generation and review of Phase II Scientific and Technical Report.
1.2.5.1
Report Generation
Generation of Phase II Scientific and Technical Report.
1.2.5.2
Milestone: Report
Completion of Phase II Scientific and Technical Report.
1.2.5.3
Report Review
CBMS review of Phase II Scientific and Technical Report.
1.2.5.4
Decision Point: Stable Helper Cell

Line Selection
Selection of best performing stable helper cell lines for advancement to

Phase III (Induction/Transduction Optimization).
1.2.6

(Bioreliance)
1.2.6.1
sVero MCB
1.2.6.2
Stable Helper Cell Line Pools
Off-site storage of stable helper cell line pool cell banks.
1.2.6.2.1
EB66 - Lac
Off-site storage of stable EB66-Lac helper cell line pool cell bank.
1.2.6.2.2
EB66 - Tet
Off-site storage of stable EB66-Tet helper cell line pool cell bank.
BioFactura, Inc.
Page 121 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.2.6.2.3
sVero - Lac
Off-site storage of stable sVero-Lac helper cell line pool cell bank.
1.2.6.2.4
sVero - Tet
Off-site storage of stable sVero-Tet helper cell line pool cell bank.
1.3
Induction/Transduction Optimization
Induction and transduction optimization using stable helper cell lines and
VEE VRP.
1.3.1
Preliminary Transduction Study
Determination of transduction efficiency of parental EB66 and sVero cell

lines with VEE VRP.
1.3.1.1
Cell Lines Expansion
Expansion of parental cell lines.
1.3.1.1.1
sVero
Expansion of sVero parental cell line.
1.3.1.1.2
EB66
Expansion of EB66 parental cell line.
1.3.1.1.3
Adherent Vero
Expansion of adherent Vero parental cell line.
1.3.1.2
Transduction
Transduction of parental cell lines with VEE VRP and testing of efficiency
and gene-of-interest expression.
1.3.1.2.1
Transduction of all three cell lines at

multiple M.O.I.s
Transduction of parental cell lines with VEE VRP at different multiplicities

of infection.
BioFactura, Inc.
Page 122 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.1.2.2
In-vitro Reactivity
Determination and comparison of identity and activity of VRP generated

antigen using an enzyme linked immunosorbent assay.
1.3.1.2.3
Decision Point: Parental Suspension

Cell Lines Transduction Suitability
Selection of parental cell lines with acceptable VRP transduction

efficiencies.
1.3.2
Induction/Transduction Optimization
Induction and transduction optimization using selected stable helper cell

lines and VEE VRP.
1.3.2.1
VRP Production - Lac Cell Lines
VRP production study using selected Lac-inducible stable helper cell lines
and VEE VRP.
1.3.2.1.1
Lac Cell Lines Expansion
Expansion of selected Lac-inducible stable helper cell lines.
1.3.2.1.1.1
sVero Thaw and Expansion
Thaw and expansion of selected Lac-inducible sVero stable helper cell lines.
1.3.2.1.1.2
EB66 Thaw and Expansion
Thaw and expansion of selected Lac-inducible EB66 stable helper cell lines.
1.3.2.1.2
Induction at multiple IPTG

concentrations and times
Induction of selected Lac-inducible stable helper cell lines at multiple IPTG

concentrations and times.
1.3.2.1.3
Transduction at Multiple MOIs
Transduction of selected Lac-inducible stable helper cell lines with VEE

VRP at different multiplicities of infection.
1.3.2.1.4
VRP Harvest
BioFactura, Inc.
Page 123 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.2.2
VRP Production - Tet Cell Lines
VRP production study using selected Tet-inducible stable helper cell lines
and VEE VRP.
1.3.2.2.1
Tet Cell Lines Expansion
Expansion of selected Tet-inducible stable helper cell lines.
1.3.2.2.1.1
sVero Thaw and Expansion
Thaw and expansion of selected Tet-inducible sVero stable helper cell lines.
1.3.2.2.1.2
EB66 Thaw and Expansion
Thaw and expansion of selected Tet-inducible EB66 stable helper cell lines.
1.3.2.2.2
Induction at multiple doxycycline

concentrations and times
Induction of selected Tet-inducible stable helper cell lines at multiple

doxycycline concentrations and times.
1.3.2.2.3
Transduction at Multiple MOIs
Transduction of selected Tet-inducible stable helper cell lines with VEE

VRP at different multiplicities of infection.
1.3.2.2.4
VRP Harvest
1.3.2.3
VRP Testing
Testing of harvested VRP.
1.3.2.3.1
CPE Assay
1.3.2.3.2
VRP Titration

BioFactura, Inc.
Page 124 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.2.3.3
In-vitro Reactivity

1.3.2.3.4
Decision Point: Selection of Systems

for VRP Production Testing
Selection of two best performing systems for advancement to VRP

production and in vivo testing.
1.3.3
VRP Production
Production of test lots of VEE VRP vaccine using two best performing
systems in the stable helper cell lines.
1.3.3.1
VRP Production in System #1
Production of a test lot of VEE VRP vaccine using best performing System
#1.
1.3.3.1.1
Cell Line Expansion
Thaw and expansion of System #1 stable helper cell line.
1.3.3.1.2
Induction
Induction of System #1 stable helper cell line.
1.3.3.1.3
Transduction
Transduction of System #1 stable helper cell line.
1.3.3.1.4
VRP Purification
1.3.3.1.4.1
VRP Harvest
1.3.3.1.4.2
CPE Assay
BioFactura, Inc.
Page 125 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.3.1.4.3

Go/No-Go

1.3.3.1.4.4
1.3.3.1.4.5
1.3.3.1.4.6
SDS-PAGE Analysis

purified VRP.
1.3.3.1.4.7
1.3.3.1.4.8

Material
1.3.3.2
VRP Production in System #2
Production of a test lot of VEE VRP vaccine using best performing System
#2.
1.3.3.2.1
Cell Line Expansion
Thaw and expansion of System #2 stable helper cell line.
1.3.3.2.2
Induction
Induction of System #2 stable helper cell line.
1.3.3.2.3
Transduction
Transduction of System #2 stable helper cell line.
BioFactura, Inc.
Page 126 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.3.2.4
VRP Purification
1.3.3.2.4.1
VRP Harvest
1.3.3.2.4.2
CPE Assay
1.3.3.2.4.3

Go/No-Go

1.3.3.2.4.4
1.3.3.2.4.5
1.3.3.2.4.6
SDS-PAGE Analysis

purified VRP.
1.3.3.2.4.7
1.3.3.2.4.8

Material
1.3.4
VRP Testing
materials.
BioFactura, Inc.
Page 127 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.4.1
VRP Titration
Determination and comparison of yeild of VRP using an indirect

1.3.4.2
In-vitro Reactivity

1.3.4.3

1.3.4.4

1.3.4.5
1.3.4.6
1.3.5
Helper Cell Line Banking
Generation and testing of cell banks for the System #1 and System #2 stable
helper cell lines.
1.3.5.1
Generation of accession cell banks for the System #1 and System #2 stable
helper cell lines.
1.3.5.2
Milestone: Helper Cell Line ACB
Completion of accession cell banks for the System #1 and System #2 stable
helper cell lines.
1.3.5.3
PMCB Testing (Bioreliance)
Pre-master cell bank testing prior to best performing System #1 or System #2

stable helper cell line master cell bank generation.
BioFactura, Inc.
Page 128 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.5.4
Decision Point: MCB Generation
Selection of best performing stable helper cell line for generation of cGMP
master cell bank.
1.3.5.5
cGMP MCB Generation & Testing

(Bioreliance)
Generation of a master cell bank for the best performing stable helper cell
line.
1.3.5.6
Milestone: Helper Cell Line MCB
Completion of best performing stable helper cell line master cell bank.
1.3.6
Phase III Scientific and Technical

Report (CDRL A003)
Generation and review of Phase II Scientific and Technical Report.
1.3.6.1
Report Generation
Generation of Phase II Scientific and Technical Report.
1.3.6.2
Milestone: Report
Completion of Phase II Scientific and Technical Report.
1.3.6.3
Report Review
CBMS review of Phase II Scientific and Technical Report.
Decision Point: Selection of

Production System for Process
Development
(Bioreliance)
Selection of best performing production system for advancement to Phase IV

(Process Development).
sVero MCB
1.3.6.4
1.3.7
1.3.7.1
BioFactura, Inc.
Page 129 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.3.7.2
1.3.7.2.1
EB66 - Lac
1.3.7.2.2
EB66 - Tet
1.3.7.2.3
sVero - Lac
1.3.7.2.4
sVero - Tet
1.3.7.3
Helper Cell Line MCB
Off-site storage of best performing stable helper cell line master cell bank.
1.4
Process Development
Preliminary process development, scale-up, and consistency testing of best

performing production system.
1.4.1
Batch Medium Optimization
Optimization of production batch medium.
1.4.1.1
Timecourse Evaluation of Spent

Medium-No Induction
Timecourse evaluation of spent medium during a batch-mode production

process.
1.4.1.1.1
Cell Line Expansion
Expansion of stable helper cell line.
BioFactura, Inc.
Page 130 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.1.1.2
Shaker Timecourse Study
Shaker flask timecourse study in batch-mode.
1.4.1.1.3
Carbon Source Analysis
Analysis of primary carbon source uptake.
1.4.1.1.4
Amino Acid Analysis
Analysis of amino acid uptake.
1.4.1.2
Reformulation and Testing of Initial

Carbon Source Concentrations-No
Induction
Timecourse evaluation of reformulated spent medium during a batch-mode

production process.
1.4.1.2.1
1.4.1.2.2
Carbon Source Analysis
1.4.1.2.3
Amino Acid Analysis (HPLC)
1.4.1.3
Reformulation and Testing of

Optimized Batch Medium-With
Induction
Timecourse evaluation of reformulated spent medium during a batch-mode

production process with induction of expression of VEE VRP structural
proteins.
1.4.1.3.1
1.4.1.3.2
Carbon Source Analysis (biochemistry

analysis)
BioFactura, Inc.
Page 131 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.1.3.3
1.4.1.3.4
VEE Protein Expression Analysis

(ELISA)
Analysis of expression of VEE VRP structural proteins by enzyme linked

immunosorbent assay.
1.4.2
Feed Supplement Optimization
Optimization of production feed supplement.
1.4.2.1
Primary Carbon Feed Study-No

Induction
Timecourse evaluation of spent medium during primary carbon source fed

batch-mode production process.
1.4.2.1.1
Shaker flask timecourse study in fed batch-mode.
1.4.2.1.2

analysis)
1.4.2.1.3
1.4.2.2
Primary Carbon Plus Amino Acids

Feed Study-No Induction
Timecourse evaluation of spent medium during primary carbon source plus

amino acids fed batch-mode production process.
1.4.2.2.1
Shaker flask timecourse study in fed batch-mode.
1.4.2.2.2

analysis)
BioFactura, Inc.
Page 132 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.2.2.3
1.4.2.3
Custom Feed Studies Plus

Supplements-No Induction
Timecourse evaluation of spent medium during primary carbon source plus

amino acids plus supplements fed batch-mode production process.
1.4.2.3.1
MEM Vitamins Addition Study
Shaker flask timecourse study in fed batch-mode with MEM vitamins

addition.
1.4.2.3.2
Yeast Extract Addition Study
Shaker flask timecourse study in fed batch-mode with yeast extract addition.
1.4.2.3.3
Sodium Pyruvate Addition Study
Shaker flask timecourse study in fed batch-mode with sodium pyruvate

addition.
1.4.2.3.4
Selenium Addition Study
Shaker flask timecourse study in fed batch-mode with selenium addition.
1.4.2.3.5

analysis)
1.4.2.3.6
1.4.2.4
Milestone: Feed/Supplement Strategy
Selection of best performing batch formulation and feed/supplement strategy

for advancement to Pilot Production.
1.4.3
Pilot Production
Pilot production study using best performing batch formulation and

feed/supplement strategy prior to 5L bioreactor engineering runs.
BioFactura, Inc.
Page 133 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.3.1
Cell Line Expansion
Thaw and expansion of stable helper cell line using batch formulation and
feed/supplement strategy.
1.4.3.2
Induction
Induction of stable helper cell line.
1.4.3.3
Transduction
Transduction of stable helper cell line.
1.4.3.4
VRP Recovery
Recovery of VRP.
1.4.3.4.1
VRP Harvest
1.4.3.4.2
CPE Assay
1.4.3.4.3

Go/No-Go

1.4.3.5

analysis)
1.4.3.6
Amino Acid Analysis
1.4.3.7
VRP Testing
materials.
BioFactura, Inc.
Page 134 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.3.7.1
VRP Titration

1.4.3.7.2
In-vitro Reactivity

1.4.3.8
Decision Point: Process scale-up

Go/No-go
Go/no-go decision for scale-up of process to 5L bioreactor engineering runs.
1.4.4
5L Process Scale-up
Scale-up of process to 5L bioreactor engineering runs and consistency

testing.
1.4.4.1
Engineering Run #1
5L bioreactor Engineering Run #1.
1.4.4.1.1
Cell Line Expansion
1.4.4.1.2
Induction
1.4.4.1.3
Transduction
1.4.4.1.4
VRP Purification
1.4.4.1.4.1
VRP Harvest
BioFactura, Inc.
Page 135 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.4.1.4.2
CPE Assay
1.4.4.1.4.3

Go/No-Go

1.4.4.1.4.4
1.4.4.1.4.5
1.4.4.1.4.6
SDS-PAGE Analysis

purified VRP.
1.4.4.1.4.7
1.4.4.1.4.8

Material
1.4.4.2
Engineering Run #2
1.4.4.2.1
Cell Line Expansion
1.4.4.2.2
Induction
BioFactura, Inc.
Page 136 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.4.2.3
Transduction
1.4.4.2.4
VRP Purification
1.4.4.2.4.1
VRP Harvest
1.4.4.2.4.2
CPE Assay
1.4.4.2.4.3

Go/No-Go

1.4.4.2.4.4
1.4.4.2.4.5
1.4.4.2.4.6
SDS-PAGE Analysis

purified VRP.
1.4.4.2.4.7
1.4.4.2.4.8

Material
BioFactura, Inc.
Page 137 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.4.3
Engineering Run #3
1.4.4.3.1
Cell Line Expansion
1.4.4.3.2
Induction
1.4.4.3.3
Transduction
1.4.4.3.4
VRP Purification
1.4.4.3.4.1
VRP Harvest
1.4.4.3.4.2
CPE Assay
1.4.4.3.4.3

Go/No-Go

1.4.4.3.4.4
1.4.4.3.4.5
BioFactura, Inc.
Page 138 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.4.3.4.6
SDS-PAGE Analysis

purified VRP.
1.4.4.3.4.7
1.4.4.3.4.8

Material
1.4.5
VRP Testing
materials.
1.4.5.1
VRP Titration

1.4.5.2
In-vitro Reactivity

1.4.5.3

1.4.5.4

1.4.5.5
1.4.5.6
BioFactura, Inc.
Page 139 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.6
Phase IV Scientific and Technical

Report (CDRL A003)
Generation and review of Phase IV Scientific and Technical Report.
1.4.6.1
Report Generation
Generation of Phase IV Scientific and Technical Report.
1.4.6.2
Milestone: Report
Completion of Phase IV Scientific and Technical Report.
1.4.6.3
Report Review
CBMS review of Phase IV Scientific and Technical Report.
1.4.7

(Bioreliance)
1.4.7.1
sVero MCB
1.4.7.2
1.4.7.2.1
EB66 - Lac
1.4.7.2.2
EB66 - Tet
1.4.7.2.3
sVero - Lac
BioFactura, Inc.
Page 140 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.4.7.2.4
sVero - Tet
1.4.7.3
Helper Cell Line MCB
Off-site storage of best performing stable helper cell line master cell bank.
1.5
Project Management
Project Management section
1.5.1
Project Start & Finish
Start and end of project activities
1.5.1.1
Decision Point: Contract Award
Official notification by Government of award of contract
1.5.1.2
Milestone: Project Start
Initiation of project technical activities
1.5.1.3
Milestone: Project Completion
Completion of project technical activities
1.5.2
Program Reporting & Meetings
Program Reporting & Meetings section
1.5.2.1
Project Kick-off Meeting
Meeting of all stakeholders (Biofactura, USAMRIID subcontractor,

Government representative)
1.5.2.2
Contractor Progress, Status, and

Management Report & IMS ( CDRL
A001 & A002)
Contractor Progress, Status, and Management Report & IMS ( CDRL A001
& A002) section
BioFactura, Inc.
Page 141 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.1
CPR Report 1
Monthly CPR report & IMS update
1.5.2.2.1.1
Report Generation
Monthly CPR report generation & IMS update
1.5.2.2.1.2
Milestone: Report Submitted
Monthly CPR report & IMS submission
1.5.2.2.2
CPR Report 2
1.5.2.2.2.1
Report Generation
1.5.2.2.2.2
1.5.2.2.3
CPR Report 3
1.5.2.2.3.1
Report Generation
1.5.2.2.3.2
1.5.2.2.4
CPR Report 4
BioFactura, Inc.
Page 142 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.4.1
Report Generation
1.5.2.2.4.2
1.5.2.2.5
CPR Report 5
1.5.2.2.5.1
Report Generation
1.5.2.2.5.2
1.5.2.2.6
CPR Report 6
1.5.2.2.6.1
Report Generation
1.5.2.2.6.2
1.5.2.2.7
CPR Report 7
1.5.2.2.7.1
Report Generation
BioFactura, Inc.
Page 143 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.7.2
1.5.2.2.8
CPR Report 8
1.5.2.2.8.1
Report Generation
1.5.2.2.8.2
1.5.2.2.9
CPR Report 9
1.5.2.2.9.1
Report Generation
1.5.2.2.9.2
1.5.2.2.10
CPR Report 10
1.5.2.2.10.1
Report Generation
1.5.2.2.10.2
BioFactura, Inc.
Page 144 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.11
CPR Report 11
1.5.2.2.11.1
Report Generation
1.5.2.2.11.2
1.5.2.2.12
CPR Report 12
1.5.2.2.12.1
Report Generation
1.5.2.2.12.2
1.5.2.2.13
CPR Report 13
1.5.2.2.13.1
Report Generation
1.5.2.2.13.2
1.5.2.2.14
CPR Report 14
BioFactura, Inc.
Page 145 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.14.1
Report Generation
1.5.2.2.14.2
1.5.2.2.15
CPR Report 15
1.5.2.2.15.1
Report Generation
1.5.2.2.15.2
1.5.2.2.16
CPR Report 16
1.5.2.2.16.1
Report Generation
1.5.2.2.16.2
1.5.2.2.17
CPR Report 17
1.5.2.2.17.1
Report Generation
BioFactura, Inc.
Page 146 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.17.2
1.5.2.2.18
CPR Report 18
1.5.2.2.18.1
Report Generation
1.5.2.2.18.2
1.5.2.2.19
CPR Report 19
1.5.2.2.19.1
Report Generation
1.5.2.2.19.2
1.5.2.2.20
CPR Report 20
1.5.2.2.20.1
Report Generation
1.5.2.2.20.2
BioFactura, Inc.
Page 147 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.21
CPR Report 21
1.5.2.2.21.1
Report Generation
1.5.2.2.21.2
1.5.2.2.22
CPR Report 22
1.5.2.2.22.1
Report Generation
1.5.2.2.22.2
1.5.2.2.23
CPR Report 23
1.5.2.2.23.1
Report Generation
1.5.2.2.23.2
1.5.2.2.24
CPR Report 24
BioFactura, Inc.
Page 148 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.2.24.1
Report Generation
1.5.2.2.24.2
1.5.2.3
CDRL A004 Quarterly Program

Review
CDRL A004 Quarterly Program Review section
1.5.2.3.1
Quarterly Program Review 1
Quarterly Program Review
1.5.2.3.1.1
Presentation Preparation
Quarterly Program Review presentation preparation
1.5.2.3.1.2
Milestone: Presentation Submitted
Quarterly Program Review presentation submitted for review prior to the

briefing
1.5.2.3.1.3
Quarterly Briefing
Quarterly Program Review Government briefing
1.5.2.3.2
1.5.2.3.2.1
1.5.2.3.2.2

briefing
BioFactura, Inc.
Page 149 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.3.2.3
Quarterly Briefing
1.5.2.3.3
1.5.2.3.3.1
1.5.2.3.3.2

briefing
1.5.2.3.3.3
Quarterly Briefing
1.5.2.3.4
1.5.2.3.4.1
1.5.2.3.4.2

briefing
1.5.2.3.4.3
Quarterly Briefing
1.5.2.3.5
BioFactura, Inc.
Page 150 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.3.5.1
1.5.2.3.5.2

briefing
1.5.2.3.5.3
Quarterly Briefing
1.5.2.3.6
1.5.2.3.6.1
1.5.2.3.6.2

briefing
1.5.2.3.6.3
Quarterly Briefing
1.5.2.3.7
1.5.2.3.7.1
1.5.2.3.7.2

briefing
BioFactura, Inc.
Page 151 of 218
CWBS
NUMBER
CWBS
ELEMENT NAME
CWBS
DEFINITION
1.5.2.3.7.3
Quarterly Briefing
1.5.2.3.8
1.5.2.3.8.1
1.5.2.3.8.2

briefing
1.5.2.3.8.3
Quarterly Briefing
1.5.3
Project Support
Project Support
1.5.3.1
Initial Procurement
Procurement of supplies and materials needed by project start date to

commence tasks
BioFactura, Inc.
Page 152 of 218
6.3
Subcontractor Quotes and License Agreements
Proposal for Production and Characterization of a Non-Campaign

Vero Master Cell Bank
Proposal: P-16804 - BioFactura Vero MCB - v01
Submitted by:
Sue Rose
Account Manager
BioReliance Corporation
14920 Broschart Road
Rockville, MD 20850
Submitted to:
Dr. Darryl Sampey
BioFactura
9430 Key West Ave
Suite: 125
Rockville, MD 20850
Issue Date
13-MAR-2012
THE INFORMATION CONTAINED IN THIS PROPOSAL IS SUBJECT TO THE FOLLOWING RESTRICTIONS:

Data contained in all pages of this proposal shall not be used or disclosed, except for evaluation purposes
This proposal is valid for the next ninety (90) days from the issue date.
CONFIDENTIAL
BioFactura, Inc.
P-16804 - BioFactura Vero MCB - v01
Page 153 of 218

Vero Master Cell Bank
1.
Project Overview
This proposal describes the strategy for production of a Non-Campaign Vero Master
Cell Bank (MCB) An overview of the proposed work and price for the project is below.
Milestones
M1
M2
M3
M4
Description
Pre-bank Testing
Pilot Study
Non-Campaign MCB Production (cGMP) 300 vials**
MCB Cell Line Characterization
Price
$5,165
$5,398
$26,819
$122,606
Storage of Master and Working Cell Banks (12 months)*

TOTAL
$159,988
*Note: The pricing for the storage will be sent as a quote once the bank production is
completed.
**Note: The price for 100 Vials for MCB Production would be $20,120
2.
Introduction to BioReliance
BioReliance specializes in biologics testing, cGMP cell bank and viral manufacturing,
toxicology and viral clearance services. With nearly 700 employees and 60 years
experience, BioReliance have the scientific expertise and regulatory knowledge to
partner our clients through clinical development and commercial testing. Over the
years, BioReliance has led the industry, including performing safety testing for the
first polio vaccine (1985), the first commercial mammalian-derived biologic (1981),
and the first gene therapy product to enter clinical trials (1990).
To ensure the safety of biopharmaceutical products produced in living cells, global
regulatory agencies require that cells used in the manufacture of these products be
banked and characterized to the highest possible standards. Therefore building in
quality at the first step in development is critical, ultimately leading to the success of
your project. BioReliances cell banking services offer a confident, convenient and
timely service in bioproduction from preliminary testing of seed stocks to preparing
and qualifying cGMP master and working cell banks
CONFIDENTIAL
BioFactura, Inc.
Page 154 of 218
3.
Why you should select BioReliance for cell bank manufacturing?
Efficiency
On-time delivery
Experience
Cell bank manufacturing since early 1980s, with testing of over 1000
banks
Full service including cell expansion, testing and long-term storage
Proven track record established business with >60 years experience.
Serves over 1000 customers, including the majority of the worlds leading
biopharma, biotech and pharmaceutical companies.
Seamless service providing cell banking and testing
Facilities
Global facility with manufacturing capabilities in Glasgow, UK and

Rockville, MD, offering flexible scheduling results
Facilities for cGMP mammalian and insect cell banking
Large selection of laboratory equipment dedicated for manufacturing
Technical
Support
Dedicated project team assigned to keep you informed of your banks

production and testing progress on a regular basis
Team available in advance to finalize technical specifications and
recommend a compliant safety testing plan - personnel are available to
meet directly with the authorities to review client projects.
Regulatory advice - regular dialogue with the FDA, EMEA and other
Regulatory Authorities help ensure the advice we provide is up to date
and relevant. Expert scientists provide technical and regulatory support
before, during and after completion of the study.
Custom solutions
Quality Service
Continuous program for material management and control (MMC), QC

and QA support for incoming raw material testing, in-process checks, and
pre/post-cell banking certification of all areas
All equipment and suites undergo validation on a regular basis
The RA/QA Department takes primary and final responsibility for assuring
the quality and integrity of all data generated in compliance with the FDA
GLPs and cGMPs. All production is performed in conformance with FDA
cGMP regulations (21 CFR 210, 211, 600, 610)
Project
Management
Primary point of contact appointed for each project
CONFIDENTIAL
BioFactura, Inc.
Custom plan of action prepared where project is unique
Page 155 of 218
4.
Initiation of a cGMP Production

An advantage to partnering with BioReliance is the appointment of a Project Manager,
assigned to act as primary contact for the overall planning and management of the project.
The Project Manager will maintain timelines and monitor the budget as well as maintain
timely communication with the client. A Project Manager (overseeing all aspects of the entire
client campaign) and a Manufacturing Lead Scientist (overseeing all technical aspects of the
campaign) will be assigned to the client to manage the GMP production and testing of the
MCB.
Cell Banking projects begin with the client completing a cell banking questionnaire. This
document is then used to produce the QA controlled technical specification which is agreed
to by both the BioReliance Cell Banking Group and the Client. Batch production records are
then generated and approved by the Quality Assurance Group. The production process is
performed by fully gowned and qualified technicians trained on the cell banking SOPs. Once
the cells reach the required density they are frozen down in a validated, controlled rate
freezer and stored in the vapor phase of liquid nitrogen until released by our Quality
Assurance Group.
5.
Project Details
Milestone 1: Pre-bank Testing on Seed Material
Assay
510120GMP.BSV
510150GMP.BSV
102063GMP.BSV
Description
Isolator Sterility Testing Using a Direct
Inoculation Method
Sterility Isolator Method Suitability Testing
Using a Direct Inoculation Method
Test for presence of Agar-Cultivable and Nonagar Cultivable Mycoplasma without Avian
Controls (USP, EP, 1993 PTC)
Total:
Qty
Price
$1,058
$1,641
$2,467
$5,165
The cell line starting material must be certified sterile and free from Mycoplasma
contamination prior to initiation of MCB production in a clean room suite. Therefore,
BioReliance recommends and requires screening of the Seed Material for Sterility and
Mycoplasma.
If the assays perform per specification, BioReliance will move to the next milestone
If further testing and/or repeats are required, BioReliance will work with the client to
determine the scope of that work and either amend this proposal or provide a separate
proposal
CONFIDENTIAL
BioFactura, Inc.
Page 156 of 218
Milestone 2: Pilot Study

Assay
604000.BSV
Description
Non-GMP Cell Bank
Qty
1
Price
$5,398
Non-GMP pilot study to confirm growth conditions and successful recovery of cells from
freezing
Require seed material release testing prior to Pilot initiation
Pilot study size is very small (5-10 vials) and will be used strictly for culture growth and
recovery determination (extra vials discarded)
Information will be used to finalize Technical Specification with the client to prepare for
GMP manufacture of cell bank (Milestone 3)
Milestone 3: MCB Production (cGMP)
Assay
602000.BSV
602000.BSV
Description
cGMP Cell Banking Non Campaign (300 vials)
Qty
1
1
Price
$26,819
$20,120
*Note: Pricing is based on BioReliances best estimate of scope of project. Changes to

scope, including those discovered upon review of the cell bank questionnaire may result in
additional cost to the client, such as custom media, expedited shipping cost, etc
Following successful completion of the pilot study, BioReliance will proceed with the following
steps to manufacture the cell bank:
Generation of a fully Quality Assured audited Production Technical Specification.
Generation of fully audited customized GMP Production Instructions (GPIs).
Preparation of the clean room suite by full environmental clean down and monitoring.
Quality Systems Room and Production Initiation Approval
Cell Line initiation and expansion within the clean room
Harvest and cryopreservation of 300 or 100 vials @ 1 x 107 cells/ml (1ml vials)
depending on the number of vials selected for production.
Recovery of vials from the beginning, middle and end of the bank to confirm viability
Audit of the Batch Manufacturing Records
Generation of the Production Final Report
Submission of vials for appropriate characterization testing
Price includes previously agreed materials used during production (standard cryovials,
media, etc)
CONFIDENTIAL
BioFactura, Inc.
Page 157 of 218
Milestone 4: MCB Cell Line Characterization

Assay
Description
TAT Days
(estimated)
Qty
Price
003800.BSV
28-day In Vitro Virus Assay GMP, 3 Cell

Lines
35
$12,602
032900.BSV
Bovine 9CFR In Vitro Assay for 7 Viruses
45
$ 6,850
020000.BSV
Client Cell Culture for Sample Preparation
49
$0.00
107202GMP.BUK
Detection of Simian viruses by QPCR
42
$35,957
510120GMP.BSV*

Inoculation Method (1 Sample)
21
$1,478
378002GMP.BUK
Karyology of non-human mammalian cell

lines (50 metaphases)
77
$14,544
511011.BSV
Mycobacteria Assay, No Bioburden
77
$1,670
511010.BSV
Mycobacteria, No Bioburden, Qualification

Study
77
$1,670
033901.BSV
Porcine Mod. 9CFR In Vitro Viruses Assay,

PT-1 Cells
45
$4,707
102062GMP.BSV**
Qualification of the Test Article for the

Detection of Agar-Cultivable Mycoplasma in
accordance with USP/EP/PTC/JP
Requirements (Without Avian Controls)
42
$4,649
300115GMP.BSV
Qualitative Polymerase Chain Reaction

(PCR) Assay for Detection of HIV-I/II
(Human Panel)
28
$3,394
300104GMP.BSV
Qualitative Polymerase Chain Reaction

(PCR) Assays for Detection of SV40
(Human Panel I)
28
$2,595
105230.BSV
Retrovirus Detection by qPERT
35
$2,545
510150GMP.BSV*

21
$1,628
102063GMP.BSV**
Test for presence of Agar-Cultivable and

Non-agar Cultivable Mycoplasma without
Avian Controls (USP, EP, 1993 PTC)
35
$2,220
013013GMP.BUK
Transmission Electron Microscopic

Examination of Cell Cultures (200 Cell
profiles) - US Clients
49
$5,155
135
$20,942
001000.BSV
Total
Tumor Formation in Nude Mice Post

Injection of Cell Suspension
(all prices reflect 10% discount)
$122,606
*BioReliance recommends following the ICH guidelines for MCB testing for sterility:
1% of the total number of vials
**BioReliance recommends performing a Mycoplasmastasis assay to qualify
the Mycoplasma test result for USP, EP and PTC
Upon completion of Sterility and Mycoplasma testing BioReliance will move to the next
milestone.
CONFIDENTIAL
BioFactura, Inc.
Page 158 of 218
6.
Storage Options
On successful completion of the vialing process, the cell bank(s) will be transferred to
BioReliances cGMP Inventory Management facility for temporary storage whilst release
testing of the cell bank(s) is conducted. This temporary storage is provided at no additional
cost to the client.
Once release testing on the bank(s) has completed with satisfactory results, the client is
required to provide disposition by indicating one of the options below:
1. The cell bank(s) should be stored in BioReliances cGMP BioRepository facility. The
client agrees to pay the storage costs noted on a separate quote to be generated after
the completion of the production of the bank. BioReliance will be responsible for
transfer of the cell bank(s) to the facility at no additional cost to the client.
2.
BioReliance should ship the cell bank(s) to a client designated cGMP facility. For
such transfer, the client will provide BioReliance with their preferred courier account
number.
*Note: Should disposition not be provided, continued storage at BioReliances cGMP Inventory
Management facility will be charged to the client at a rate of $1,000 per month from the
date release testing is completed. Further, if after 90 days from completion of release
testing the client still has not provided disposition the cell bank(s) will be transferred to
BioReliances cGMP BioRepository facility and the client will be charged at a rate of
$1,000 per month until client disposition is received.
Please note that BioReliances cGMP Inventory Management facility is not a long term
storage solution for client cell banks.
7.
Required from the client

Completed questionnaire for cell bank manufacturing
Review and approval of technical specification for Milestone 3
3 vials of seed material for Milestone 1 (Prebank)
3 vials of seed material for Milestone 2 (Pilot)
3 vials of seed material for Milestone 3 for Manufacturing
Signed Purchase Order referencing the proposal and/or quote (contract) prior to project
initiation
Approved Documentation and a Quote for Storage to be sent to the client upon
completion of Milestone 3 (MCB Manufacturing)
8.
Deliverable to the client

Separate final reports for each assay in Milestones 1 and 4
Technical specification for Milestones 3
cGMP cell banks (MCB)
Final Reports for Milestone 3
CONFIDENTIAL
BioFactura, Inc.
Page 159 of 218
9.
Contact Details
BioReliance point of contact for this project will be:
Name
Title
Phone No.
Sue Rose
Account Manager
(240) 328-8565
Joe Crouse
Program Manager
(601) 610-2605
Email
sue.rose@bioreliance.com
joe.crouse@bioreliance.com
Client point of contact for this project will be:

Dr. Darrryl Sampey
CEO
(301) 315-8002
dsampey@biofacture.com
Name
Title
Phone No.
Email
10.
Timelines
Upon receipt of signed proposal and purchase order, BioReliance PM will review capacity
with Operational leaders to determined actual timelines
PM will generate a Gantt chart to be reviewed and agreed to with the client at a project
kick off meeting
11.
Payment Terms
Unless superseded by a separate, signed written agreement between BioReliance and
Client, invoices shall be paid in accordance with the following terms, contingent on a
satisfactory credit review:
60% upon Lab Initiation and 40% upon order
completion
All Milestones
In addition, unless superseded by a separate, signed written agreement between

BioReliance and Client, payment shall be due net thirty (30) days from the date of the
invoice.
12.
Cancellation
Unless superseded by a separate, signed written agreement between BioReliance and Client
the following cancellation fee will apply to each Project:
13.
Cancellation within 2 weeks of Lab Initiation

of any Milestone:
20% of the total price of applicable

Milestone(s)
Cancellation after Lab Initiation of any

Milestone:
50% of applicable Milestone(s)
Cancellation after Lab Completion of any

Milestone:
Terms and Conditions

Except to the extent superceded by a separate signed written agreement between
BioReliance and Client, the services described in this quotation will be governed by the
relevant BioReliance Statement of Terms and Conditions, which are included herewith, or
incorporated herein by reference.
http://www.bioreliance.com/downloadable_forms_conditions.aspx
CONFIDENTIAL
BioFactura, Inc.
Page 160 of 218
14.
Repeats
Repeat testing may be subject to additional price to the client and quote will be provided.
15.
Risk assessment and safety

Any known safety hazards associated with the test articles or reagents supplied for use in
these studies must be reported to BioReliance in order to allow a full risk assessment of the
study to be conducted. Please be aware that there may be a requirement for licences to
import and/or handle certain biological or infectious materials, and it is essential that these be
in place before shipment of materials is arranged. Please note that no work shall commence
until all relevant risk assessments and licences are in place.
Please also note that BioReliance is required by the UK Health and Safety Executive under
European Commission Directive 94/51/EC to have a risk assessment of any GMO present in
our European facility. Therefore, if the material to be supplied is classified as a Genetically
Modified Organism (GMO), we request that you inform us of the safety assessment for the
test article. Alternatively, if requested by you, BioReliances own Genetic Safety Committee
can do an assessment for you.
16.
Approval
BioFactura:
BioReliance Corporation:
________________________
Signature
_______________________
Signature
________________________
Name
Susan B. Rose
Name
________________________
Title
Account Manager
Title
________________________
Date
13 March 2012
Date
Confidentiality
This document has been prepared by and remains the sole property of BioReliance. It is submitted to
the Client solely for use in evaluating BioReliances qualifications and/or quotations concerning the
particular projects for which it was prepared. This document is confidential to BioReliance, and the
Client agrees to treat the document in accordance with the terms of any Confidentiality Agreements
previously signed and, in any event, shall not disclose to any third party without the consent of
BioReliance not to be unreasonably withheld.
CONFIDENTIAL
BioFactura, Inc.
Page 161 of 218

EB66 Master Cell Bank
Proposal: P-16806 - BioFactura EB66 MCB - v01
Submitted by:
Sue Rose
Account Manager
BioReliance Corporation
14920 Broschart Road
Rockville, MD 20850
Submitted to:
Dr. Darryl Sampey
BioFactura
9430 Key West Ave
Suite: 125
Rockville, MD 20850
Issue Date
13-MAR-2012
THE INFORMATION CONTAINED IN THIS PROPOSAL IS SUBJECT TO THE FOLLOWING RESTRICTIONS:

Data contained in all pages of this proposal shall not be used or disclosed, except for evaluation purposes
This proposal is valid for the next ninety (90) days from the issue date.
CONFIDENTIAL
BioFactura, Inc.
P-16806 - BioFactura EB66 MCB - v01
Page 162 of 218
Proposal for Production and Characterization of a NonCampaign EB66 Master Cell Bank
1.
Project Overview
This proposal describes the strategy for production of a Non-Campaign EB66 Master
Cell Bank (MCB) An overview of the proposed work and price for the project is below.
Milestones
M1
M2
M3
M4
Description
Pre-bank Testing
Pilot Study
Non-Campaign MCB Production (cGMP) 300 Vials**
MCB Cell Line Characterization
Price
$5,165
$5,398
$26,819
$148,261
Storage of Master and Working Cell Banks (12 months)*

TOTAL
185,643
*Note: The pricing for the storage will be sent as a quote once the bank production is
completed.
**Note: The price for 100 Vials for MCB Production would be $20,120
2.
Introduction to BioReliance
BioReliance specializes in biologics testing, cGMP cell bank and viral manufacturing,
toxicology and viral clearance services. With nearly 700 employees and 60 years
experience, BioReliance have the scientific expertise and regulatory knowledge to
partner our clients through clinical development and commercial testing. Over the
years, BioReliance has led the industry, including performing safety testing for the
first polio vaccine (1985), the first commercial mammalian-derived biologic (1981),
and the first gene therapy product to enter clinical trials (1990).
To ensure the safety of biopharmaceutical products produced in living cells, global
regulatory agencies require that cells used in the manufacture of these products be
banked and characterized to the highest possible standards. Therefore building in
quality at the first step in development is critical, ultimately leading to the success of
your project. BioReliances cell banking services offer a confident, convenient and
timely service in bioproduction from preliminary testing of seed stocks to preparing
and qualifying cGMP master and working cell banks
CONFIDENTIAL
BioFactura, Inc.
Page 163 of 218
3.
Why you should select BioReliance for cell bank manufacturing?
Efficiency
On-time delivery
Experience
Cell bank manufacturing since early 1980s, with testing of over 1000
banks
Full service including cell expansion, testing and long-term storage
Proven track record established business with >60 years experience.
Serves over 1000 customers, including the majority of the worlds leading
biopharma, biotech and pharmaceutical companies.
Seamless service providing cell banking and testing
Facilities
Global facility with manufacturing capabilities in Glasgow, UK and

Rockville, MD, offering flexible scheduling results
Facilities for cGMP mammalian and insect cell banking
Large selection of laboratory equipment dedicated for manufacturing
Technical
Support
Dedicated project team assigned to keep you informed of your banks

production and testing progress on a regular basis
Team available in advance to finalize technical specifications and
recommend a compliant safety testing plan - personnel are available to
meet directly with the authorities to review client projects.
Regulatory advice - regular dialogue with the FDA, EMEA and other
Regulatory Authorities help ensure the advice we provide is up to date
and relevant. Expert scientists provide technical and regulatory support
before, during and after completion of the study.
Custom solutions
Quality Service
Continuous program for material management and control (MMC), QC

and QA support for incoming raw material testing, in-process checks, and
pre/post-cell banking certification of all areas
All equipment and suites undergo validation on a regular basis
The RA/QA Department takes primary and final responsibility for assuring
the quality and integrity of all data generated in compliance with the FDA
GLPs and cGMPs. All production is performed in conformance with FDA
cGMP regulations (21 CFR 210, 211, 600, 610)
Project
Management
Primary point of contact appointed for each project
CONFIDENTIAL
BioFactura, Inc.
Custom plan of action prepared where project is unique
Page 164 of 218
4.
Initiation of a cGMP Production

An advantage to partnering with BioReliance is the appointment of a Project Manager,
assigned to act as primary contact for the overall planning and management of the project.
The Project Manager will maintain timelines and monitor the budget as well as maintain
timely communication with the client. A Project Manager (overseeing all aspects of the
entire client campaign) and a Manufacturing Lead Scientist (overseeing all technical
aspects of the campaign) will be assigned to the client to manage the GMP production and
testing of the MCB.
Cell Banking projects begin with the client completing a cell banking questionnaire. This
document is then used to produce the QA controlled technical specification which is
agreed to by both the BioReliance Cell Banking Group and the Client. Batch production
records are then generated and approved by the Quality Assurance Group. The
production process is performed by fully gowned and qualified technicians trained on the
cell banking SOPs. Once the cells reach the required density they are frozen down in a
validated, controlled rate freezer and stored in the vapor phase of liquid nitrogen until
released by our Quality Assurance Group.
5.
Project Details
Milestone 1: Pre-bank Testing on Seed Material
Assay
510120GMP.BSV
510150GMP.BSV
102063GMP.BSV
Description
Inoculation Method
Test for presence of Agar-Cultivable and Nonagar Cultivable Mycoplasma without Avian
Controls (USP, EP, 1993 PTC)
Total:
Qty
Price
$1,058
$1,641
$2,467
$5,165
The cell line starting material must be certified sterile and free from Mycoplasma
contamination prior to initiation of MCB production in a clean room suite. Therefore,
BioReliance recommends and requires screening of the Seed Material for Sterility and
Mycoplasma.
If the assays perform per specification, BioReliance will move to the next milestone
If further testing and/or repeats are required, BioReliance will work with the client to
determine the scope of that work and either amend this proposal or provide a separate
proposal
CONFIDENTIAL
BioFactura, Inc.
Page 165 of 218
Milestone 2: Pilot Study

Assay
604000.BSV
Description
Non-GMP Cell Bank
Qty
1
Price
$5,398
Non-GMP pilot study to confirm growth conditions and successful recovery of cells from
freezing
Require seed material release testing prior to Pilot initiation
Pilot study size is very small (5-10 vials) and will be used strictly for culture growth and
recovery determination (extra vials discarded)
Information will be used to finalize Technical Specification with the client to prepare for
GMP manufacture of cell bank (Milestone 3)
Milestone 3: MCB Production (cGMP) Non-Campaign
Assay
602000.BSV
602000.BSV
Description
Qty
1
1
Price
$26,819
$20,120
*Note: Pricing is based on BioReliances best estimate of scope of project. Changes to

scope, including those discovered upon review of the cell bank questionnaire may result in
additional cost to the client, such as custom media, expedited shipping cost, etc
Following successful completion of the pilot study, BioReliance will proceed with the
following steps to manufacture the cell bank:
Generation of a fully Quality Assured audited Production Technical Specification.
Generation of fully audited customized GMP Production Instructions (GPIs).
Preparation of the clean room suite by full environmental clean down and monitoring.
Quality Systems Room and Production Initiation Approval
Cell Line initiation and expansion within the clean room
Harvest and cryopreservation of 100 or 300 vials @ 1 x 107 cells/ml (1ml vials)
depending on how many vials selected for production.
Recovery of vials from the beginning, middle and end of the bank to confirm viability
Audit of the Batch Manufacturing Records
Generation of the Production Final Report
Submission of vials for appropriate characterization testing
Price includes previously agreed materials used during production (standard
cryovials, media, etc)
CONFIDENTIAL
BioFactura, Inc.
Page 166 of 218
Milestone 4: MCB Cell Line Characterization

Assay
Description
TAT Days
(estimated)
Qty
Price
003800.BSV
28-day In Vitro Virus Assay GMP, 3 Cell

Lines
35
$12,602
020000.BSV
Client Cell Culture for Sample Preparation
49
$0.00
060510GMP.BUK
In vitro Assay for the Detection of ALV

(Subgroups A, B and J) using Chicken
Embryo Fibroblast Cells
63
$9,637
380801.BSV
Isoenzyme Analysis, GMP
21
$1,943
510120GMP.BSV*

Inoculation Method (1 Sample)
26
$1,478
378003GMP.BUK
Karyology analysis of avian cell lines
77
$14,544
105099.BSV
Porcine Circovirus Type 1 and 2 Detection

by PCR
28
$2,545
033901.BSV
Porcine Mod. 9CFR In Vitro Viruses Assay,

PT-1 Cells
45
$4,707
102062GMP.BSV**
Qualification of the Test Article for the

Detection of Agar-Cultivable Mycoplasma
in accordance with USP/EP/PTC/JP
Requirements (Without Avian Controls)
56
$4,648
107208GMP.BUK
RT-PCR for the Detection of Avian

Leukosis Virus type J (ALV-J)
42
$4,596
107217GMP.BUK
Real time PCR detection of Chicken

anemia virus (CAV)
42
$4,596
107333GMP.BUK
Real time PCR detection of Duck

adenovirus type 1 (DAdV-1)
30
$4,596
107335GMP.BUK
Real time PCR detection of Duck circovirus

(DuCV)
30
$4,596
107336GMP.BUK
Real time PCR detection of Duck hepatitis

B virus (DHBV)
30
$4,596
107334GMP.BUK
Real time PCR detection of Duck

parvovirus (MDPV)
30
$4,596
107092GMP.BUK
Real time-PCR Detection of Avian

Leukosis Virus (ALV) &
Reticuloendotheliosis Virus (REV)
42
$12,550
107003GMP.BUK
Real time-PCR Detection of Bornavirus
14
$4,596
105230.BSV
Retrovirus Detection by qPERT
30
$2,545
510150GMP.BSV*

26
$1,628
102063GMP.BSV
Test for presence of Agar-Cultivable and

Non-agar Cultivable Mycoplasma without
Avian Controls (USP, EP, 1993 PTC)
35
$2,220
005012.BSV
Test for the Presence of Inapparent

Viruses in a Test Article Used for the
Production of Viral Vaccines
56
$18,945
CONFIDENTIAL
BioFactura, Inc.
Page 167 of 218
013013GMP.BUK
001000.BSV
Total
Transmission Electron Microscopic

Examination of Cell Cultures (200 Cell
profiles) - US Clients
Tumor Formation in Nude Mice Post
Injection of Cell Suspension
(all prices reflect 10% discount)
49
$5,155
135
$20,942
$148,261
Note: Oncogenicity and Induction work may be required.

*BioReliance recommends following the ICH guidelines for MCB testing for sterility:
1% of the total number of vials
**BioReliance recommends performing a Mycoplasmastasis assay to qualify
the Mycoplasma test result for USP, EP and PTC
Upon completion of Sterility and Mycoplasma testing BioReliance will move to the next
milestone.
6.
Storage Options
On successful completion of the vialing process, the cell bank(s) will be transferred to
BioReliances cGMP Inventory Management facility for temporary storage whilst release
testing of the cell bank(s) is conducted. This temporary storage is provided at no
additional cost to the client.
Once release testing on the bank(s) has completed with satisfactory results, the client is
required to provide disposition by indicating one of the options below:
1. The cell bank(s) should be stored in BioReliances cGMP BioRepository facility.
The client agrees to pay the storage costs noted on a separate quote to be
generated after the completion of the production of the bank. BioReliance will be
responsible for transfer of the cell bank(s) to the facility at no additional cost to the
client.
2.
BioReliance should ship the cell bank(s) to a client designated cGMP facility. For
such transfer, the client will provide BioReliance with their preferred courier
account number.
*Note: Should disposition not be provided, continued storage at BioReliances cGMP Inventory
Management facility will be charged to the client at a rate of $1,000 per month from the
date release testing is completed. Further, if after 90 days from completion of release
testing the client still has not provided disposition the cell bank(s) will be transferred to
BioReliances cGMP BioRepository facility and the client will be charged at a rate of
$1,000 per month until client disposition is received.
Please note that BioReliances cGMP Inventory Management facility is not a long term
storage solution for client cell banks.
CONFIDENTIAL
BioFactura, Inc.
Page 168 of 218
7.
Required from the client

Completed questionnaire for cell bank manufacturing
Review and approval of technical specification for Milestone 3and 5
3 vials of seed material for Milestone 1 (Prebank)
3 vials of seed material for Milestone 2 (Pilot)
3 vials of seed material for Milestone 3 for Manufacturing
Signed Purchase Order referencing the proposal and/or quote (contract) prior to
project initiation
Approved Documentation and a Quote for Storage to be sent to the client upon
completion of Milestone 3 (MCB Manufacturing)
8.
Deliverable to the client

Separate final reports for each assay in Milestones 1 and 4
Technical specification for Milestones 3
cGMP cell banks (MCB)
Final Reports for Milestone 3
9.
Contact Details
BioReliance point of contact for this project will be:

Name
Title
Phone No.
Sue Rose
Account Manager
(240) 328-8565
Joe Crouse
Program Manager
(601) 610-2605
Email
sue.rose@bioreliance.com
joe.crouse@bioreliance.com
Client point of contact for this project will be:

Name
Title
Phone No.
Email
CONFIDENTIAL
BioFactura, Inc.
Darryl Sampey
CEO
(301) 315-8002
dsampey@biofactura.com
Page 169 of 218
10.
Timelines
Upon receipt of signed proposal and purchase order, BioReliance PM will review
capacity with Operational leaders to determined actual timelines
PM will generate a Gantt chart to be reviewed and agreed to with the client at a project
kick off meeting
11.
Payment Terms
Client, invoices shall be paid in accordance with the following terms, contingent on a
satisfactory credit review:
60% upon Lab Initiation and 40% upon order
completion
All Milestones
In addition, unless superseded by a separate, signed written agreement between

BioReliance and Client, payment shall be due net thirty (30) days from the date of the
invoice.
12.
Cancellation
Client the following cancellation fee will apply to each Project:
Cancellation within 2 weeks of Lab Initiation
of any Milestone:
20% of the total price of applicable

Milestone(s)
Cancellation after Lab Initiation of any

Milestone:
Cancellation after Lab Completion of any

Milestone:
13.
Terms and Conditions

Except to the extent superceded by a separate signed written agreement between
BioReliance and Client, the services described in this quotation will be governed by the
relevant BioReliance Statement of Terms and Conditions, which are included herewith, or
incorporated herein by reference.
http://www.bioreliance.com/downloadable_forms_conditions.aspx
14.
Repeats
Repeat testing may be subject to additional price to the client and quote will be provided.
CONFIDENTIAL
BioFactura, Inc.
Page 170 of 218
15.
Risk assessment and safety

Any known safety hazards associated with the test articles or reagents supplied for use in
these studies must be reported to BioReliance in order to allow a full risk assessment of
the study to be conducted. Please be aware that there may be a requirement for licences
to import and/or handle certain biological or infectious materials, and it is essential that
these be in place before shipment of materials is arranged. Please note that no work shall
commence until all relevant risk assessments and licences are in place.
Please also note that BioReliance is required by the UK Health and Safety Executive
under European Commission Directive 94/51/EC to have a risk assessment of any GMO
present in our European facility. Therefore, if the material to be supplied is classified as a
Genetically Modified Organism (GMO), we request that you inform us of the safety
assessment for the test article. Alternatively, if requested by you, BioReliances own
Genetic Safety Committee can do an assessment for you.
16.
Approval
BioFactura:
BioReliance Corporation:
________________________
Signature
_______________________
Signature
________________________
Name
Susan B. Rose
Name
________________________
Title
Account Manager
Title
________________________
Date
13 March 2012
Date
Confidentiality
This document has been prepared by and remains the sole property of BioReliance. It is submitted
to the Client solely for use in evaluating BioReliances qualifications and/or quotations concerning
the particular projects for which it was prepared. This document is confidential to BioReliance, and
the Client agrees to treat the document in accordance with the terms of any Confidentiality
Agreements previously signed and, in any event, shall not disclose to any third party without the
consent of BioReliance not to be unreasonably withheld.
CONFIDENTIAL
BioFactura, Inc.
10
Page 171 of 218
March 13, 2012
Quote # Q-16802-v2
MCB Storage
Dr. Darryl Sampey

BioFactura
9430 Key West Ave
Suite: 125
Rockville, MD 20850
Assay
900001.BRP*
Description
Eukaryotic Bank Storage for 12 Months, cGMP (every 50
vials >150 vials)
Qty
Total Price
USD 567.00
900000.BRP*
Eukaryotic Bank Storage for 12 Months, cGMP (up to

150 vials)
USD 4,329.00
900040.BRP*
cGMP Storage for 1 Month (up to 150 vials)
USD 361.80
900040.BRP*
cGMP Storage for 1 Month (up to 150 vials)
USD 723.60
Total Quote Value:
USD 5,981.40
* Quoted pricing listed for storage of one bank.

* For Storage of a 100 vial bank for 1 year: $4,329.00
* For Storage of a 100 vial bank by month: $361.00
* For Storage of a 300 vial bank for 1 year: $4,896.00 ( $4,329.00 + $567.00 = $4,896.00)
* For Storage of a 300 vial bank for 1 month: $723.60
The prices shown in this quotation are valid until 12/31/2012. Any modifications to the standard
protocol and/or the standard report for GLP/GMP testing may result in additional cost to the
sponsor.
There may be circumstances where assay initiation or audited final report delivery is required in a
shorter time frame than what is reflected by BioReliance normal turnaround time, or the
turnaround time agreed to in a client Master Service Agreements. It may be possible to shorten
turnaround times, but discussion and agreement is required in advance. A rush surcharge is
charged for such 'fast tracking' of studies. Requests for fast-tracked results/reports are subject to
BioReliance laboratory capacity and may not always be possible. Contact your BioReliance
Program Manager to discuss specific fast-track study needs.
BioReliance Corporation | 14920 Broschart Road Rockville, Maryland 20850 | 301-738-1000
BioFactura, Inc.
Page 172 of 218
Except to the extent superseded by a separate signed written agreement between BioReliance
and the Client, the services described in this quotation will be governed by the relevant
BioReliance Statement of Terms and Conditions, which are incorporated herein by reference.
Terms and Conditions are available at
http://www.bioreliance.com/downloadable_forms_conditions.aspx.
Invoices shall be paid in accordance with the following terms, contingent on a satisfactory credit
review: 100% billed upon order booking.
A hard copy purchase order or equivalent is required prior to the initiation of the work quoted.
All purchase orders and payments should be addressed to and reference BioReliance
Corporation.
__________________________________
Sue Rose
Account Manager
cc: Sylvia Mateo
Project Manager
BioReliance Corporation | 14920 Broschart Road Rockville, Maryland 20850 | 301-738-1000
BioFactura, Inc.
Page 173 of 218
EB66 Research License Terms

EB66 cell line for a human VEE-VRP vaccine
platform.
CONFIDENTIAL
CONTACT
BioFactura, Inc.
Prepared for BioFactura, Inc.

Louis Cantolupo Dir., Business Development loucantolupo@vivalis.com +33 (0)2 28 07 37 10
Vivalis s.a. 6, rue Alain Bombard 44800 Saint-Herblain France
Page 174 of 218
This research license term sheet is for discussion purposes only and is not intended as an offer. The
transactions contemplated hereby are subject to approval of the parties senior management, completion of
due diligence, and negotiation and execution of definitive agreements. It is provided to BioFactura in support
of their grant application under the CBMS JPMO BAA 07-01: An Improved Production Process for the
Manufacture of VEE VRP Vaccines.
Scope
Non-exclusive license for the research use of the EB66 cell line by BioFactura in
support of the program, An Improved Production Process for the Manufacture of
VEE VRP Vaccines (the Program) under BAA 07-01 issued by the CBMS JPMO.
Licensee
BioFactura, Inc.
Technology
EB66 cell line.
Field of Use
Venezuelan Equine Encephalitis (VEE) viral replicon particle (VRP) vaccine research.
License Term
Twenty-five months commencing from the receipt of the EB66 cell line.
Should BioFactura be notified the funds to support the Program will not occur
within six months of the receipt of the EB66 cell line, the license shall terminate
upon said notification.
Territory
World-wide.
Exclusivity
Non-exclusive; human influenza prevention and therapy is excluded.
Sublicense/
Contractual Rights
Not withheld without unreasonable request. Certain countries and territories may
be excluded and should be discussed with Vivalis.
Training and
Support
Training in EB66 cell line use is included for up to two persons up to four
consecutive days at Vivaliss facilities in Saint-Herblain, France. Transportation and
accommodations are not included.
Reasonable technical support to BioFactura is provided by Vivalis during the
License Term. Should BioFactura require on-site support of Vivalis staff, a rate of
1,200 per day will apply per staff member. Transportation and accommodations
shall be reimbursed to Vivalis by BioFactura.
Payments
Upfront
0.00 for the implementation of EB66 cells at BioFactura prior to grant award.
Project Start
80,000 due upon receipt of grant award for remainder of the License Term
(including time in arrears).
March 13, 2012
BioFactura, Inc.
EB66 Cell Line Research License Terms | CONFIDENTIAL
Page 175 of 218
Section 6.4
TET-System License Draft
Negotiated Terms: 50% USD 11,250 due each 6 months (Partial Internal [Pharmaceutical]
Research License)
NONBINDING DRAFT FOR DISCUSSION PURPOSES ONLY
Biofactura TET Agreement
NON-EXCLUSIVE LICENSE AGREEMENT

FOR PARTIAL INTERNAL [PHARMACEUTICAL] RESEARCH
This Agreement, effective
(the "Effective Date"), is between
TET Systems GmbH & Co. KG, a German law limited partnership having its principal
place of business at Im Neuenheimer Feld 582, 69120 Heidelberg, Germany ("TET"),
and
BioFactura, Inc. a [!] corporation organized under the laws of [!] having its principal
place of business at 9430 Key West Ave, Suite 125, Rockville, Maryland 20850, USA
("COMPANY").
BACKGROUND
TET is the owner of the patent portfolio relating to tetracycline regulated gene
expression in eukaryotes, referred to under this Agreement as the Patent Rights.
TET is willing to grant, and COMPANY wishes to accept, a non-exclusive license under
the Patent Rights for the purpose of conducting in-house research for COMPANY'S own,
internal purposes only, under the terms and subject to the conditions set forth herein.
TET and COMPANY agree as follows:
ARTICLE 1 - DEFINITIONS
1.1
As used throughout this Agreement and its Appendices and unless the context
requires otherwise, the following capitalized terms shall have the meanings
ascribed to them below in this Article 1.
1.2
"Affiliate" of either Party shall mean any corporation, association or other

business entity which directly or indirectly controls, is controlled by, or is under
common control with the Party in question. For purposes of this definition control
shall refer to the power, directly or indirectly to direct the affairs of another entity.
1.3
"Agreement" shall mean this Non-Exclusive License Agreement for Partial

Internal [Pharmaceutical] Research Only.
1.4
"Anniversary Date" shall mean the anniversary of the Effective Date in any given
year.
1.5
"Authorized Suppliers" shall mean those companies which are licensed by TET to
sell TET Product(s), to sell transgenic animals the creation, manufacture, use or
sale of which is covered by the Patent Rights, or to provide services relating to
the TET Products, the TET System or the Patent Rights. The current list of
Authorized Suppliers is available on www.tet-systems.com and may be amended
by TET from time to time as appropriate.
Confidential
BioFactura, Inc.
-1-
internal Partial License v1
Page 176 of 218
1.6
"Bioprocessing/Manufacturing" shall mean the use of the TET-System in one or

more steps in the production of a product, where such a product (i) is intended for
a commercial purpose and (ii) does not contain the TET-System itself.
1.7
"Cellular Screening Systems" shall mean the use of compound libraries with less
than thousand (1,000) molecules on cellular systems expressing a gene of
interest with the TET-System to identify promising candidates for further
pharmaceutical development.
1.8
"COMPANY Group" shall mean COMPANY and its Affiliates, but notwithstanding
the foregoing, no Affiliate shall be deemed to form part of the COMPANY Group
unless it is identified in a list of Affiliates to be provided by COMPANY to TET
from time to time.
1.9
"Confidential Information" shall mean all information disclosed by TET and/or

Company under this Agreement. Information shall not qualify as Confidential
Information if, prior to the receipt from the disclosing party, it was already publicly
available or in the possession of the other Party without a duty of confidentiality.
Information shall cease to qualify as Confidential Information once it has become
publicly available without breach of this Agreement, is rightfully obtained by the
Parties from another source without duty of confidentiality, or is independently
developed or ascertained by each Party.
1.10
"Contract Research" shall mean use of the TET-System in the performance of

research or development for a Third Party.
1.11
"Contract Screening" shall mean use of the TET-System in the performance of

Screening for a Third Party.
1.12
"Effective Date" shall mean the date first written above.
1.13
"Grant Back Option" shall have the meaning ascribed to it under Section 2.7.
1.14
"Improvement" means any discovery, development, invention, enhancement or

modification, patentable or not, that claim or cover the composition of, or method
of using the technology described in the Patent Rights, the TET System and/or
TET Product(s).
1.15
"Improvement Rights" shall have the meaning ascribed to it under Section 2.7.
1.16
"Licensee Number" shall mean 225 which is the number assigned TET to
COMPANY following execution of this Agreement which number shall entitle
COMPANY to purchase TET Products from Authorized Suppliers.
1.17
"Licensed Territory" shall mean North America, or that additional territory or

combination of territories, which COMPANY may select from the list on Appendix
B Section VI, B.2 at some future time.
Confidential
BioFactura, Inc.
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Page 177 of 218
1.18
"Non-Exclusive" shall mean that TET shall be free to grant licenses under the
Patent Rights to other business entities at its own discretion.
1.19
"Organismic Screening Systems" shall mean the use of compound libraries with
less than thousand (1,000) molecules on transgenic organisms including fungi,
nematodes and insects or parts thereof expressing a gene of interest with the
TET-System to identify promising candidates for further pharmaceutical
development.
1.21
"Partial Internal Research License" (Partial License) shall mean the license
granted under this Agreement for [pharmaceutical] research and discovery
including the Partial Licensed Field(s) of Use.
1.22
Partial Licensed Field of Use" shall mean in-house use of the TET System as a
Research Tool for target validation and Study of Gene Function and the following
Partial Field(s) of use as selected by ticking the corresponding boxes:
o
o
o
o
"
Vector Development (including cellular and gene therapy)

Transgenic Organisms
Organismic Screening Systems
Cellular Screening Systems
Production strain development,
each for internal research purposes only. The Partial Licensed Field of Use shall,
to the exclusion of all other uses, be limited to the following activities:
[Pharmaceutical] research and discovery only. The Partial Licensed Field of Use
specifically excludes
(i)
the commercialization, sale or transfer of the TET-System to third parties,
(ii)
the commercialization, sale or transfer of reagents, including, but not
limited to, cell lines, plasmids, vectors, receptors, promoters, embryos,
animals, chemical entities, pharmaceuticals, and other products or agents
which incorporate the TET-System or a component of the TET System,
(iii)
the use of the TET-System for applications involving human subjects or
the preparation of substances intended for human use,
(iv)
Screening (unless expressly expanded thereto under this Agreement),
and
(v)
Bioprocessing/Manufacturing, Quality Assurance, Quality Control,
Contract Research or Contract Screening (to be licensed under a
separately negotiated license agreement).
1.23
"Party" shall mean TET or COMPANY, as the case may be; and Parties shall
mean TET and COMPANY, collectively.
1.24
"Patent Rights" shall mean the patent(s) and patent applications listed in
Appendix A, including any division, continuation, continuation-in-part, substitute,
renewal, reissue, extension, confirmation, reexamination or registration thereof
and any patent issuing thereon, including any substitute, renewal, reissue,
extension, confirmation, reexamination, registration or foreign counterpart thereof
which are owned or controlled by TET.
Confidential
BioFactura, Inc.
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Page 178 of 218
1.25
"Production Strain Development" shall mean the use of the TET-System to

identify and generate stable cell lines or organisms expressing a gene of interest
at sufficient levels for further development with the intent to use such cells or
organisms for production of biological materials.
1.26
"Results" shall mean any and all information, data, know-how, products (whether
or not containing TET Products or the TET System or any component or portions
thereof) and the like, whether patentable or not, arising out of the conduct of the
licenses granted under this Agreement and all intellectual property relating
thereto.
1.27
"Screening" shall mean the use of the TET-System in any assay or series of
assays, including in vitro, in vivo, and ex vivo assays, where the purpose of the
assay(s) is to identify gene products or new chemical entities as candidates for
diagnostic or pharmaceutical development from a library or other collection of
one thousand (1,000) or more molecules (high throughput screening). The term
Screening shall not include the use of the TET-System in assays directed toward
mechanistic proof-of-concept (which assays are covered by the Partial Licensed
Field of Use).
1.28
"TET Product(s)" shall mean any TET-System research reagent(s) or research

tool(s), the creation, manufacture, use, or sale of which is covered by the Patent
Rights.
1.29
"TET-System" shall mean the tetracycline (or tetracycline analog) regulated gene
expression technology, including both the overall system and any of its individual
components, as claimed in the Patent Rights.
1.30
"Third Parties" shall mean persons or entities other than COMPANY, COMPANY
Group, TET and their respective Affiliates.
1.31
"Transgenic Organism" shall mean the generation, propagation, cross-breeding

and maintenance of transgenic organisms comprising animals and plants or
multicellular organisms carrying parts of the TET-System for the intended use of
Target Validation.
1.32
"Vector Development" (including cellular and gene therapy) shall mean the
design and generation of plasmids, non-viral and viral vectors carrying TET
components for the intended use of developing genetic therapies to treat
disease.
ARTICLE 2 - GRANT
2.1
License Grant. TET hereby grants to COMPANY, upon and subject to all the
terms and conditions of this Agreement,
Confidential
BioFactura, Inc.
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Page 179 of 218
2.2
(a)
a Non-Exclusive license in the Licensed Territory under the Patent Rights,

to utilize the TET-System and TET-Product(s) in the Partial Licensed
Field of Use; and
(b)
a Non-Exclusive (sub)license in the Licensed Territory under the

Improvement Rights to utilize the TET-System in the Partial Licensed
Field of Use to the extent such Improvement Rights are transferred or
exclusively licensed to TET following the exercising of the Grant Back
Option.
Sublicensing/Assignment.
(a)
The COMPANY does not have the right to sublicense or assign the rights
granted under Section 2.1 and commits not to attempting to grant any
sublicenses or to transfer the rights except that COMPANY may, subject
to its taking full responsibility for compliance with this agreement, grant
sublicenses or transfer its rights to any COMPANY Group member.
COMPANY has to immediately notify to TET the sublicenses granted to
any COMPANY Group member. The sublicense granted to any
COMPANY Group member will expire automatically once the sublicensee
leaves the COMPANY Group.
(b)
In case of granting sublicenses to any COMPANY Group member the

License Fee and the Annual License Maintenance Fee payable by the
COMPANY to the TET have to be calculated pursuant to Article 3 taking
into account the accumulated number of employees of the COMPANY
and the sublicensing member of the COMPANY Group.
(c)
In the event that a Third Party licensee of TET or of IP Merchandisers

GmbH & Co. KG, an entity authorized by TET to license out TET`s patent
portfolio becomes member of the COMPANY Group TET will upon
request in writing by the COMPANY consent to such license agreement
between the Third Party and TET or IP Merchandisers being transferred
into a sublicense agreement between the COMPANY and its new
COMPANY Group member with effect of the next Anniversary Date of
such license. In case of transfer the payments due under Article 3 shall be
recalculated according to Section 2.2. (b). Notwithstanding the payment
due under Article 3, COMPANY shall pay to TET a transfer fee equal to
the amount of the Annual License Maintenance Fee which would have to
be paid to TET or to IP Merchandisers by the former Third Party licensee
if it would not have become a COMPANY Group member.
(d)
In the event that a Third Party licensee of a previous owner of the Patent
Rights becomes member of the COMPANY Group and terminates its
license agreement with the previous owner of the Patent Rights
COMPANY has to immediately notify TET of its intention to grant its new
COMPANY group member a sublicense. In case of sublicensing the
payments due under Article 3 shall be recalculated according to Section
2.2. (b). Notwithstanding the payment due under Article 3, COMPANY
shall pay to TET a sublicensing fee to the amount of the Annual License
Confidential
BioFactura, Inc.
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Maintenance Fee which would have to be paid to TET or to IP

Merchandisers by the former Third Party licensee if it would not have
become a COMPANY Group.
2.3
Expanding the Partial Licensed Field of Use. COMPANY may elect at any
time to expand the Partial Licensed Field of Use under this Agreement to include
any additional activity listed on;
(i)
Appendix B in Section V. (Optional Additional Fields of Use), and
(ii)
Appendix B in Section VI. (Optional Fields of Use) subsections A.
(Screening) and B.2 (additional Territory Partial), by giving TET written
notice of COMPANY's decision, along with the full payment associated
with such additional activities and due under Paragraph 3.3 below.
2.4
Narrowing the Partial Licensed Field of Use. COMPANY may elect to narrow
the Partial Licensed Field of Use to eliminate any or all activities listed on
Appendix B, on the third, or any subsequent, Anniversary Date, by giving TET
written notice of COMPANY's intentions at least ninety (90) days in advance.
2.5
Purchasing Reagents. Promptly following the Effective Date, TET will provide
COMPANY and the Authorized Suppliers with COMPANY's Licensee Number,
thereby authorizing the sale of TET Products to COMPANY by Authorized
Suppliers. COMPANY shall be responsible for all other interactions with
Authorized Suppliers, including all costs relating to the purchase and use of TET
Products. COMPANY agrees to indemnify and hold TET and any of its Affiliates
harmless from and against any such costs.
2.6
Excluded Uses. COMPANY hereby agrees and warrants that it shall not:
(i) purchase TET Products for any purpose other than its own, internal use under
this Agreement,
(ii) use the Patent Rights and the Improvement Rights, TET Products or the TETSystem in any way for the preparation or manufacture of materials intended for
use in or on humans, or
(iii) commercialize, import, manufacture, use, offer for sale, sell, or otherwise
exploit any TET Product or the TET-System, except as expressly provided in this
Agreement, without first entering into a written commercial license with TET, with
respect to such activities. The availability of such a commercial license to
COMPANY shall be determined at TET`s sole discretion, and shall be subject to
IP Merchandisers third party obligations.
2.7
Grant Back Option. If COMPANY performs Improvements and elects to outlicense or sell such Improvements and/or related rights (the Improvement
Rights), COMPANY hereby agrees to grant TET the right of first refusal for
acquiring such Improvement Rights by means of licensing or transfer on terms
not less favorable than those offered to any Third Party (the Grant Back
Option). TET`s right of first refusal shall become exercisable with its receipt of all
information, including any Confidential Information, which may be necessary or
desirable in order to evaluate the available technology rights, and shall expire on
the first to occur of: (i) TET giving formal notice to COMPANY that it does not
wish to pursue said right, or (ii) after six (6) months of the date on which TET
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received all required information unless the parties are as of this date engaged in
negotiations on the exercise of the Grant Back Option.
2.8
Results. Subject to the Grant Back Option COMPANY shall retain all right, title
and interest in and the unrestricted right to use the Results. COMPANY shall
have the unrestricted right to publish or otherwise disclose the Results.
ARTICLE 3 - CONSIDERATION, PAYMENTS AND REPORTS,
3.1
License Fee. COMPANY shall pay TET a license fee of [!] USD (US$ [!]) within
thirty (30) days of receipt of an invoice from TET. Standard license terms are
shown in App. B.
3.2
Bi-Annual License Maintenance Fee. Every six months following the Effective
Date, COMPANY shall from pay TET a license maintenance fee of [!] USD (US$
[!]) payable by COMPANY thirty (30) days following the receipt by COMPANY of
an invoice from TET.
3.3
Modification to the Field of Use. Where COMPANY has elected to modify the
Licensed Field of Use and/or the Licensed Territory pursuant to Sections 2.3 or
2.4, the annual license fee shall be determined as follows:
(a) For expansions of the Partial Licensed Field of Use or Licensed Territory, the
additional license fee calculated in accordance with the fee schedule shown
on Appendix B is due with the notice of expansion according to Section 2.3.
The additional license fee may be reduced by fifty percent (50 %) if, at the
time of COMPANY's written notice to TET, there are fewer than six (6)
months remaining before the next Anniversary Date; and
(b) For narrowing of the Partial Licensed Field of Use or Licensed Territory, no
rebates or credits on the Annual License Maintenance Fee paid for the year
in which COMPANY elected to narrow the Partial Licensed Field of Use or
Licensed Territory shall be available. Decreases in the Annual License
Maintenance Fee shall only take effect on the Anniversary Date which occurs
at least ninety (90) days after COMPANY's written notice to TET according to
Section 2.4.
3.4
Fee for (Sub) License under Improvement Rights. Following an exercising of

the Grant Back Option TET shall be entitled to reasonably adjust the license fees
payable by COMPANY under this Agreement for including the Improvement
Rights in accordance with Section 2.1 (b). Such adjustment shall include a
reasonable contribution to any expenses incurred by TET for acquiring the
Improvement Rights, unless the right to use the Improvement Rights by
COMPANY has been taken into account when agreeing on the terms for
exercising the Grant Back Option.
3.5
Payments. All payments due under this Agreement are payable in USD
Currency. Late payments shall incur interest at an annual rate of twelve percent
(12 %) compounded daily. All required payments shall be wire transferred into
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the bank account stated on the invoice with a confirmation of the transfer mailed,
e-mailed or faxed to the following address:
TET Systems GmbH & Co. KG
Attn. Controllers Office
Im Neuenheimer Feld 582
69120 Heidelberg, Germany
Fax +49 6221 588 04 04
Email: info@tet-systems.com
3.6
Report.
On each Anniversary Date COMPANY shall promptly report
(a) the number of its and the sublicensing COMPANY Group members
employees as of the Anniversary Date;
(b) an updated list of its Affiliates.
In the event that COMPANY does not provide TET with such report promptly on
each Anniversary Date, TET is entitled to calculate the Annual License
Maintenance Fee due on that Anniversary Date on the basis of the highest
threshold regarding the total number of employees as stated in Appendix B,
Section 1.
ARTICLE 4 MARKETING
Use of Names. TET shall have the right to publish COMPANYs name/logo in a listing of
Licensees published on www.tet-systems.com and in any publicity, news release, or
other public announcement or comment promoting TETs business, whether written,
electronic, or oral to indicate COMPANY being a licensee of TET and its affiliates. TET
will give COMPANY the opportunity to review the form and content of any such
announcement and to comment upon it before it is published.
ARTICLE 5 CONFIDENTIALITY
5.1
Confidential
BioFactura, Inc.
Nondisclosure. During the Term of the Agreement according to Section 6.1

and after its termination, each Party will maintain all Confidential Information of
the other Party as confidential and will not disclose any Confidential Information
to any Third Party or use any Confidential Information for any purpose except
(a) as expressly authorized by this Agreement; or (b) for the disclosure to its
Affiliates, employees, agents, consultants and other representatives, who have
a need to know such Information and who are bound by obligations of
confidentiality at least as restrictive as set forth herein. Each Party will use at
least the same standard of care as it uses to protect proprietary or confidential
information of its own to ensure that its Affiliates, employees, agents,
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consultants and other representatives do not disclose or make any unauthorized

use of the Confidential Information.
5.2
Authorized Disclosures. Each Party shall be permitted to disclose Confidential

Information:
(a)
to the extent that, such Confidential Information is required to be disclosed

to comply with applicable laws or regulations (such as disclosure to the
United States Securities and Exchange Commission) or with an
enforceable or final court or administrative order; provided however, that
such Party shall first have given written notice of such required disclosure
to the other Party, made reasonable efforts to narrow the scope of
Confidential Information required to be disclosed and to obtain a
protective order requiring that the Confidential Information to be disclosed
be used only for the purposes for which disclosure is required, taken
reasonable steps to allow the other Party to seek to protect the
confidentiality of the Confidential Information required to be disclosed, and
obtained written advice from its counsel that, notwithstanding the
foregoing measures, the Confidential Information is nonetheless required
to be disclosed; or
(b)
to establish rights or enforce obligations under this Agreement, but only to

the extent such disclosure is necessary and provided that such Party
seeks confidential treatment of the Confidential Information to be
disclosed.
ARTICLE 6 - PATENT RIGHTS
6.1
Prosecution. TET shall have the sole right, but no obligation, to pursue the
preparation, filing, prosecution and maintenance of the Patent Rights and, to the
extent that it exercised the Grant Back Option, the Improvement Rights, and
other legal proceedings relating thereto.
6.2
Enforcement. If COMPANY becomes aware that any Patent Rights, and to the
extent TET has exercised its Grant Back Option, the Improvement Rights, are
being infringed, are likely to be infringed or have been infringed by any Third
Party, or that TET Products have been misappropriated by a Third Party,
COMPANY shall promptly notify TET. TET shall have the right, but not the
obligation, to institute, prosecute and control any action, suit, or proceeding with
respect to such infringement or misappropriation, including any declaratory
judgment action, at its own expense, using counsel of its own choosing.
COMPANY shall render any reasonable assistance to TET in any of such
proceedings at its own expense.
6.3
Infringement of Third Party IP Rights. If the practice by COMPANY of the

license granted hereunder results in any allegation or claim of infringement of the
Intellectual Property of a Third Party against COMPANY, COMPANY shall have
the exclusive right to defend any such claim, suit, or proceeding, at its own
expense, by counsel of its own choosing and shall have the sole right and
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authority to settle any such suit; provided however, that COMPANY shall not
enter into any agreement, consent to any judgment or forego the possibility of
any appeal without the prior formal consent of TET. For the purpose of this Article
6 Intellectual Property shall mean patents, trademarks, service marks, logos,
trade names, rights in designs, copyright, utility models, and rights in any knowhow, in each case whether registered or not and including applications for
registration, and all rights or forms of protection having equivalent or similar effect
anywhere in the world.
6.4
Third Party Rights. COMPANY hereby acknowledges that in order to exploit the
rights granted herein, COMPANY may require licenses under patent or other
property rights other than those licensed herein. COMPANY hereby agrees that it
shall be COMPANY's sole responsibility to satisfy itself as to the need for such
licenses and, if necessary, to obtain such licenses.
ARTICLE 7 - TERM OF AGREEMENT
7.1
Term. This Agreement shall be effective as of the Effective Date and shall
continue in full force and effect until the expiration of the last to expire of the
Patent Rights, unless sooner terminated under this Article 7.
7.2
Termination by TET. This Agreement may be terminated by TET with immediate

effect (i) upon formal notification to COMPANY of any material breach of this
Agreement and, where such breach is capable to be remedied, has not been
remedied in full within thirty (30) days of the first notification, or (ii) if COMPANY
becomes insolvent, files a petition under any bankruptcy or insolvency act, or has
any such petition filed against it or any of its assets.
7.3
Termination by COMPANY. This Agreement may be terminated without cause

at any time by COMPANY upon sixty (60) days formal notice to TET, and upon
payment to TET of any fees currently or past due hereunder at the date the
termination by COMPANY takes effect.
7.4
Effect of Termination.
(a) Accrued Rights and Obligations. Termination of this Agreement for any
reason shall not release COMPANY from any liability which, at the effective
date of such termination, has already accrued to TET or which is attributable
to a period prior to such termination, nor preclude either Party from pursuing
any rights and remedies it may have hereunder, or at law or in equity which
accrued or are based upon any event occurring prior to such termination.
(b) Cessation of Use. Upon any termination of this Agreement, COMPANY shall
promptly cease any and all uses of the TET-System, TET Products, the
Patent Rights and to the extent TET has exercised the Grant Back Option,
the Improvement Rights. Furthermore, COMPANY shall promptly destroy any
such materials, including its own improvements, modifications or derivatives
of TET Products where such improvements, modifications or derivatives are
covered by the Patent Rights and/or the Improvement Rights to the extent
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TET has exercised the Grant Back Option, and shall provide TET with formal
evidence as to their full and comprehensive destruction. In the event that
COMPANY does not provide TET with such evidence within four (4) weeks of
the effective date of termination TET shall be entitled to claim from
COMPANY on every Anniversary Date until such evidence is provided,
liquidated damages equal to the amount of the Annual License Maintenance
Fee which would have to be paid by Company if the Agreement was not
terminated.
7.5
Survival. Articles 2.7, 5, 7.4, 7.5, 9, 10, and 11 hereof shall survive termination of
this Agreement for any reason.
ARTICLE 8 - NOTICES
8.1
Any formal notice required or permitted to be given under this Agreement shall be
sufficient if sent by certified mail, postage pre-paid, facsimile transmission, or email (return receipt),
if to TET, to:

Attn.
Managing
Director
Geschaeftsfuehrer
Im Neuenheimer Feld 582
69120 Heidelberg / Germany
(CEO)/
Fax +49 6221 588 04 04

Email: info@tet-systems.com
if to COMPANY, to
or to other such address as a Party may specify by formal notice.

8.2
Any written notice required or permitted to be given under this Agreement shall
be sufficient if sent by the means allowed under Section 8.1 or by facsimile or
email transmission to the contact details identified in accordance with Section
8.1.
ARTICLE 9 - COMPLIANCE WITH GOVERNMENTAL OBLIGATIONS
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COMPANY shall ensure that any research conducted under this Agreement will comply
with all applicable governmental regulations in force and effect. COMPANY shall comply
with and provide all information and assistance necessary to comply with any
governmental requests relating to this Agreement.
ARTICLE 10 - NO WARRANTY
10.1
Disclaimer of Warranties. Nothing in this Agreement is or shall be construed

as:
(a) A warranty or representation as to the validity or scope of the Patent Rights
and Improvement Rights;
(b) A warranty or representation that anything made, used, sold, imported or
disposed of under any license granted in this Agreement is or will be free from
infringement of patents, copyrights, and other rights of Third Parties;
(c) An obligation to bring or prosecute actions or suits against third parties for
infringement of the Patent Rights; or
(d) Granting by implication, estoppel, or otherwise any licenses or rights under
patents or other rights of TET and its Affiliates or operating units, or Third Parties
other than expressly provided herein, regardless of whether such patents or other
rights are dominant or subordinate to any of the Patent Rights, Improvement
Rights or TET Product(s).
10.2
No Other Warranty. COMPANY acknowledges that the Patent Rights claim

materials and methods which are experimental in nature. TET makes no
warranties express or implied of any kind (including without limitation
warranties of merchantability, fitness for a particular purpose, or noninfringement), and hereby expressly disclaims any warranties,
representations or guarantees of any kind as to the Patent Rights, TETSystem or TET Products. No biological materials are being provided to
COMPANY under this Agreement.
10.3
Indemnification. COMPANY agrees that it shall indemnify, defend and hold

harmless TET and its officers, employees and agents and their respective
successors, heirs and assigns (the Indemnitees), against any liability, damage,
loss, or expense (including reasonable attorneys fees and expenses) of any kind
incurred by or imposed upon any of the Indemnitees in connection with any
claims, suits, actions, demands or judgments arising out of any theory of liability
(including without limitation actions in the form of tort, warranty, or strict liability
and regardless of whether such action has any factual basis) relating to
COMPANYs use of the TET-System, TET-Product, any of the Patent Rights or
Improvement Rights under this Agreement.
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ARTICLE 11 - MISCELLANEOUS
11.1
Governing Law; jurisdiction. This Agreement shall be governed by and

construed in accordance with the laws of Germany without having any regard to
the conflicts of law provisions thereof. The Regional Court in Mannheim
(Landgericht Mannheim) shall have exclusive jurisdiction to hear any dispute
arising out of or in relation to this Agreement.
11.2
Severability; Waiver. In the event that any provision of this Agreement is

determined to be invalid or unenforceable by a court of competent jurisdiction,
the remainder of the Agreement shall remain in full force and effect without said
provision. The Parties undertake to replace the invalid provision or parts thereof
by a new provision which will approximate as closely as possible to the economic
or legal result intended by the Parties. The failure of a Party to enforce any
provision of the Agreement shall not be construed to be a waiver of the right of
such Party to thereafter enforce that provision or any other provision or right.
11.3
Entire Agreement. This Agreement, with its Appendices, constitutes the entire
agreement between the parties, both oral and written, with respect to the subject
matter hereof. There are no covenants, promises, agreements, warranties,
representations, conditions or understandings, either oral or written, between the
Parties other than as set forth herein. No amendment or change hereof or
addition hereto shall be effective or binding on either of the parties hereto unless
it is in formal writing and signed by or on behalf of both Parties.
IN WITNESS THEREOF, TET and COMPANY have caused this Agreement to be

executed by their duly authorized representatives as of the Effective Date.
by
Title
Dr. Ernst Boehnlein

Managing Director (CEO)/ Geschaeftsfuehrer
Date
COMPANY
By
Title
Date
Confidential
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____________
______
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APPENDIX A
SUMMARY OF TET SYSTEMS GMBH & CO. KG-OWNED PATENTS AND
PATENT APPLICATIONS CLAIMING THE TET-SYSTEM
ISSUED PATENTS:
U.S. Patents:
1.
Patent No.
5,464,758
Issue date
November 7, 1995
2.
5,589,362
December 31,
1996
3.
5,654,168
August 5, 1997
4.
5,789,156
August 4, 1998
5.
5,814,618
6.
5,859,310
September 29,
1998
January 12, 1999
7.
5,866,755
February 2, 1999
8.
5,888,981
March 30, 1999
9.
5,912,411
June 15, 1999
10.
6,004,941
11.
6,087,166
December 21,
1999
July 11, 2000
12.
6,136,954
October 24, 2000
13.
6,242,667
June 5, 2001
14.
6,252,136
June 26, 2001
15.
6,271,341
August 7, 2001
16.
6,271,348
August 7, 2001
17.
6,914,124
July 5, 2005
Confidential
BioFactura, Inc.
Title
Tight Control of Gene Expression
in Eukaryotic Cells by Tetracycline
Responsive Promoters
Tetracycline-Regulated
Transcriptional Modulators with
Altered DNA Binding Specificities
Tetracycline-Inducible
Transcriptional Activator and
Transcriptional Units
Transcriptional Inhibitors
Methods for Regulating Gene
Expression
Mice Transgenic for a
Tetracycline-Controlled
Transcriptional Activator
Animals Transgenic for a
Transcriptional Inhibitor
Expression
Mice Transgenic for a TetracyclineInducible Transcriptional Activator
Expression
Transcriptional Activators with
Graded Transactivation Potential
Transcriptional Activator Fusion
Proteins
Transgenic Organisms Having
Transcriptional Regulatory Systems
Transgenic Organisms Having
Transcriptional Regulatory Systems
Transcriptional Activators With
Graded Transactivation Potential
Transcriptional Inhibitor Fusion
Proteins
-14-
Inventors
Gossen and Bujard
Bujard, Gossen,
Hillen, Helbl, and
Schnappinger
Bujard and Gossen
Bujard and Gossen

Bujard and Gossen
Bujard, Gossen,
Salfeld, and Voss
Bujard and Gossen
Bujard, Gossen,
Salfeld, and Voss
Bujard and Gossen
Bujard and Gossen
Baron, Gossen, and
Bujard
Bujard and Gossen
Bujard and Gossen
Bujard, Gossen,
Salfeld, and Voss
Baron, Gossen and
Bujard
Bujard and Gossen
Bujard and Gossen
Page 189 of 218
18.
7,541,446
June 2, 2009
19.
7,666,668
February 23, 2010
Transcriptional Activator Fusion

Proteins
Tet repressor-based transcriptional
regulatory proteins
Chromosomal loci for the stringent
control of gene activities via
transcription activation systems
Hillen, Bujard and

Urlinger
Bujard and
Schonig
Non-U.S. Patents:
20.
Country
Australia
Patent No.
684524
Issue date
May 14, 1998
21.
Canada
2,165,162
May 23, 2000
22.
Australia
746850
August 15, 2002
23.
Australia
755417
April 3, 2003
24.
Germany
May 22, 2003
25.
Norway
DE
19851413
0315375
26.
Canada
2,193,122
August 23, 2005
27.
Europe
0804565
September 21, 2005
28.
Australia
783233
January 19, 2006
29.
Japan
4054058
February 27, 2008
30.
Australia
2003263199
August 14, 2008
31.
Canada
2,294,598
September 23, 2008
32.
Europe
1 532 260
December 10, 2008
33.
Japan
4424761
December 18, 2009
Confidential
BioFactura, Inc.
August 25, 2003
-15-
Title
Tight Control of Gene
Expression in Eukaryotic Cells
by Tetracycline Responsive
Promoters
Tight Control of Gene
Expression in Eukaryotic Cells
by Tetracycline Responsive
Promoters
Tetracycline Regulated
Transcriptional Modulators
Graded Transactivation
Potential
Verfahren zur Auswahl von
Mutanten von tTA und rtTA
Novel TET Repressor-Based
Transcriptional Regulatory
Proteins
Chromosomal Loci for the
Stringent Control of Gene
Activities via Transcription
Activation Systems
Potential
Chromosomal Loci for the
Stringent Control of Gene
Activities via Transcription
Activation Systems
Potential
Inventors
Bujard, Gossen,
Salfeld, and Voss
Bujard, Gossen,
Salfeld, and Voss
Bujard and Gossen

Baron, Gossen and
Bujard
Hillen
Bujard and Gossen
Bujard and Gossen
Bujard and Gossen
Hillen, Bujard, and
Urlinger
Bujard and Gossen
Bujard and
Schoenig
Baron, Gossen, and

Bujard
Schoenig and
Bujard
Baron, Gossen, and

Bujard
Page 190 of 218
34.
Europe
1200607
February 24, 2010
35.
Europe
0990030
March 03, 2010
36.
37.
Germany
Japan
19851415
4682176
November 04, 2010

February 10, 2011
38.
39.
Europe
Japan
1954811
4820344
June 08, 2011

September 9, 2011
40.
Japan
4836375
October 7, 2011
Novel TET Repressor-Based

Proteins
Potential
Mutanter Transaktivator
Transcriptional
Modulators
Inducible Expression Systems
TET Repressor-Based
Proteins
Hillen, Bujard and

Urlinger
Baron, Gossen, and
Bujard
Hillen, W.
Bujard and Gossen
Berkhout and Das

Bujard and Gossen
Hillen, Bujard and
Urlinger
PENDING PATENT APPLICATIONS:

Pending U.S. Patent Applications:
Application No./
Publication No.
1.
12/085,107
20100040649
2.
13/121,673/
20110247088
Publication date
Title
Inventors
February 18, 2010
Inducible Expression Systems
Berkhout and Das
October 06, 2011
Tetracycline inducible transcription

control sequence
Bujard and Loew
Pending Non-U.S. Patent Applications:

Country
Publication date
Title
Inventors
December 14,
2000
Novel TET RepressorBased Transcriptional

Regulatory Proteins
Transcriptional
Modulators
Chromosomal Loci for
the Stringent Control of
Gene Activities via
Transcription Activation
Systems
Transcriptional
Activators With
Potential
Hillen, Bujard and

Urlinger
3.
Canada
4.
European
Patent
Office
Canada
00204031.9
1092771
April 18, 2001
2,497,263
August 6, 2003
European
Patent
Office
08 168 539.8
November 7,
2008
5.
6.
Confidential
BioFactura, Inc.
Application No./
Publication No.
2376665
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Bujard and Gossen
Bujard and
Schoenig
Baron, Gossen,
and Bujard
Page 191 of 218
7.
Japan
2008-289475
November 12,
2008
8.
WO2010/037593
PCT/EP2009/060728
April 08, 2010
9.
European
Patent
Office
Australia
May 24, 2007
10.
Canada
20060316288
2006316288
2630348
11.
Japan
April 16, 2009
12.
Australia
2008541096
2009515550
2009299987
13.
Canada
2739192
20090819
April 08, 2010
Confidential
BioFactura, Inc.
May 24, 2007
April 08, 2010
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Transcriptional
Activators With
Potential
Tetracycline inducible
transcription control
sequence
Inducible Expression
Systems
Systems
Systems
sequence
sequence
Baron, Gossen,
and Bujard
Bujard and Lw
Berkhout and Das

Berkhout and Das
Berkhout and Das
Bujard and Loew
Bujard and Loew
Page 192 of 218
Appendix B
Price List in US$*
TET-System Research License and Optional Fields of Use
Scale: Total number of Employees
Up to 49
I. Full Basic Internal [Pharmaceutical] Research
st
License (1 Year)
II. Annual Maintenance Fee
5000 +
15.000,00
24.000,00
42.000,00
75.000,00
15.000,00
24.000,00
42.000,00
75.000,00
11.250,00
18.000,00
31.500,00
Not avail.
11.250,00
18.000,00
31.500,00
Not avail.
1.275,00
2.000,00
3.500,00
Not avail.
18.000,00
24.000,00
30.000,00
37.500,00
12.000,00
18.000,00
24.000,00
34.500,00
9.000,00
13.875,00
18.000,00
Not avail.
Non-exclusive
Includes all in-house research for internal purposes, such
as proof-of concept work with transgenics and knock-outs
Use in one Territory**
Does NOT include Screening, Bioprocessing /
Manufacturing, Contract Research or Screening
No commercialization rights are included.
III. Partial Internal [Pharmaceutical] Research

st
License (1 Year)
IV. Annual Partial Maintenance Fee
50 to 499 500-4999
Non-exclusive
Includes in-house use of the TET System as a Research
Tool for Target Validation and Study of Gene Function and
one of the following partial fields of use for internal
purposes (as selected in the License Agreement):
Vector Development
Transgenic Organism
Production strain Development
Use in one Territory**
Does NOT include Screening, Bioprocessing /
Manufacturing, Contract Research or Screening
No commercialization rights are included.
st
V. Optional Additional Fields of Use (1 year and

Annual Maintenance Fee): each of the following
Vector development
Transgenic organisms
Production strain development
VI. Optional Fields of Use (Additions to the Full or

Partial Basic Research License)
A. Screening
B.1 Each additional Territory Full:
B.2 Each additional Territory Partial:
Territories:
North America
Europe
Asia & Australia
Rest of World
Confidential
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C. Bioprocessing & Manufacturing:

By separate Agreement to be negotiated case-by-case
D. Contract Research and Contract Screening

E. Commercialisation rights
Availability to be determined at TET`s Discretion
* Prices are subject to change without notice until a license agreement between COMPANY and TET has been signed.
** Territory as defined in the License Agreement (Licensed Territory without additional or combination of territories)
Confidential
BioFactura, Inc.
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Section 6.5
sVero Cell Line LicenseZelltek/Gemabiotech
EVALUATION LICENSE AND EXCLUSIVE OPTION AGREEMENT

THIS EVALUATION LICENSE AND EXCLUSIVE OPTION AGREEMENT (this
Agreement) is entered into as of this 28 day of February, 2012 (the Effective
Date), by and between
Gemabiotech, S.A., located at San Vladimiro 3056, 1st
Floor, San Isidro, Province of Buenos Aires, Argentina (Licensor), and
BioFactura, Inc., a Delaware corporation, having a principal place of business at 9430
Key West Ave, Suite 125, Rockville, MD 20850 (Licensee).
WHEREAS, Licensee wishes to evaluate a serum-free suspension adapted Vero cell
line for making VRPs of alpha- and filoviruses in order to determine whether or not to
enter a definitive, written exclusive license agreement with Licensor (the Evaluation);
and
WHEREAS, Licensor is willing to grant to Licensee a non-exclusive license to
undertake such Evaluation and an exclusive option to an exclusive license under the
terms set forth in this Agreement.
NOW, THEREFORE, in consideration of the foregoing premises and the following
mutual promises, covenants, and conditions, the parties hereto agree as follows:
1.
EVALUATION LICENSE
Subject to the terms and conditions of this Agreement, Licensor grants to Licensee,
and Licensee hereby accepts, for the duration of the Term (as defined below) and for
the exclusive purpose of Licensees undertaking the Evaluation: a royalty-free, nonexclusive license, without the right to grant any sublicense to any third party, (i) under
any and all Licensor Intellectual Property Rights (as defined below) necessary to
undertake such Evaluation and (ii) to use Licensors Proprietary Information.
2.
PROPRIETARY INFORMATION AND CONFIDENTIALITY
Subject to Section 3 below, neither party shall disclose to any third party or use for
any purposes other than the performance of the Evaluation, any and all, privileged
records or other proprietary information or materials disclosed by one party to the
other party pursuant to this Agreement (collectively, Proprietary Information),
without the prior written consent of the party whose Proprietary Information is being
disclosed. Each party shall use the other partys Proprietary Information solely in
furtherance of the Evaluation. Each party may disclose Proprietary Information to
employees requiring access thereto in furtherance of the Evaluation; provided that
prior to making any such disclosures each such employee shall be apprised of the
duty and obligation to maintain such Proprietary Information in confidence and to not
use such Proprietary Information for any purpose other than the Evaluation. All
Proprietary Information shall remain the sole property of the disclosing party. Except
as expressly provided under this Agreement, no right or license is granted by either
party solely by virtue of a partys disclosure of its Proprietary Information. Each party
shall treat the other partys Proprietary Information as it would treat its own
proprietary information, but in no event shall it use less than a reasonable degree of
care under the circumstances. The obligations of non-disclosure and non-use shall
not apply to the following: (a) information that, at the time of disclosure hereunder, is
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available to the public; (b) information that, after disclosure hereunder, becomes
available to the public, except through breach of this Agreement; (c) information that a
party can demonstrate through contemporaneous written records was in its
possession at the time of disclosure by the other party and that was not acquired from
such other party or any of such other partys affiliates; (d) information that becomes
available to a party from a third party that is not legally or contractually prohibited
from disclosing such information; (e) information that is independently developed by
the receiving party without reference to or use of the disclosing partys Proprietary
Information; or (f) information that is required to be disclosed by any law, regulation,
or order of court; provided that, prior to disclosing Proprietary Information of the other
party, the receiving party shall first make reasonable efforts to notify the disclosing
party and provide it with an opportunity to prevent or limit disclosure pursuant to
such law, regulation or court order. The terms of this Agreement supersede any
previous non-disclosure agreements or any other preliminary representations or
understandings that have been entered into by the parties to this Agreement with
regard to the Evaluation. Within ten (10) business days of the expiration or early
termination of this Agreement, each party shall, at its sole cost and expense, (i) return
the other partys Proprietary Information or (ii) upon request by the other party,
destroy the other partys Proprietary Information and provide the other party written
certification of such destruction.
3.
PUBLICATION
In the event that the Licensee intends to publish and/or present, in the form of
papers, presentations at academic conferences or otherwise about the Result of the
Research conducted by Licensee using the Material or Proprietary Information
(hereinafter referred to as the Publications), Licensee shall inform Licensor about the
text to be published thirty (30) days prior to any such public disclosure or Publication,
and shall include in such Publications the name of Licensor (Zelltek) and Universidad
Nacional del Litoral and Licensors Provider Scientists as a co-author. Licensor shall
have 30 days from receipt of the proposed publication to present any written
comments to Licensee. Licensee shall adopt Licensors comments insofar as such
comments relate to the protection of Licensors Proprietary Information. Licensee shall,
at the request of Licensor, withhold any such submission for an additional period, not
to exceed 90 days, to allow Licensor to file patent applications or to take any other
action designed to protect Licensees patent, copyright, trademark or any other
proprietary rights.
4.
INTELLECTUAL PROPERTY RIGHTS
(a)
Invention shall mean any and all discoveries, developments, modifications,
improvements inventions (whether or not patentable), or works of authorship,
including but not limited to methods, processes, software, and tangible research
products created by a party or the parties during the performance of this Agreement.
Intellectual Property Rights means any and all copyrights, trademarks, service
marks, patent applications (including any and all substitutions, divisions,
continuations, and continuations-in-part derived from or claiming priority to such
patent applications), patents (including patents of addition, reissues, renewals,
registrations, extensions, and supplementary protection certificates issuing
therefrom), trade secrets and other intellectual property rights, anywhere in the world.
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Ownership of Inventions and Intellectual Property Rights thereon shall be determined

by the inventorship laws of the United States. Except as specifically set forth in this
Agreement, neither Licensee nor Licensor grants any right or license, or transfers by
operation of this Agreement, to the other party hereto any Intellectual Property Rights
that such party owns or controls as of, on or after the Effective Date.
(b)
Exclusive Option.
(i)
Licensor hereby grants to Licensee an exclusive first option (the
Option) for the period commencing on the Effective Date and ending eighteen (18)
months thereafter (the Option Period), to acquire an exclusive, royalty-bearing,
worldwide license (including the right to sublicense through multiple tiers of
sublicensees), under any and all Intellectual Property Rights, whether owned solely by
Licensor or jointly with any third party (collectively, Licensor Intellectual Property
Rights), to make, have made, use, offer for sale, sell and import VRPs of alpha- and
filoviruses using or derived from Licensors serum-free suspension adapted Vero cell
line (the Field), subject to the terms and conditions of a definitive, written exclusive
license agreement that shall be negotiated in good faith. Licensee shall have the right
but not the obligation, to exercise the Option by notifying Licensor at any time in
writing during the Option Period. For the purpose of clarity, Licensor shall not grant to
any third party any right or license under any Licensor Intellectual Property Rights in
the Field during the Term of this Agreement.
(ii)
Unless otherwise agreed in writing by the parties, the parties shall
negotiate in good faith the provisions of such a definitive license agreement within one
(1) year of Licensees exercise of the Option (the Negotiation Period). If Licensee
decides to not exercise the Option granted in this Section 4(b), or Licensee and
Licensor are unable to enter into a license agreement prior to the end of the
Negotiation Period, then in either such event, Licensor shall be free to offer a
commercial license to any third party respecting any Licensor Intellectual Property
Rights or to dispose of its interest in any Licensor Intellectual Property Rights in any
way it deems appropriate. Notwithstanding the foregoing sentence, in the event that
Licensee and Licensor are unable to enter into a license agreement prior to the end of
the Negotiation Period and thereafter any third party offers to accept from Licensor a
commercial license under Licensor Intellectual Property Rights in the Field, then in
such event Licensor shall notify Licensee of the terms and conditions of such thirdparty offer, and Licensee shall have the right of first refusal to match such terms and
conditions. Licensee shall exercise such right of first refusal by providing written
notice to Licensor within ten (10) business days following Licensees receipt of notice of
such third-party offer or such right shall expire.
5.
TERM AND TERMINATION
(a)
Unless earlier terminated in accordance with the provisions of this Agreement,
the term of this agreement shall commence on the Effective Date and shall terminate
upon the later of the expiration of the Option Period or the Negotiation Period, if any
(the Term).
(b)
This Agreement may be terminated by Licensee or Licensor upon at least sixty
(60) days prior written notice to the other party of such partys material breach of any
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of the terms and conditions of this Agreement, which breach the other party fails to
cure within such notice period.
(c)
This Agreement may be terminated by Licensee upon thirty (30) days prior
written notice to Licensor.
(d)
Expiration or termination of this Agreement shall have no affect on and shall be
without prejudice to any rights that have accrued to the benefit of a party prior to
such expiration or termination, except that the Option shall expire and Licensor shall
have no obligation to enter into any other agreement with Licensee in the event that
Licensor terminates this Agreement in accordance with Section 5(b) or Licensee
terminates this Agreement in accordance with Section 5(c).
6.
WARRANTIES; INDEMNIFICATION; LIMITATION OF LIABILITY
(a)
Each party represents and warrants to the other that: (i) it has full authority to
enter into this Agreement (including, with respect to Licensor, the authority to grant
the license to Licensee granted under Section 1 and the Option granted under Section
4(b)); and (ii) the performance of its obligations under this Agreement will not violate
the terms of any other agreement or contract to which it is a party or by which it is
bound. Each party hereby covenants that it shall not, and shall ensure that its
affiliates do not, enter into any such agreement or understanding during the Term.
(b)
Licensee shall indemnify and hold harmless Licensor, its affiliates, and their
respective directors, officers, employees and agents (collectively, Licensor
Indemnitees) from and against any and all expenses (including, without limitation,
attorneys fees), claims, liability, loss, damages or costs (collectively, Losses) arising
out of or resulting from any gross negligence or willful misconduct by Licensee; in
each case except to the extent that any of the foregoing arises out of or results from
any Licensor Indemnitees negligence, willful misconduct or breach of this Agreement.
(c)
Licensor shall indemnify and hold harmless Licensee, its affiliates, and their
respective directors, officers, employees and agents (collectively, Licensee
Indemnitees) from and against any and all Losses in connection with or in any way
arising out of or resulting from: (i) the breach of any warranty to Licensee set forth in
this Agreement; (ii) any actual or alleged infringement or violation of any third-party
Intellectual Property Rights or other proprietary rights arising from Licensees
performance of the Evaluation in accordance with the terms and conditions of this
Agreement; or (iii) any gross negligence or willful misconduct by Licensor; in each case
except to the extent that any of the foregoing arises out of or results from any Licensee
Indemnitees negligence, willful misconduct or breach of this Agreement.
(d)
EXCEPT FOR ANY DAMAGES OR LIABILITIES ARISING FROM A PARTYS
BREACH OF ITS CONFIDENTIALITY OBLIGATIONS OR FOR WHICH SUCH PARTY
HAS AN INDEMNITY OBLIGATION UNDER THIS AGREEMENT, NEITHER PARTY
SHALL BE LIABLE TO THE OTHER PARTY FOR ANY INCIDENTAL, INDIRECT,
SPECIAL, PUNITIVE, CONSEQUENTIAL OR LIKE DAMAGES, INCLUDING, WITHOUT
LIMITATION, ANY LOST PROFITS OF SUCH OTHER PARTY.
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7.
NOTICES
All notices required or permitted to be given under this Agreement shall be in writing
and shall be delivered by personal delivery, by certified or registered mail, return
receipt requested, facsimile transmission (receipt verified) or by internationally
recognized courier service. Any such notice shall be deemed effective: (a) when
personally delivered; (b) five (5) business days after dispatch by certified or registered
mail, return receipt requested; (c) on the date of a facsimile transmission (receipt
verified); or (d) the second business day after dispatch by an internationally recognized
courier service, as the case may be. All such notices shall be sent as follows:
If to Licensee:
original to:
Alexander Matschiner, Chief Operating Officer

Rockville, Maryland 20850
U.S.A.
with a copy to:
As above
If to Licensor:
original to:
Carlos Dupetit, General Manager

San Vladimiro 3056, 1st Floor
San Isidro, Province of Buenos Aires
Argentina
copy to:
As above
Either party may change its address or other contact information by notifying the
other party hereto as set forth above.
8.
USE OF OTHER PARTYS NAME
Neither Licensee nor Licensor shall use directly or by implication the names of the
other party, nor any of the other partys affiliates or contractors, nor any abbreviations
thereof, or of any employee of the other party in connection with any products,
publicity, promotion, financing, advertising, or other public disclosure without the
prior written permission of the other party.
9.
WAIVERS
No waiver of any term or provision of this Agreement shall be effective unless in

writing and signed by the party waiving such term or provision. No waiver of any term
or provision of this Agreement in any one or more instances shall be deemed to be, or
construed as, a further or continuing waiver of any such term or provision, or of any
other term or provision, of this Agreement.
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10.
SEVERABILITY
If any provision of this Agreement shall be held by a court of competent jurisdiction to

be invalid, illegal or unenforceable, the legality, validity and enforceability of the
remaining provisions of this Agreement shall not be affected or impaired thereby. In
the event that any provision of this Agreement shall be determined to be illegal or
unenforceable, that provision will be limited or eliminated to the minimum extent
necessary so that this Agreement shall otherwise remain in full force and effect and
enforceable.
11.
NO ORAL MODIFICATIONS
No change, modification, extension, or termination of this Agreement, or any provision

contained herein, shall be valid unless made in writing and signed by duly authorized
representatives of the parties.
13.
RELATIONSHIP OF PARTIES; NO THIRD-PARTY BENEFICIARIES
The relationship of the parties is that of independent contractors, and neither party
will incur any debts or make any commitments for the other party except to the extent
expressly provided in this Agreement. Nothing in this Agreement is intended to create
or will be construed as creating between the parties the relationship of joint venturers,
co-partners, employer/employee or principal and agent. Neither party shall have any
responsibility for the hiring, termination or compensation of the other partys
employees or contractors or for any employee benefits of any such employee or
contractor. This Agreement shall not confer any rights or remedies upon any third
party.
13.
GOVERNING LAW
This Agreement shall be governed by and construed in accordance with the laws of the
State of Maryland. The parties hereby agree to venue in and submit to the exclusive
jurisdiction of the state and/or federal courts located within the State of Maryland for
any suit, hearing or other legal proceeding in the event of any dispute or controversy
arising under or relating to this Agreement.
14.
ENTIRE AGREEMENT
This Agreement, including all Exhibits, constitutes the complete agreement of the
parties and supersedes all prior agreements and understandings, oral or written,
between the parties respecting the subject matter hereof.
15.
ASSIGNMENT; BINDING EFFECT
Neither party shall assign or transfer this Agreement, in whole or in part, without the
prior written consent of the other party, except that Licensee may assign its respective
rights and obligations under this Agreement to any of its affiliates or any third party
acquiring all or substantially all of the assets of Licensee to which this Agreement
relates. This Agreement shall be binding upon and inure solely to the benefit of
Licensee and Licensor, their successors and permitted assigns.
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16.
HEADINGS
The headings in this Agreement are for the convenience of reference only and are not
substantive parts of this Agreement nor shall they affect its interpretation.
17.
SURVIVAL
The rights and obligations of the parties shall continue under Sections 2, 3, 5(d) and 6
through 18 notwithstanding expiration or termination of this Agreement.
18.
COUNTERPARTS AND SIGNATURES
This Agreement and any amendments hereto may be executed in counterparts and all
such counterparts taken together shall be deemed to constitute one and the same
instrument. The parties agree that scanned signatures affixed to any one of the
originals and delivered by facsimile or email or other electronic means shall be valid,
binding and enforceable. The signatories hereto warrant and represent that they have
the competent authority on behalf of their respective organizations to enter into the
obligations of this Agreement.
IN WITNESS WHEREOF, the parties have caused this Evaluation License and
Exclusive Option Agreement to be executed by their duly authorized representatives as
of the Effective Date.
BIOFACTURA, INC.
GEMABIOTECH, S.A.
By:
By:
Printed Name:
Printed Name:
Title:
Title:
Date:
Date:
WCSR 7099628v1
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Section 6.6
BioFactura, Inc.
USAMRIID Collaborative R&D Agreement Draft
Page 202 of 218
A COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

Between
BioFactura, Inc.
Rockville, Maryland 20850
(Cooperator)
and
(USAMRIID)
Fort Detrick, Maryland 21702-5011
(Laboratory)
Article 1. Background
1.00 This Agreement is entered into under the authority of the Federal
Technology Transfer Act of 1986, 15 U.S.C. 3710a, et seq., between the
Cooperator and the Laboratory, the parties to this Agreement.
1.01 Laboratory, on behalf of the U.S. Government, and Cooperator
desire to cooperate in research and development on A Novel Production
Process for the Manufacturing of VEE VRP Vaccines according to the
attached Statement of Work (SOW) described in Appendix A. NOW,
THEREFORE, the parties agree as follows:
Article 2. Definitions
2.00 The following terms are defined for this Agreement as follows:
2.01 "Agreement" means this cooperative research and development
agreement.
2.02 "Invention" and "Made" have the meanings set forth in Title 15
U.S.C. Section 3703(9) and (10).
2.03 "Proprietary Information" means information marked with a
proprietary legend which embodies trade secrets developed at private expense
or which is confidential business or financial information, provided that such
information:
(i) is not generally known, or which becomes generally known or available
during the period of this Agreement from other sources without obligations
concerning their confidentiality;
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(ii) has not been made available by the owners to others without obligation
concerning its confidentiality; and
(iii) is not already available to the receiving party without obligation
concerning its confidentiality.
(iv) is not independently developed by or on behalf of the receiving party,
without reliance on the information received hereunder.
2.04 "Subject Data" means all recorded information first produced in the
performance of this Agreement.
2.05 "Subject Invention" means any Invention Made as a consequence of,
or in relation to, the performance of work under this Agreement.
Article 3. Research Scope and Administration
3.00 Statement of Work. Research performed under this Agreement shall
be performed in accordance with the SOW incorporated as a part of this
Agreement at Appendix A. It is agreed that any descriptions, statements, or
specifications in the SOW shall be interpreted as goals and objectives of the
services to be provided under this Agreement and not requirements or
warranties. Laboratory and Cooperator will endeavor to achieve the goals and
objectives of such services; however, each party acknowledges that such goals
and objectives, or any anticipated schedule of performance, may not be
achieved.
3.01 Review of Work. Periodic conferences shall be held between the
parties for the purpose of reviewing the progress of work. It is understood that
the nature of this research is such that completion within the period of
performance specified, or within the limits of financial support allocated, cannot
be guaranteed. Accordingly, all research will be performed in good faith.
3.02 Principal Investigator. Any work required by the Laboratory under
the SOW will be performed under the supervision of Pamela J. Glass, Ph.D.,
USAMRIID, 1425 Porter Street, Fort Detrick, MD 21702-5011, Phone: 301-6194742, Fax: 201-619-2290, Email: pamela.glass@us.army.mil, who, as coprincipal investigator has responsibility for the scientific and technical conduct of
this project on behalf of the Laboratory. Any work required by the Cooperator
under the SOW will be performed under the supervision of Darryl Sampey,
BioFactura, Inc., 9430 Key West Avenue, Suite 125, Rockville, MD 20850,
Phone: 301-315-8002, Fax: 240-597-6340, Email: dsampey@biofactura.com,
who, as co-principal investigator has responsibility for the scientific and technical
conduct of this project on behalf of the Cooperator.
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3.03 Collaboration Changes. If at any time the co-principal investigators

determine that the research data dictates a substantial change in the direction of
the work, the parties shall make a good faith effort to agree on any necessary
change to the SOW and make the change by written notice to the addresses
listed in section 13.05 Notices.
3.04 Progress Reports. The parties shall prepare an annual report of
progress and a final technical report of the results of this project. Annual reports
should be completed within 1 month of the anniversary date of agreement
execution. A final report should be completed within six months after completion
of the SOW. All reports should be sent electronically to
BPPPROGRESSREPORTS@amedd.army.mil .
Article 4. Ownership and Use of Physical Property
4.01 Ownership of Materials or Equipment. All materials or equipment
developed or acquired under this Agreement by the parties shall be the property
of the party which developed or acquired the property, except that government
equipment provided by Laboratory (1) which through mixed funding or mixed
development must be integrated into a larger system, or (2) which through
normal use at the termination of the Agreement has a salvage value that is less
than the return shipping costs, shall become the property of Cooperator.
4.02 Use of Provided Materials. Both parties agree that any materials
relating to them which were provided by one party to the other party will be used
for research purposes only. The materials shall not be sold, offered for sale,
used for commercial purposes, or be furnished to any other party without
advance written approval from the Provider's official signing this Agreement or
from another official to whom the authority has been delegated, and any use or
furnishing of material shall be subject to the restrictions and obligations imposed
by this Agreement.
Article 5. Financial Obligation
5.00 Advance Payment. The performance of research by Laboratory
under this Agreement is conditioned on the advance payment by Cooperator of
Laboratory's agreed upon costs for the performance of such research.
5.01 Deposit Account. Cooperator shall pay $226,845.00 per Appendix B
to Laboratory for the performance of the research specified by Article 3.00. The
check should be made payable to the U.S. Treasury and mailed to the address
below. Please reference Project XXXXX on your check for ease in identification.
USAMRIID
Attn: Budget Office
1425 Porter Street
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Phone: 301-619-8303 Fax: 301-619-4619
Laboratory shall not be obligated to perform any of the research specified herein,
or to take any other action required by this Agreement, if the agreed to funds are
not deposited as required by this Article.
5.02 Insufficient and Excess Funds. Laboratory shall not be required to
continue its research and development activities under this Agreement if the
funds provided by Cooperator are insufficient to cover Laboratory's agreed upon
costs for such continued activities. Funds not expended by Laboratory shall be
returned to Cooperator upon Laboratory's submission of a final fiscal report to
Cooperator.
5.03 Accounting Records. Laboratory shall maintain separate and distinct
current accounts, records, and other evidence supporting all its expenditures
under this Agreement. Laboratory shall provide Cooperator a semi-annual report
accounting for the use of Cooperator's funds and a final fiscal report within four
months after completing the SOW or ending its research activities under this
Agreement. The accounts and records of Laboratory shall be available for
reasonable inspection and copying by Cooperator and its authorized
representative.
Article 6. Patent Rights
6.00 Reporting. The parties shall promptly report to each other all
Subject Inventions reported to either party by its employees. All Subject
Inventions Made during the performance of this Agreement shall be listed in the
Final Report required by this Agreement.
6.01 Cooperator Employee Inventions. Laboratory waives any ownership
rights the U.S. Government may have in Subject Inventions Made by Cooperator
employees and agrees that Cooperator shall have the option to retain title in
Subject Inventions Made by Cooperator employees. Cooperator shall notify
Laboratory promptly upon making this election and agrees to timely file patent
applications on Cooperator's Subject Invention at its own expense. Cooperator
agrees to grant to the U.S. Government on Cooperator's Subject Inventions a
nonexclusive, nontransferable, irrevocable, paid-up license in the patents
covering a Subject Invention, to practice or have practiced, throughout the world
by, or on behalf of the U.S. Government. The nonexclusive license shall be
evidenced by a confirmatory license agreement prepared by Cooperator in a
form satisfactory to Laboratory.
6.02 Laboratory Employee Inventions. Laboratory shall have the initial
option to retain title to, and file patent application on, each Subject Invention
Made by its employees. The Laboratory agrees to grant an exclusive license to
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any invention arising under this Agreement to which it has ownership to the
Cooperator in accordance with Title 15 U.S. Code Section 3710a, on terms
negotiated in good faith. Any invention arising under this Agreement is subject to
the retention by the U.S. Government of nonexclusive, nontransferable,
irrevocable, paid-up license to practice, or have practiced, the invention
throughout the world by or on behalf of the U.S. Government.
6.03 Joint Inventions. Any Subject Invention patentable under U.S. patent
law which is Made jointly by Laboratory employees and Cooperator employees
under the Scope of Work of this Agreement shall be jointly owned by the parties.
The parties shall discuss together a filing strategy and filing expenses related to
the filing of the patent covering the Subject Invention. If a party decides not to
retain its ownership rights to a jointly owned Subject Invention, it shall offer to
assign such rights to the other party, pursuant to Paragraph 6.05, below.
6.04 Government Contractor Inventions. In accordance with 37 Code of
Federal Regulations 401.14, if one of Laboratorys Contractors conceives an
invention while performing services at Laboratory to fulfill Laboratorys obligations
under this Agreement, Laboratory may require the Contractor to negotiate a
separate agreement with Cooperator regarding allocation of rights to any Subject
Invention the Contractor makes, solely or jointly, under this Agreement. The
separate agreement (i.e., between the Cooperator and the Contractor) shall be
negotiated prior to the Contractor undertaking work under this Agreement or, with
the Laboratorys permission, upon the identification of a Subject Invention. In the
absence of such a separate agreement, the Contractor agrees to grant the
Cooperator an option for a license in Contractors inventions of the same scope
and terms set forth in this Agreement for inventions made by Laboratory
employees.
6.05 Filing of Patent Applications. The party having the right to retain title
to, and file patent applications on, a specific Subject Invention may elect not to
file patent applications, provided it so advises the other party within 90 days from
the date it reports the Subject Invention to the other party. Thereafter, the other
party may elect to file patent applications on the Subject Invention and the party
initially reporting the Subject Invention agrees to assign its ownership interest in
the Subject Invention to the other party.
6.06 Patent Expenses. The expenses attendant to the filing of patent
applications shall be borne by the party filing the patent application. Each party
shall provide the other party with copies of the patent applications it files on any
Subject Invention, along with the power to inspect and make copies of all
documents retained in the official patent application files by the applicable patent
office. The parties agree to reasonably cooperate with each other in the
preparation and filing of patent applications resulting from this Agreement.
Article 7. Exclusive License
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7.00 Grant. The Laboratory agrees to grant to the Cooperator an

exclusive license in each U.S. patent application, and patents issued thereon,
covering a Subject Invention, which is filed by the Laboratory subject to the
reservation of a nonexclusive, nontransferable, irrevocable, paid-up license to
practice and have practiced the Subject Invention on behalf of the United States.
7.01 Exclusive License Terms. The Cooperator shall elect or decline to
exercise its right to acquire an exclusive license to any Subject Invention within
six months of being informed by the Laboratory of the Subject Invention. The
specific royalty rate and other terms of license shall be negotiated promptly in
good faith and in conformance with the laws of the United States.
Article 8. Background Patent(s)
8.00 Laboratory Background Patent(s): Laboratory has filed patent
application(s), or is the assignee of issued patent(s) which contain(s) claims that
are related to research contemplated under this Agreement. No license(s) to
this/these patent applications or issue patents is/are granted under this
Agreement, and this/these application(s) and any continuations to it/them are
specifically excluded from the definitions of Subject Invention contained in this
Agreement.
8.01 Cooperator Background Patent(s): Cooperator has filed patent
application(s), or is the assignee of issued patent(s) which contain(s) claims that
are related to research contemplated under this Agreement. No license(s) to
this/these patent applications or issue patents is/are granted under this
Agreement, and this/these application(s) and any continuations to it/them are
specifically excluded from the definitions of Subject Invention contained in this
Agreement.
Article 9. Subject Data and Proprietary Information
9.00 Subject Data Ownership. Subject Data shall be jointly owned by the
parties. Each party, upon request to the other party, shall have the right to
review and to request delivery of all Subject Data, and delivery shall be made to
the requesting party within two weeks of the request, except to the extent that
such Subject Data are subject to a claim of confidentiality or privilege by a third
party.
9.01 Proprietary Information/Confidential Information. Each party shall
place a proprietary notice on all information it delivers to the other party under
this Agreement that it asserts is proprietary. The parties agree that any
Proprietary Information or Confidential Information furnished by one party to the
other party under this Agreement, or in contemplation of this Agreement, shall be
used, reproduced and disclosed by the receiving party only for the purpose of
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carrying out this Agreement, and shall not be released by the receiving party to
third parties unless consent to such release is obtained from the providing party.
9.02 Army limited-access database. Notwithstanding anything to the
contrary in this Article, the existence of established CRADAs specifying areas of
research and their total dollar amounts may be documented on limited access,
password-protected websites of the U.S. Army Medical Research and Materiel
Command (the parent organization of Laboratory), to provide the Commands
leadership with a complete picture of military research efforts.
9.03 Laboratory Contractors. Cooperator acknowledges and agrees to
allow Laboratorys disclosure of Cooperators proprietary information to
Laboratorys Contractors for the purposes of carrying out this Agreement.
Laboratory agrees that it has or will ensure that its Contractors are under written
obligation not to disclose Cooperators proprietary information, except as
required by law or court order, before Contractor employees have access to
Cooperators proprietary information under this Agreement.
9.04 Release Restrictions. Laboratory shall have the right to use all
Subject Data for any Governmental purpose, but shall not release Subject Data
publicly except: (i) Laboratory in reporting on the results of research may publish
Subject Data in technical articles and other documents to the extent it determines
to be appropriate; and (ii) Laboratory may release Subject Data where release is
required by law or court order. The parties agree to confer prior to the
publication of Subject Data to assure that no Proprietary Information is released
and that patent rights are not jeopardized. Prior to submitting a manuscript for
review which contains the results of the research under this Agreement, or prior
to publication if no such review is made, each party shall be offered an ample
opportunity to review any proposed manuscript and to file patent applications in a
timely manner.
9.05 FDA Documents. If this Agreement involves a product regulated by
the U.S. Food and Drug Administration (FDA), then the Cooperator or the U.S.
Army Medical Research and Materiel Command, as appropriate, may file any
required documentation with the FDA. In addition, the parties authorize and
consent to allow each other or their contractors or agents access to, or to crossreference, any documents filed with the FDA related to the product.
Article 10. Termination
10.00 Termination by Mutual Consent. Cooperator and Laboratory may
elect to terminate this Agreement, or portions thereof, at any time by mutual
consent.
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10.01 Termination by Unilateral Action. Either party may unilaterally

terminate this entire Agreement at any time by giving the other party written
notice, not less than 30 days prior to the desired termination date.
10.02 Termination Procedures. In the event of termination, the parties
shall specify the disposition of all property, patents and other results of work
accomplished or in progress, arising from or performed under this Agreement by
written notice. Upon receipt of a written termination notice, the parties shall not
make any new commitments and shall, to the extent feasible, cancel all
outstanding commitments that relate to this Agreement. Notwithstanding any
other provision of this Agreement, any exclusive license entered into by the
parties relating to this Agreement shall be simultaneously terminated unless the
parties agree to retain such exclusive license.
Article 11. Disputes
11.00 Settlement. Any dispute arising under this Agreement which is not
disposed of by agreement of the principal investigators shall be submitted jointly
to the signatories of this Agreement. A joint decision of the signatories or their
designees shall be the disposition of such dispute. However, nothing in this
section shall prevent any party from pursuing any and all administrative and/or
judicial remedies which may be allowable.
Article 12. Liability
12.00 Property. Neither party shall be responsible for damages to any
property provided to, or acquired by, the other party pursuant to this Agreement.
12.01 Cooperator's Employees. Cooperator agrees to indemnify and hold
harmless the U.S. Government for liability of any kind involving an employee of
Cooperator arising in connection with this Agreement, and for all liabilities arising
out of the use by Cooperator of Laboratory's research and technical
developments, or out of any use, sale or other disposition by Cooperator of
products made based on Laboratory's technical developments, except to the
extent the liability is due to the negligence of Laboratory under the provisions of
the Federal Tort Claims Act. This provision shall survive termination or expiration
of this Agreement.
12.02 No Warranty. The parties make no express or implied warranty as
to any matter whatsoever, including the conditions of the research or any
Invention or product, whether tangible or intangible, Made, or developed under
this agreement, or the ownership, merchantability, or fitness for a particular
purpose of the research or any Invention or product. Material provider makes no
representation that the use of Material will not infringe any patent or other
proprietary rights of third parties.
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Article 13. Miscellaneous

13.00 Governing Law. The construction, validity, performance, and
effect of this Agreement shall be governed for all purposes by the laws applicable
to the United States Government.
13.01 Export Control and Biological Select Agents and Toxins. The
obligations of the parties to transfer technology to one or more other parties,
provide technical information and reports to one or more other parties, and
otherwise perform under this Agreement are contingent upon compliance with
applicable United States export control laws and regulations. The transfer of
certain technical data and commodities may require a license from a cognizant
agency of the United States Government or written assurances by the Parties
that the Parties shall not export technical data, computer software, or certain
commodities to specified foreign countries without prior approval of an
appropriate agency of the United States Government. The Parties do not, alone
or collectively, represent that a license shall not be required, nor that, if required,
it shall be issued. In addition, where applicable, the parties agree to fully comply
with all laws, regulations, and guidelines governing biological select agents and
toxins.
13.02 Independent Contractors. The relationship of the parties to this
Agreement is that of independent contractors and not as agents of each other or
as joint venturers or partners.
13.03 Use of Name or Endorsements. (a) The parties shall not use the
name of the other party on any product or service which is directly or indirectly
related to either this Agreement or any patent license or assignment agreement
which implements this Agreement without the prior approval of the other party.
(b) By entering into this Agreement, Laboratory does not directly or indirectly
endorse any product or service provided, or to be provided, by Cooperator, its
successors, assignees, or licensees. Cooperator shall not in any way imply that
this Agreement is an endorsement of any such product or service. Press
releases or other public releases of information shall be coordinated between the
parties prior to release, except that the Laboratory may release the name of the
Cooperator and the title of the research without prior approval from the
Cooperator.
13.04 Survival of Specified Provisions. The rights specified in provisions
of this Agreement covering Patent Rights, Subject Data and Proprietary
Information, and Liability shall survive the termination or expiration of this
Agreement.
13.05 Notices. All notices pertaining to or required by this Agreement
shall be in writing and shall be signed by an authorized representative addressed
as follows:
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If to Cooperator: BioFactura, Inc.

Rockville, MD 20850
Phone: 301-316-8002 Fax: 240-597-6340
If to Laboratory: USAMRIID
Business Plans and Programs Office
1425 Porter Street
Phone: 301-619-6886 Fax: 301-619-8379
Any party may change such address by notice given to the other in the manner
set forth above.
Article 14. Duration of Agreement and Effective Date
14.01 Effective Date. This Agreement shall enter into force as of the date
it is signed by the last authorized representative of the parties.
14.02 Signature Execution. This Agreement may be executed in one or
more counterparts by the parties by signature of a person having authority to
bind the party, which may be by facsimile signature, each of which when
executed and delivered, by facsimile transmission, mail, or email delivery, will be
an original and all of which will constitute but one and the same Agreement.
14.03 Expiration Date. This Agreement will automatically expire two (2)
years from effective date unless it is revised by written notice and mutual
agreement.
[Signatures follow on next page]
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IN WITNESS WHEREOF, the Parties have caused this agreement to be

executed by their duly authorized representatives as follows:
BioFactura, Inc.______________________
(Organization Title)
__________________________________
(Signature)
Date: _______________
__________________________________
(Typed Name)
__________________________________
(Title)
U. S. Army Medical Research Institute of Infectious Diseases
_________________________________
Bernard L. DeKoning
Colonel, Medical Corps
Commanding
Date: _______________
For the USAMRIID Principal Investigator:

I hereby acknowledge the terms and conditions of this Agreement:
____________________________________
Pamela J. Glass, Ph.D.
Date: _______________
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APPENDIX A
STATEMENT OF WORK
Title: A Novel Production Process for the Manufacturing of VEE VRP Vaccines
Background: BioFactura has designed an improved scalable cell culture
bioprocess for the production of Virus Replicon Particle (VRP) vaccines based on
the attenuated strain of the replication defective VEE virus, V3014. BioFacturas
proposed production methods will not only speed up the advanced development
process leading to FDA approval for a broad range of VRP vaccines, but also
offer a significant reduction in cost and time over the current manufacturing
process.
Although the VEE VRP platform has proven to yield protective vaccines
for the range of filoviruses (Ebola, Marburg) and alphaviruses (WEE, VEE, and
EEE), the current process for production of VRPs is low yielding and poorly
scalable to cGMP manufacture. BioFacturas process will replace the currently
used adherent Vero cell line with a stable suspension Vero (sVero) cell line
(Zelltek) or stable suspension EB66 cell line (Vivalis) that expresses the VRP
structural proteins using a tightly controlled inducible promoter. Furthermore,
BioFacturas production process will replace the current bottleneck of
electroporation with a simple VRP transduction step to transport the replicon
coding for the pathogen genes of interest into the stable sVero or EB66 cell line.
Upon development and optimization, this process will provide a universal
scalable production method for any VEE VRP vaccine using a common stable
helper cell line and modular replicon induction step. Elements of this process
may also be applicable to other VRP- and VLP-based vaccines and platforms.
The current manufacturing process developed by AlphaVax has
demonstrated production yields of 2-6x10^11 Focus Forming Units (FFU) per
batch. Assuming a human dose of 10^10 FFU (based on the filovirus vaccines),
the current process yields 20-60 vaccine doses per batch. This level of
productivity is orders of magnitude below what would be considered acceptable
and economically feasible in the drug industry. BioFactura has identified several
key bottlenecks in the current manufacturing process including the use of
adherent Vero cells, the requirement of three plasmid co-transfection, and the
use of electroporation for the co-transfection. The most significant bottleneck in
the current AlphaVax-developed manufacturing process is the requirement for
the electroporation of the production Vero cell lines to initiate VRP generation.
For large-scale cGMP manufacture (>2000-2500 doses/batch), this step carries
high risks of contamination and process variability, and is prohibitively cost and
labor intensive. Other alternative methods utilizing liposome- and/or chemicalmediated transfection approaches also carry significant disadvantages and risks
such as low efficiency, high cost, and introduction of unwanted contaminants to
the process.
This collaborative research will be supported at USAMRIID by funding
received from BioFactura (USAMRIID number XXXXX).
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Objectives: BioFactura will develop a novel process for the scalable

manufacture of VEE VRPs in a stable suspension (sVero or EB66) helper cell
line. In collaboration with Dr. Pamela Glass of USAMRIID the lead VEE VRP
vaccine candidate will be used as a model for these manufacturing process
changes. To mitigate risk, two cell lines and two inducible promoter systems (TetOn 3G and Lac Switch II) will be evaluated with subsequent down-selection prior
to advancing the best performing system. Vero in addition to MRC-5 are the only
FDA approved cell lines for the commercial manufacture of live virus and virallyvectored vaccines (principally due to the absence of endogenous retroviruses).
BioFactura proposes to use Vero because MRC-5 has been demonstrated to
produce lower titers of VEE virus. Vivalis maintains a Drug Master File with the
FDA for the EB66 cell line, and vaccine candidates produced in EB66 cells have
been approved by the US FDA and Japanese MHW for use in human clinical
studies. The Company does not recommend using any other currently available
manufacturing cells lines due to complex downstream process development
requirements, significantly increased manufacturing cost, and higher risk of
failure.
BioFacturas stable cell line process development approach will be milestone
gated to reduce risk and allow for go/no-go decisions by CBMS. The proposed
key milestones are as follows:
1. Demonstration of baseline VEE VRP productivity and bioactivity in the
suspension Vero and EB66 cell lines in serum-free medium using the current
electroporation process.
2. Generation of scalable stable sVero and EB66 helper cell lines capable of
inducible expression of the VEE structural subunits creating a universal helper
cell line.
3. Determination of optimal induction and transduction conditions using the target
vaccine product (lead VEE VRP candidate) as the replicon delivery vector.
4. Integration of unit operations and demonstration of process scalability in
bioreactors.
At each milestone, vaccine product will be generated using the current
downstream protocols and compared to a reference lot (lead vaccine
candidateAlphaVax). Assays will include indirect immunofluorescence assay
yield determination (FFU), in vitro reactivity (epitope retention based on
monoclonal antibody reactivity in an ELISA), and in vivo immunogenicity. In
addition, we propose to conduct a full panel of cell line release tests to comply
with cGMP requirements for Master Cell Banks.
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Collaboration:
USAMRIID agrees to:
Electroporate suspension cell lines with three VRP plasmids (VEE

vaccine) and perform downstream processing to generate purified VRP
(BSL-3).
Compare sVero generated VRP to VRP reference (manufactured using
standard methods)Yield (FFU/batch normalized to cell density), in vitro
reactivity (epitope retention based on reactivity with monoclonal antibodies
in an ELISA), in vivo immunogenicity in mice (total IgG and neutralizing
serum antibody responses), protective efficacy in mice, and test for
replication competent virus (BSL-3).
Induce stable helper cell lines to initiate VRP structural protein expression
and electroporate cells with the single VRP replicon (VEE vaccine).
Perform downstream processing to generate purified VRP (BSL-3).
Compare stable cell line generated VRP to VRP reference (manufactured
using standard methods)Yield (FFU/batch normalized to cell density), in
vitro reactivity (epitope retention based on reactivity with monoclonal
antibodies in an ELISA), in vivo immunogenicity in mice (total IgG and
neutralizing serum antibody responses), protective efficacy in mice, and
test for replication competent virus (BSL-3).
Expand and induce stable helper cell lines to initiate VRP structural
protein expression and transduce with VEE VRP particles at optimal MOI
(VEE vaccine). Perform downstream processing to generate purified VRP
(BSL-3).
Compare VRP transduced stable helper cell line generated VRP to VRP
reference (manufactured using standard methods)Yield (FFU/batch
normalized to cell density), in vitro reactivity (epitope retention based on
reactivity with monoclonal antibodies in an ELISA), in vivo immunogenicity
in mice (total IgG and neutralizing serum antibody responses), protective
efficacy in mice, and test for replication competent virus (BSL-3).
Cell culture process integration at 5-L bioreactor scale (BSL-3).
Cooperator agrees to:
Obtain parental suspension cell banks and create new working banks.
Test working banks at BioReliance for adventitious agents.
Confirm growth characteristics and morphology confirm to the norm.
Construct inducible mammalian expression vectors (plasmid DNA) coding
for the VEE structural proteins (GPs and capsid) using both Tet-On 3G
(doxycycline inducible, Clontech) and Lac Switch II (IPTG inducible,
Agilent) systems.
Transfect parental cells using electroporation with either vector (two sets
of transfections).
Select for stable cell lines using appropriate antibiotic/drug strategy.
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Scale up stable pools and evaluate growth characteristics and morphology

(VEE protein toxicity issues due to leaky promoters).
Induce VRP structural protein expression and test for presence of VEE
structural proteins by western blot.
Isolate best performing clones by limiting dilution in medium with an
optimized supplement that promotes cell growth at low density (e.g., one
cell per well). Clones will emerge in 14-21 days and will be characterized
for growth and productivity in 6-well plates. Best performers will be scaled
up to 30-mL shaker culture in production medium and further
characterized.
Perform VEE VRP (VEE vaccine) transductions experiments using
parental suspension cells to determine optimal MOI (assay for presence of
replicon in cells)
Batch medium optimization in spinner flasks and 5-L bioreactor.
Optimize feed supplements in spinner flasks and 5-L bioreactor.
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Budget Out Year Summary
Programs
Project List
Budget Summary
Create New Budget
Query/Report
EOR
Budget Detail
Research Support
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Help
Print View
Budget Summary Information

Additional Project Editors
PI
Plan
Number
Sponsor
Plan
Glass, Doctor Pamela Jo
Sponsor
DRAFT
Short Title
VEE VRP manufacturing
Long Title
A Novel Production Process for the

Mnaufacturing of VEE VRP Vaccines
NB-16381
NB-16381
Internal Project ID: 16126
Oracle Project ID: 8276
Summary Data
Detailed Budget
2013
Direct Cost
Labor
53,686
Travel
Transport
Rentals
Printing
Cont Pers
24,600
Cont Serv
Cont Research
Supplies
Equipment
Direct Cost Sub
Total:
0
23,764
0
102,050
Other Direct Cost Breakdown

Vet Med
Aerosol Services
Pathology
Cell Culture
Hybridoma
Regulatory Affairs
Regulated Studies
SIP
Visual Information
Statistics
Clin Lab
Clin Research
Spore Prod
Research Serology
Facility Infrastructure
Other
Direct
Indirect
UFR
Total
104,173
20,622
0
226,845
https://riid-vision.detrick.army.mil/budget_tool/Interface/OutYearSummary.aspx?Project_ID=16126&External_System_ID=8276[2/24/2012 5:33:12 PM]
BioFactura, Inc.
Page 218 of 218

BioFactura-CBMS VRP Proposal

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BioFactura-CBMS VRP Proposal

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1.

Lead Organization Submitting Proposal: BioFactura, Inc.

Contractors Reference Number:

Technical Point of Contact:

Other Small Business

An Improved Production Process for the Manufacture of

Mr. Darryl Sampey, President & CEO

Administrative Point of Contact:

Date Proposal Prepared:

March 15, 2012

1. COVER PAGE ............................................................................................................................1

Acronyms, Abbreviations, and Symbols

ACB Accession Cell Bank

Figure 1. Vero helper cell line-based VEE VRP

Stable suspension helper cell

Recycling of VEE VRPs

2.3.1 Replicon-Helper System from Attenuated Venezuelan Equine Encephalitis Virus

2.3.3 sVero Parental Cell Line Origin

High cell densities as suspension cells (>20 millions cells/mL)

2.3.5 BioFactura Quality System

Proposed Technical Approach

2.4.1 Technical Approach Introduction

determination (FFU), in vitro reactivity (epitope retention based on monoclonal antibody

Project Technical Phases

CWBS 1.1.1.2 sVero Cell Bank

CWBS 1.1.2.2-.3 Vero Cell Line Expansion and Electroporation (BSL-3)

CWBS 1.1.2.4 VRP Purification

CWBS 1.1.2.4.1 VRP Harvest

CWBS 1.1.2.4.2-.3 Cytopathic Effect (CPE) Assay

CWBS 1.1.2.4.4-.8 VRP Filtration, Chromatography, and Formulation

CWBS 1.1.4.2 In-vitro Reactivity

CWBS 1.1.4.3 In-vivo Immunogenicity

CWBS 1.2.1.1.1-.8 EB66 Stable Helper Cell Line Generation

CWBS 1.2.1.2 Tet Induction System

CWBS 1.2.1.2.1-.8 EB66 Stable Helper Cell Line Generation

o CWBS 1.3.1 Preliminary Transduction Study

o CWBS 1.4.5 VRP Testing

3. PROJECT MANAGEMENT SECTION

Phase I: Suspension Parental Cell Lines (CWBS 1.1)

o CWBS 1.1.1 Working Cell Banks

CWBS 1.1.1.2 sVero Cell Bank

CWBS 1.1.2.2-.3 Vero Cell Line Expansion and Electroporation (BSL-3)

CWBS 1.1.2.4 VRP Purification

CWBS 1.1.2.4.1 VRP Harvest

CWBS 1.1.2.4.2-.3 Cytopathic Effect (CPE) Assay

CWBS 1.1.2.4.4-.8 VRP Filtration, Chromatography, and Formulation

CWBS 1.1.4.2 In-vitro Reactivity

CWBS 1.1.4.3 In-vivo Immunogenicity

o CWBS 1.1.5 Phase I Scientific and Technical Report (CDRL A003)

Phase II: Suspension Helper Cell Lines (CWBS 1.2)

o CWBS 1.2.1 EB66 Helper Cell Lines

CWBS 1.2.1.1 Lac Induction System

CWBS 1.2.1.1.1-.8 EB66 Stable Helper Cell Line Generation

CWBS 1.2.1.2 Tet Induction System

CWBS 1.2.1.2.1-.8 EB66 Stable Helper Cell Line Generation

Phase III: Induction/Transduction Optimization (CWBS 1.3)

o CWBS 1.3.1 Preliminary Transduction Study

Phase IV: Process Development (CWBS 1.4)

o CWBS 1.4.1 Batch Medium Optimization

Project Management (CWBS 1.5)

o CWBS 1.5.2 Program Reporting & Meetings

CWBS 1.5.2.3 Quarterly Program Review

CWBS and CWBS Dictionary

3.2.1 Acronyms, Abbreviations, and Symbols