Trials@uspto.

gov
571-272-7822

Paper: 13
Entered: June 10, 2016

UNITED STATES PATENT AND TRADEMARK OFFICE

____________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________
GENERICO, LLC and
FLAT LINE CAPITAL, LLC,
Petitioners,
v.
DR. FALK PHARMA GMBH,
Patent Owner.
____________
Case IPR2016-00297
Patent 8,865,688 B2
____________

Before LORA M. GREEN, GRACE KARAFFA OBERMANN, and

ELIZABETH M. ROESEL, Administrative Patent Judges.
ROESEL, Administrative Patent Judge.

DECISION
Institution of Inter Partes Review
37 C.F.R. 42.108

IPR2016-00297
Patent 8,865,688 B2
Petitioners, GeneriCo, LLC and Flat Line Capital, LLC, filed a
Petition seeking inter partes review of claims 1 and 16 of U.S. Patent No.
8,865,688 B2 (Ex. 1001, the 688 patent). Paper 1 (Pet.). Patent
Owner, Dr. Falk Pharma GmbH, filed a Preliminary Response. Paper 11
(Prelim. Resp.).
We have jurisdiction under 35 U.S.C. 314(a), which provides that an
inter partes review may by authorized only if the information presented in
the Petition and the Preliminary Response shows that there is a reasonable
likelihood that Petitioners would prevail with respect to at least one of the
claims challenged in the Petition. Applying that standard, we institute an
inter partes review of claims 1 and 16 of the 688 patent for the reasons and
on the ground set forth below.
Our findings of fact and conclusions of law are based on the record
developed thus far, before the filing of Patent Owners Response. This is
not a final decision as to the patentability of any challenged claim. Any final
decision will be based on the full record developed during the trial.
I. BACKGROUND
A. Related Matters
Pursuant to 37 C.F.R. 42.8(b)(2), the parties identify the following
district court actions in which the 688 patent is being asserted: Salix
Pharmaceuticals, Inc. et al. v. Novel Laboratories, Inc., Nos. 1-15-cv-00027
and 1-15-cv-00213 (D. Del.) (consolidated) and Salix Pharmaceuticals, Inc.
et al v. Mylan Pharmaceuticals, Inc. et al., No. 1-15-cv-00109 (N.D.
W.Va.). Pet. 1; Paper 6 (Patent Owners mandatory notices). According to
Patent Owner, Salix Pharmaceuticals, Ltd. is the original assignee and

IPR2016-00297
Patent 8,865,688 B2
currently the exclusive licensee of the 688 patent and is a real party-ininterest. Prelim. Resp. 2 n.1; Paper 6.
B. Information Relied Upon
Petitioners patentability challenges are primarily based on the
following references:
S. S. Davis, The Design and Evaluation of Controlled Release
Systems for the Gastrointestinal Tract, 2 J. CONTROLLED RELEASE 2738
(1985), Ex. 1009 (Davis-1985);
Salix Announces Statistically Significant Top-Line Results of a Unique
Granulated Mesalamine Product Registration Study in Ulcerative Colitis
(September 2007),
http://www.sec.gov/Archives/edgar/containers/fix021/1009356/00011931
2507195530/dex992.htm, Ex. 1012 (Sept. 2007 Press Release);
XIFAXAN Trials Initiated in C. difficile-Associated Diarrhea,
Irritable Bowel Syndrome and Hepatic Encephalopathy. New Article
[online] EndoNurse, 12 January 2006, Ex. 1014 (Endonurse);
Bogentoft, EP 0 040 590 A2, published November 25, 1981, Ex. 1015
(EP590);
Y. Marakhouski et al., A Double-blind Dose-escalating Trial
Comparing Novel Mesalazine Pellets with Mesalazine Tablets in Active
Ulcerative Colitis, 21 ALIMENT PHARMACOL. THER. 133140 (2005),
Ex. 1024 (Marakhouski); and
M. Brunner et al., Gastrointestinal Transit and Release of 5aminosalicylic Acid from 153Sm-labelled Mesalazine Pellets vs. Tablets in
Male Healthy Volunteers, 17 ALIMENT. PHARMACOL. THER. 11631169
(2003), Ex. 1025 (Brunner).
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In addition, Petitioners rely on the Declaration of George A. Digenis,
Ph.D., Ex. 1002 (Digenis Decl.).
C. Asserted Grounds of Unpatentability
Petitioners assert that claims 1 and 16 are unpatentable under
35 U.S.C. 103(a) based upon the following grounds:
Reference(s)
1

Sept. 2007 Press Release, Endonurse, and Davis-1985

Sept. 2007 Press Release, Endonurse, Davis-1985, and EP590

Sept. 2007 Press Release, Endonurse, and Davis-1985, and

Marakhouski

Sept. 2007 Press Release, Endonurse, and Davis-1985, and Brunner

II. ANALYSIS
A. The 688 Patent (Ex. 1001)
The 688 patent relates to a method of maintaining the remission of

ulcerative colitis (UC) by administration of a once-daily dosage of

granulated mesalamine.1 Ex. 1001, Abstract, 1:15. The 688 patent explains
that UC is an inflammatory disease of the colonic mucosa and that the goal
of treatment is to induce and maintain remission of the disease. Id. at 1:15
17, 1:4950. According to the 688 patent, maintenance medications must
be taken for a prolonged period of time to enable subjects to stay in
remission. Id. at. 1:5559.

Other names for mesalamine include 5-aminosalicylic acid, 5-ASA, and

mesalazine. See, e.g., Ex. 1001, 5:36, cols. 2125 (Example 7, Tables 59);
Prelim. Resp. 3.
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The 688 patent acknowledges that oral mesalamine formulations are
known in the art for treating UC. Id. at 1:602:3. The patent identifies
problems with prior art delivery systems, including: premature release, the
possibility of dose dumping, and sensitivity to conditions that increase
gastric pH and cause premature release of mesalamine (e.g., ingestion of a
meal), id. at 2:38. According to the 688 patent, bowel diseases, such as
UC, are not adequately controlled using currently available formulations. Id.
at 2:1215.
For a description of the granulated mesalamine formulations, the 688
patent refers to three earlier patents or publications. Id. at 2:911, 10:4752
(incorporating by reference U.S. Patent/Publication Nos. 6,277,412;
6,551,620; and 2003/0133983).
The 688 patent describes two Phase III clinical studies in which 562
subjects (study 1: 305 subjects; study 2: 257 subjects) were randomized 2:1
to receive either a 1.5 gram granulated mesalamine formulation or placebo
once daily in the morning for six months. According to the 688 patent, in
both studies, the proportion of subjects who remained relapse-free at six
months was greater for the granulated mesalamine formulation than for
placebo. Id. at 17:135 (Example 5, Table 2); see also id. at Figures 13
(patient disposition and results of study 1); 6:437:25 (summarizing results
of phase 3 studies discussed in Examples); 16:125 (Example 2); 25:14
33:64 (Examples 811, Tables 1014).
The 688 patent also describes pharmacokinetic studies comparing
absorption of mesalamine granules: (1) administered once and twice daily,
and (2) administered under fed and fasted conditions. Id. at 7:2631; id. at
14:5815:5 (Example 1evaluation of effect of a high fat meal intake on
5

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Patent 8,865,688 B2
absorption of mesalamine granules); id. at 16:4767 (Example 4Effect of
Food on Absorption and Disposition of Granulated Mesalamine
Formulations); id. at 17:3821:15 (Example 6comparison of once daily
(QD) to twice daily (BID) administration). Based on these studies, the 688
patent concludes that granulated mesalamine formulation can be
administered once- or twice-daily, id. at 7:2628, without regard to food,
id. at 15:45, and that the rate and extent of absorption of mesalamine and
its metabolite were not affected by a high-fat meal, id. at 16:6364.
B. Illustrative Claim
The 688 patent includes 16 claims. The Petition challenges claims 1
and 16, which are directed to a method of maintaining the remission of
ulcerative colitis in a subject. Ex. 1001, 34:1022, 35:417.
Claim 1 is reproduced below with paragraph breaks and bracketed
lettering added for ease of reference:
1. A method of maintaining the remission of ulcerative
colitis in a subject comprising
[a] administering to the subject a granulated mesalamine
formulation comprising four capsules each comprising 0.375 g
of granulated mesalamine once per day in the morning, without
food, wherein:
[b] said method maintains remission of ulcerative colitis
in a subject for a period of at least 6 months of treatment;
[c] remission is defined as a DAI score of 0 or 1;
[d] the granulated mesalamine formulation is not
administered with antacids; and
[e] wherein 85% to 90% of the mesalamine reaches the
terminal ileum and colon.
Id. at 34:1022. Claim 16 is identical to claim 1, except that claim 16 recites
an additional step, advising the subject that granulated mesalamine should
not be taken with antacids, and claim 16 omits the indefinite article a in
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Patent 8,865,688 B2
the phrase, a granulated mesalamine formulation in paragraph [a].
Compare id., with id. at 35:417. The parties present the same contentions
for claim 16 as they present for claim 1. See, e.g., Pet. 39; Prelim. Resp. 21
42. Accordingly, for purposes of this decision, it is not necessary to
consider claim 16 separately from claim 1, and we generally confine our
discussion to claim 1.
C. Claim Construction
In an inter partes review, claim terms in an unexpired patent are given
their broadest reasonable interpretation in light of the specification of the
patent in which they appear. 37 C.F.R. 42.100(b); In re Cuozzo Speed
Techs., LLC, 793 F.3d 1268, 127579 (Fed. Cir. 2015), cert. granted sub
nom. Cuozzo Speed Techs. v. Lee, 136 S. Ct. 890 (mem.) (2016). Claim
terms are given their ordinary and customary meaning, as understood by one
of ordinary skill in the art in the context of the entire disclosure. In re
Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
[C]laim terms need only be construed to the extent necessary to
resolve the controversy. Wellman, Inc. v. Eastman Chem. Co., 642 F.3d
1355, 1361 (Fed. Cir. 2011)) (citing Vivid Techs., Inc. v. Am. Sci. & Engg,
Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
Petitioners propose constructions for the terms, without food and
granulated mesalamine formulation. Pet. 1724. Patent Owner disagrees
with Petitioners proposed constructions and proposes an alternative
construction for granulated mesalamine formulation. Prelim. Resp. 17
20. We determine that it is not necessary to provide an express construction
for those terms for purposes of this decision.

IPR2016-00297
Patent 8,865,688 B2
We determine further that it is not necessary to provide an explicit
construction for any claim term at this stage of the proceeding.
C. Person of Ordinary Skill in the Art
At this stage, we consider the asserted references to reflect the level of
ordinary skill in the art at the time of the invention. See Okajima v.
Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the prior art, itself, can
reflect the level of skill in the art). On the present record and based upon the
stated qualifications of Petitioners declarant, Ex. 1002 210, Ex. A, we
consider Petitioners declarant qualified to opine from the viewpoint of a
person of ordinary skill in the art.
D. Obviousness Grounds 3 and 4
Petitioners contend that claims 1 and 16 are unpatentable as obvious
over the Sept. 2007 Press Release, Endonurse, and Davis-1985 in view of
Marakhouski. Pet. 2539 (Ground 1); Pet. 4447 (addressing Ground 3 and
incorporating discussion of Ground 1). Alternatively, Petitioners contend
that claims 1 and 16 are unpatentable as obvious over the Sept. 2007 Press
Release, Endonurse, and Davis-1985 in view of Brunner. Pet. 4750
(addressing Ground 4 and incorporating discussion of Ground 1). We
address Grounds 3 and 4 together because Petitioners rely on Marakhouski
and Brunner for essentially the same teachings.

IPR2016-00297
Patent 8,865,688 B2
1. Petitioners Cited References
The Sept. 2007 Press Release is Salixs2 announcement of the
successful completion of two Phase III trials evaluating a granulated
mesalamine formulation for the maintenance of remission of UC. Ex. 1012,
1. The press release discloses that a greater proportion of subjects dosed
once-a-day with 1.5 grams of granulated mesalamine remained relapse-free
over 6 months of treatment than patients dosed with placebo. Id. The press
release describes the evaluated formulation as having an enteric pHdependent coating, which provides for delayed release, and a polymer matrix
core, which provides for extended release, where the drug begins to
release at a pH of 6.0. Id. According to the press release, this formulation
provide[s] for the distribution of the active ingredient beginning in the
small bowel and continuing throughout the colon. Id.
Endonurse is a report from Salix regarding various clinical trials,
including two late-stage trials designed to evaluate granulated mesalamine
for the maintenance of remission of ulcerative colitis. Ex. 1014, 1.
According to Endonurse, these Phase III trials [are] designed to evaluate
the efficacy and safety of granulated mesalamine, dosed four 375 mg tablets
once daily, for the maintenance of remission of ulcerative colitis. Id. at 2.
Davis-1985 is an academic paper discussing three factors relevant to
the design and evaluation of control release delivery systems for orally
administered medications: the drug, the delivery system, and the intended
destination. Ex. 1009, 27 (Abstract, Introduction). Petitioners focus on

As noted above, Salix is the original assignee and current exclusive

licensee of the 688 patent.
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Davis-1985s discussion of the third factor: DestinationCharacteristics
of the Gastrointestinal Tract. Id. at 3437. In this section, Davis-1985
discusses the physiology of the gastrointestinal tract, including the effect of
food on the pH of the stomach and on the process of gastric emptying. Id. at
34. Davis-1985 discusses observations of the transit of various
pharmaceutical formulations through the gastrointestinal tract using gamma
scintigraphy and the implications of these observations for controlled release
systems. Id. at 3436. Davis-1985 also discusses positioned release of
drugs in the colon, using 5-aminosalicylic acid for the treatment ulcerative
colitis as an example. Id. at 3637.
Marakhouski compares the clinical efficacy of a new pellet
formulation of mesalazine (5-ASA) with a conventional tablet formulation.
Ex. 1024, 134-1.3 According to Marakhouski, the pellet formulation has a
combination of delayed and prolonged release characteristics. Id. at 1341. Both formulations have a pH-dependent coating, Eudragit-L, which
dissolves at pH 6.0 in the ileocaecal region (junction between the small
intestine and the large intestine). Id. at 135-1. The pellets are small
(< 2 mm) particles containing 5-ASA embedded in a matrix polymer core,
which provides for prolonged release of the drug. Id. According to
Marakhouski, the pellet formulation prevent[s] the so-called dose-dumping
effect and can be taken independent of meals. Id. at 134-1; see also 1381 (same). Marakhouski concludes that the pellet formulation is as effective

We use the suffix -1 to refer to the first column and -2 to refer to the
second column.
3

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Patent 8,865,688 B2
and well tolerated as the standard tablet formulation for the therapy of mild
to moderately active ulcerative colitis. Id. at 138-2.
Brunner compares the gastrointestinal transit and release of pellet
and tablet formulations of mesalazine (5-ASA) using gamma scintigraphy
and plasma pharmacokinetics. Ex. 1025, Title, Summary. According to
Brunner, both formulations have a Eudragit L coating, which dissolves at pH
6.0, and the pellets additionally have a matrix polymer core that provides
prolonged release. Id. at 1164-2, 1167-2. Brunner states that the pellet
formulation could show some advantages compared with tablets, such as
passage through the stomach independent of concomitant food intake. Id.
at 1167-2. Brunner concludes that both the pellets and tablets release 5-ASA
in the same target region and pass through the gastrointestinal tract under
fasting conditions in healthy volunteers in a comparable time. Id. at 1163-1,
1168-269-1.
2. Analysis: Claim 1 of the 688 Patent
Preamble and Paragraphs [a] and [b]
Petitioners contend that the Sept. 2007 Press Release and Endonurse
each disclose a method of maintaining the remission of ulcerative colitis, as
recited in the preamble of claim 1, and that together these references teach
administering a granulated mesalamine formulation comprising four
capsules each comprising 0.375 g of granulated mesalamine once per day,
where the method maintains remission of ulcerative colitis for a period of at
least 6 months of treatment, as recited in paragraphs [a] and [b] of claim 1.
Pet. 2528, 3334.

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At this stage, Patent Owner does not substantively contest Petitioners
contentions regarding the Sept. 2007 Press Release and Endonurse, as
summarized above.
On this record, Petitioners information is sufficient to support their
argument that the Sept. 2007 Press Release and Endonurse disclose the
preamble of claim 1 and above-noted limitations of paragraphs [a] and [b].
Paragraph [a]: without food
Petitioners rely on Davis 1985, Marakhouski, and Brunner to argue
obviousness of administering a granulated mesalamine formulation without
food, as recited in claim 1, paragraph [a]. Pet. 2933, 4450.
Petitioners contend that a person of ordinary skill in the art would
have known to administer granulated mesalamine without food so that its
bioavailability via absorption through the small intestine would be
minimized and delivery to the distal ileum and colon would be maximized.
Id. at 3033, 43 (citing Ex. 1007, 1:2733;4 Ex. 1008, 1:1018;5 Ex. 1009
(Davis), 34, 36; Ex. 1010, 886;6 Ex. 1011, 4:1518).7 Petitioners further
contend that Marakhouski and Brunner each discloses that granulated
mesalamine can be administered independent of food and that it would have
been obvious to combine this teaching with the other cited references in
order to avoid dose dumping and premature release of mesalamine.

Hirakawa et al., EP 0 671 168 A1, published Sept. 13, 1995 (EP168).

Ring et al., WO 91/07949, published June 13, 1991 (PCT949).

S.S. Davis et al., Transit of Pharmaceutical Dosage Forms through the

Small Intestine, 27 GUT 886892 (1986) (Davis-1986).
7

Otterbeck, US 6,551,620, issued Apr. 22, 2003 (the 620 Patent).

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Petitioners also contend that the ability to administer the drug independent of
food is itself taught as advantageous. Id. at 4546 (citing Ex. 1024, 134); id.
at 4950 (citing Ex. 1025, 1167).
Patent Owner contends that the claimed method is contrary to an
understanding in the art that 5-ASA should be administered with and not
without food. Prelim. Resp. 35 (citing Ex. 1017, 58);8 see also id. at 2
(Salix surprisingly found that once daily, low dose granulated mesalamine
formulation could be administered without food and effectively maintain the
remission of ulcerative colitis.).
On this record, Petitioners information shows sufficiently that
Marakhouski and Brunner each discloses administration of granulated
mesalamine without food. Ex. 1024, 135-1; Ex. 2025, 1164-1. Petitioners
information also shows sufficiently that Marakhouski and Brunner disclose
that granulated mesalamine can be taken independent of meals, Ex. 1024,
134-1, or independent of concomitant food intake, Ex. 1025, 1167-2.
Patent Owner cites the prosecution history as support for its argument
that there was an understanding in the art that mesalamine should be
administered with food. Prelim. Resp. 35 (citing Ex. 1017, 58). The
prosecution history, in turn, cites dosing information for the FDA-approved
drug, Lialda, which Applicants represented was the most similar
formulation to the granulated mesalamine described in the Sept. 2007 Press
Release. Ex. 1017, 6.
On this record, however, Petitioners informationincluding
Marakhouski and Brunnercalls into question Applicants representation

688 Patent File History, 2014-06-20 Amendment.

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that Lialda was the most similar formulation. Ex. 1017, 6. Based on the
current record, it appears that Marakhouski and Brunner discuss the same
granulated mesalamine formulation as discussed in the Sept. 2007 Press
Release. That formulation is described as having an enteric pH-dependent
coating, which provides for delayed release . . . [and] that begins to release
at a pH of 6.0 and a polymer matrix core, which provides for extended
release. Ex. 1012, 1. Like the Sept. 2007 Press Release, Marakhouski and
Brunner each describe pellets having an enteric coating that dissolves and
releases 5-ASA at pH 6.0 and a matrix polymer core that provides
prolonged release of 5-ASA. Ex. 1024 (Marakhouski), 135-1, 138-1; Ex.
1025 (Brunner) 1164-2, 1167-2.
Furthermore, on this record, all four references the Sept. 2007 Press
Release, Endonurse, Marakhouski, and Brunnerappear to pertain to a
granulated mesalamine formulation provided by Patent Owner, Dr. Falk
Pharma. The Sept. 2007 Press Release and Endonurse are both
announcements relating to Salix Phase III clinical trials to evaluate a
granulated mesalamine formulation for the maintenance of remission of
UCthe same Phase III trials as are discussed in the 688 patent. Compare
Ex. 1012, 1 and Ex. 1014, 2, with Ex. 1001 6:437:25. The Sept. 2007 Press
Release states: Salix acquired rights to market granulated mesalamine in
the U.S. from Dr. Falk Pharma GmbH of Freiburg, Germany. Ex. 1012, 2.
Marakhouski and Brunner likewise appear to relate to a granulated
mesalamine formulation from Dr. Falk Pharma. Ex. 1025, 1164-2 (Brunner:
The study medication was provided by Dr[.] Falk Pharma GmbH, Freiburg,
Germany); Ex. 1024, 134-1, 138-2, 140-2 (Marakhouski cites Brunner (ref.

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21) as disclosing how 5-ASA is released from pellets in gastrointestinal
tract).
Accordingly, in view of the disclosures of Marakhouski and Brunner
and their relationship to the Sept. 2007 Press Release and Endonurse, we are
not persuaded to deny review based upon Patent Owners argument that
there was an understanding in the art that granulated mesalamine should be
administered with food, as argued during prosecution and in the Preliminary
Response.
Addressing Petitioners Ground 1, Patent Owner contends that there
would have been no motivation to combine Davis-1985 with the Sept. 2007
Press Release or Endonurse. Prelim. Resp. 3435.
On this record and for purposes of institution, we are not persuaded by
Patent Owners argument. The Sept. 2007 Press Release and Endonurse
disclose a method of maintaining the remission of ulcerative colitis,
including oral administration of a mesalamine (5-aminosalicylic acid).
Ex. 1012, 1; Ex. 1014, 2. Davis-1985 addresses positioned release of a
drug in the various regions of the colon, following oral administration,
using 5-aminosalicylic acid for the treatment of ulcerative colitis as an
example. Ex. 1009, 36. Davis-1985 also discusses bioavailability and
transit times for orally administered drugs in fed and fasted states, i.e., with
and without food. Id. at 34, 36.
The Sept. 2007 Press Release and Endonurse are silent on whether
mesalamine should be administered with or without food. On this record,
however, Petitioners information is sufficient to support their position that a
person of ordinary skill in the art would have considered the cited teachings
of Davis-1985 comparing oral administration in fed and fasted states,
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Ex. 1009, 34, 36, to be relevant in determining whether a drug that is
intended reach the lower intestine and colon, such as mesalamine (5aminosalicylic acid), should be administered with or without food. Pet. 30
33; Ex. 1002 6971, 73, 81, 82 (discussing relevant teachings of Davis1985).
The relevance and combinability of Davis-1985 is also supported by
the prosecution history, where the Examiner allowed the claims based, in
part, on a prior art teaching similar to the cited teaching of Davis-1985
regarding the effect of food on bioavailability. Compare Ex. 1019, 3
(Reasons for Allowance), with Ex. 1009 (Davis), 34; see also Pet. 2931
(analyzing Examiners and Davis-1985s discussions of bioavailability).
Despite the similarity of the prior art teachings, Petitioners declarant draws
a different conclusion from that reached by the Examiner. Ex. 1002 68
(higher bioavailability translates to lesser amounts of mesalamine available
to be deposited on the distal ileum and colon.).
Accordingly, on this record, Petitioners information is sufficient to
support their position that a person of ordinary skill in the art seeking to
practice the method disclosed in the Sept. 2007 Press Release and Endonurse
would have considered the cited teachings of Davis-1985 relevant in
determining whether granulated mesalamine should be administered with or
without food.
Patent Owner further contends that Davis-1985 does not cure the
deficiencies in the Sept. 2007 Press Release or Endonurse, including the
failure to disclose administration of granulated mesalamine without food.
Prelim. Resp. 2324, 3435.

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On this record, it appears that a person of ordinary skill in the art
would have had two choices when deciding how to administer oral
granulated mesalamine: with food or without food. Petitioners information
shows sufficiently that both of these choices would have been available to a
person of ordinary skill in the art seeking to practice a method of
maintaining remission of ulcerative colitis, as disclosed in the Sept. 2007
Press Release and Endonurse. As discussed above, for example,
Marakhouski and Brunner each discloses administration of granulated
mesalamine without food. Ex. 1024, 135-1; Ex. 2025, 1164-1.
Obviousness as to this limitation thus turns on whether administering
granulated mesalamine without food would have been predictable and would
have led to anticipated success. KSR Intl v. Teleflex Inc., 550 U.S. 398, 421
(2007) (When there is a design need or market pressure to solve a problem
and there are a finite number of identified, predictable solutions, a person of
ordinary skill has good reason to pursue the known options within his or her
technical grasp. If this leads to the anticipated success, it is likely the
product not of innovation but of ordinary skill and common sense.).
Relevant to predictability and anticipated success, Petitioners offer
two record-supported rationales for why a person of ordinary skill in the art
seeking to practice the method disclosed in the Sept. 2007 Press Release and
Endonurse would have known to administer granulated mesalamine without
food: First, Petitioners posit that Davis-1985s teachings regarding higher
bioavailability via absorption through the small intestine and faster
gastrointestinal transit times in a fasted versus a fed state would have led one
of ordinary skill in the art to conclude that a formulation intended to be
delivered to the colon, as disclosed in the Sept. 2007 Press Release and
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Endonurse, should be administered in a fasted state, i.e., without food.
Ex. 1002 6871 (citing Ex. 1009, 34, 36; Ex. 1010, 886). Second,
Petitioners posit that prior art teachings that food raises stomach pH and
suppresses gastric emptying would have led one of ordinary skill in the art to
conclude that granulated mesalamine having a pH-dependent coating, as
disclosed in the Sept. 2007 Press Release, should be administered without
food, so as to avoid dissolution of the coating and release of the drug in the
stomach, rather than in the colon. Ex. 1002 7274, 106107 (citing Ex.
1007 (EP168), 1:2733; Ex. 1008 (PCT949), 1:1018; Ex. 1009 (Davis), 34;
Ex. 1011 (the 620 Patent), 4:1518).
On this record and for purposes of institution, we determine that
Petitioners information, as summarized above, is sufficient to support their
position that, for a person of ordinary skill in the art seeking to practice a
method of maintaining the remission of ulcerative colitis, administering
granulated mesalamine without food would have been known, predictable,
and led to anticipated success.
Addressing Petitioners Grounds 3 and 4, Patent Owner contends that
neither Marakhouski nor Brunner is directed to maintaining remission of
ulcerative colitis (UC). Prelim. Resp. 39, 41. Patent Owner further contends
that Brunner does not suggest a low dose of mesalamine, as recited in claims
1 and 16. Id. at 4142.
On this record and for purposes of institution, we are not persuaded by
Patent Owners arguments. The cited teachings of Marakhouski and
Brunner pertain to whether granulated mesalamine should be administered
with or without food. Ex. 1024, 134-1, 138-1; Ex. 1025, 1167-2. Patent
Owner makes no assertion that this choice depends on whether the objective
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is to induce remission of UC (as in Marakhouski) or to maintain remission of
UC (as in the 688 patent, the Sept. 2007 Press Release, and Endonurse).
Nor does Patent Owner assert that this choice depends on whether the
dosage is high (as in Brunner) or low (as in the 688 patent, the Sept. 2007
Press Release, and Endonurse).
On this record, Patent Owners arguments distinguishing Marakhouski
and Brunner appear to be inconsistent with Applicants arguments during
prosecution. There, Applicants asserted that a skilled artisan would look to
teachings relating to Lialda, including directions for administering the drug
for the induction of remission in adult patients with active, mild to
moderate ulcerative colitis using a total daily dose of 2.4 g or 4.8 g. Ex.
1017, 6. Induction of remission of mild to moderate UC is the same goal as
disclosed in Marakhouski. Ex. 1024, 134, 135. Furthermore, the Lialda
dosage range cited by Applicants overlaps the up to 4 g daily that Patent
Owner asserts is taught by Brunner. Prelim. Resp. 41. Accordingly, on this
record, Patent Owners arguments do not persuade us to disregard the
teachings of Marakhouski and Brunner as not relevant to a method of
maintaining remission of UC using a low dosage of granulated mesalamine.
Patent Owner further argues that Marakhouski makes no comparison
between administration with and without food and only mentions in
passing that, unlike tablets, pellets avoid the risk of dose-dumping, and
therefore can be taken independent of meals. Prelim. Resp. 40.
Patent Owners argument does not persuade us to deny review.
Marakhouski discloses administration of granulated mesalamine without
food, Ex. 1024, 135-1, and further discloses that granulated mesalamine
can be taken independent of meals, id. at 134-1. A comparison between
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Patent 8,865,688 B2
administration with and without food is not necessary to persuade us to
institute review because Petitioners contention regarding a motivation to
combine Marakhouskis disclosures with the Sept. 2007 Press Release and
Endonurse is adequately supported by other information. Ex. 1002 (Digenis
Decl.) 112 (to avoid dose dumping and premature release of
mesalamine); id. 121 (ability to administer independent of food is itself
advantageous).
Accordingly, on this record, Petitioners information, as summarized
above, is sufficient to support their position that one of ordinary skill in the
art would have combined the Sept. 2007 Press Release and Endonurse with
the cited teachings of Davis-1985, as well as the cited teachings of either
Marakhouski or Brunner, and that either combination would have made it
obvious to practice the method of the Sept. 2007 Press Release and
Endonurse by administering granulated mesalamine without food.
Paragraph [a]: in the morning
Petitioners contend that a person of ordinary skill in the art would
have had a reason to administer granulated mesalamine in the morning
because that is the time when a patients stomach is most likely to be empty.
Pet. 29. Petitioners further contend that the 688 patent does not show
criticality for the in the morning limitation. Id. (citing Ex. 1001, 3:64,
13:2930; Ex. 1002 65).
At this stage, Patent Owner does not argue patentability based upon
claim 1s recitation of in the morning separate from its arguments, as
discussed above, regarding administration without food.
On this record, Petitioners information, as summarized above, is
sufficient to support their argument that one of ordinary skill in the art would
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have found it obvious to practice the method of the Sept. 2007 Press Release
and Endonurse by administering granulated mesalamine in the morning.
Paragraph [c]: remission is defined as a DAI score of 0 or 1
Petitioners contend that a person of ordinary skill in the art would
have recognized that remaining relapse-free, as disclosed in the Sept. 2007
Press Release, would be defined by a DAI score of 0 to 1. Pet. 34 (citing Ex.
1013 20).9
Meyeroff discloses: a patient is considered to be in remission for UC
if a UC-DAI score of 1 is obtained, with rectal bleeding and stool
frequency scores of 0, and at least a 1-point reduction in sigmoidoscopy
score from baseline. Ex. 1013 20.
Patent Owner argues that a DAI score of 0 or 1 is not disclosed by
the Sept. 2007 Press Release, Endonurse, Davis-1985, or Marakhouski, but
does not otherwise address Petitioners argument regarding this limitation.
On this record, Petitioners information, as summarized above, is
sufficient to support their argument that one of ordinary skill in the art would
have recognized that remaining relapse-free, as disclosed in the Sept. 2007
Press Release, would be defined by a DAI score of 0 to 1.

Meyeroff et al., US 2010/0035850 A1, published Feb. 11, 2010

(Meyeroff).
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Patent 8,865,688 B2
Paragraph [d] the granulated mesalamine formulation
is not administered with antacids
Petitioners contend that a person of ordinary skill in the art would
have known not to administer granulated mesalamine with antacids because
antacids were known to increase stomach pH and cause dissolution of the
pH-sensitive coating and release of mesalamine in the stomach and upper
small intestine instead of the distal ileum and colon. Pet. 3536 (citing Ex.
1007 (EP168), 1:2733; Ex. 1009 (Davis), 34; and Ex. 1026, 156).10
Patent Owner does not specifically address Petitioners contentions
regarding obviousness of administering granulated mesalamine without
antacids.
On this record, Petitioners information, as summarized above, is
sufficient to support their argument that one of ordinary skill in the art would
have found it obvious to practice the method of the Sept. 2007 Press Release
and Endonurse by administering granulated mesalamine without antacids.
Paragraph [e]: wherein 85% to 90% of the mesalamine
reaches the terminal ileum and colon
Petitioners contend that a person of ordinary skill in the art would
have expected that the formulation disclosed in the Sept. 2007 Press Release
would have the recited release profile85% to 90% of the mesalamine
reaches the terminal ileum and colonbecause the press release discloses
the same formulation as the 688 patent. Pet. 3738.

10

J.R.B.J. Brouwers, Advanced and Controlled Drug Delivery Systems in

Clinical Disease Management, 18(5) PHARMACY WORLD & SCIENCE 153162 (1996) (Brouwers).
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Patent Owner argues that none of the Sept. 2007 Press Release,
Endonurse, Davis-1985, or Marakhouski discloses that 85% to 90% of the
mesalamine reaches the terminal ileum and colon, but does not otherwise
address Petitioners argument regarding this limitation.
Petitioners contention appears to be based on the doctrine of
inherency. In order to establish inherency in the context of obviousness,
the limitation at issue necessarily must be present, or the natural result of
the combination of elements explicitly disclosed by the prior art. PAR
Pharma., Inc. v. TWI Pharmas., Inc., 773 F.3d 1186, 119596 (Fed. Cir.
2014). We, therefore, consider whether Petitioners objective evidence is
sufficient to show that the granulated mesalamine formulation disclosed in
the Sept. 2007 Press Release would necessarily have a release profile within
the claimed range.
The objective evidence includes the 688 patent, which provides the
following description of the granulated mesalamine formulation: each
granulated mesalamine formulation capsule contains, for example, granules
composed of mesalamine in a polymer matrix with an enteric coating that
dissolves at pH 6 and above. Ex. 1001, 10:6366; see also id. at 9:3745.
The 688 patent teaches that this formulation has a release profile whereby
85% to 90% of drug reaches the diseased area. Id. at 9:5054.
The objective evidence also includes the Sept. 2007 Press Release,
which discloses a granulated mesalamine formulation . . . [that] combines
an enteric pH-dependent coating, which provides for delayed release, and a
polymer matrix core, which provides for extended release. . . . [where]
granulated mesalamine . . . begins to release at a pH of 6.0. Ex. 1012, 1.
The Sept. 2007 Press Release also discloses that the granulated mesalamine
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IPR2016-00297
Patent 8,865,688 B2
formulation is designed to provide for the distribution of the active
ingredient beginning in the small bowel and continuing throughout the
colon. Ex. 1012, 1.11
Petitioners present no experimental data to show that the granulated
mesalamine formulation disclosed in the Sept. 2007 Press Release has the
claimed release profile, i.e., 85% to 90% of the mesalamine reaches the
terminal ileum and colon. We note, however, that the 688 patent also
contains no experimental data to support the assertion that the disclosed
mesalamine formulation provides the claimed release profile. Example 4
discloses a release profile outside the claimed range. Ex. 1001, 16:6567
(Approximately 80% of an administered oral dose of mesalamine is
estimated to be available in the colon, sigmoid, and rectum when dosed as
mesalamine granules.).
The 688 patent does not indicate obtaining the release profile
depends upon whether the drug is administered in the morning, without
food, or without antacidsconditions recited in claim 1, but not disclosed
in the Sept. 2007 Press Release. In fact, the 688 patent indicates that the
rate and extent of absorption of mesalamine and its metabolite were not
affected by a high-fat meal. Id. at 16:6364.
On this record, Petitioners objective evidence shows sufficiently that
the granulated mesalamine formulation disclosed in the Sept. 2007 Press
Release is the same as the granulated mesalamine formulation disclosed in
the 688 patent. Under these circumstances and for purposes of institution,

11

According to Dr. Digenis, a person of ordinary skill would understand

that the small bowel includes the terminal ileum. Ex. 1002 84.
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Patent 8,865,688 B2
we view Petitioners objective evidence as sufficient to support its position
that the granulated mesalamine formulation disclosed in the Sept. 2007 Press
Release would necessarily have the same release profile as disclosed in the
688 patent, i.e., that 85% to 90% of the mesalamine reaches the terminal
ileum and colon.
3. Secondary Considerations
Patent Owner contends that non-obviousness is demonstrated by
secondary considerations, including [f]ailure of others to demonstrate the
non-inferiority of a low, once daily dose of mesalamine without food for the
maintenance of remission of ulcerative colitis; [l]ong felt but unmet need
for a low, once-daily dose of granulated mesalamine for the maintenance of
remission of ulcerative colitis; and [s]kepticism by those in the field that a
once daily, low dose of granulated mesalamine administered without food
could maintain the remission of ulcerative colitis. Prelim. Resp. 43, 45, 47.
As support for these contentions, Patent Owner cites excerpts from the trial
testimony of its witnesses, Drs. Forbes, Johnson, and Greinwald, Exs. 2022
2024,12 confidential reports of clinical trials conducted by Dr. Falk Pharma
and Salix, Exs. 20252029, exhibits purportedly showing problems with
prior art tablet formulations, Exs. 2030, 2031, and exhibits relating to
adherence studies conducted before October 2004, Exs. 2016, 2018.
At this stage, the record regarding secondary considerations is
incomplete, as Patent Owner has not had an opportunity to submit

Patent Owners Exhibits 20222024 are excerpts from the November 16

and 18, 2015 trial testimony of its witnesses, William Forbes, Lorin
Johnson, and Roland Greinwald, in the related Delaware district court
litigation.
12

25

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Patent 8,865,688 B2
testimonial evidence, and Petitioners have not had an opportunity to respond
to Patent Owners arguments and exhibits. We therefore determine that it
would be premature to reach any conclusion regarding secondary
considerations. Any final decision will be based on the full record
developed during the trial, including any evidence of secondary
considerations.
4. 35 U.S.C. 325(d) and Redundancy
Patent Owner argues that Petitioners Ground 1 presents no arguments
not already considered by the PTO during prosecution, Prelim. Resp. 34, and
that Grounds 3 and 4 are horizontally redundant because Marakhouski and
Brunner are substantially similar, id. at 38 n.3.
Our governing statute provides, in relevant part, that [i]n determining
whether to institute or order a proceeding under this chapter . . . the Director
may take into account whether, and reject the petition or request because, the
same or substantially the same prior art or arguments previously were
presented to the Office. 35 U.S.C. 325(d) (emphasis added). Our
procedural rules provide: (1) the Board may authorize the review to
proceed on all or some of the challenged claims and on all or some of the
grounds of unpatentability asserted for each claim, and (2) the Board may
deny some or all grounds of unpatentability for some or all of the challenged
claims. 37 C.F.R. 42.108(a), (b).
We have considered the facts and circumstances of the instant
proceeding. We decline to exercise our discretion to deny the Petition under
35 U.S.C. 325(d). And we exercise our discretion to institute review based
on Grounds 3 and 4 in the alternative.

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IPR2016-00297
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5. Conclusion Regarding Grounds 3 and 4
On this record, we are persuaded that Petitioners demonstrate a
reasonable likelihood of prevailing on their assertion that claims 1 and 16
are unpatentable as obvious over the 2007 Press Release, Endonurse, and
Davis-1985 in view of Marakhouski or Brunner.
E. Obviousness Ground 1
Petitioners contend that claims 1 and 16 are unpatentable as obvious
over the Sept. 2007 Press Release, Endonurse, and Davis-1985. Pet. 2539
(Ground 1). We view this ground as subsumed by the above-instituted
Grounds 3 and 4 based on these same references in view of Marakhouski or
Brunner.
F. Obviousness Ground 2
Petitioners contend that claims 1 and 16 are unpatentable as obvious
over the Sept. 2007 Press Release, Endonurse, Davis-1985, and EP590.
Pet. 3944 (Ground 2).
1. Petitioners Cited Reference
EP590 discloses an oral pharmaceutical preparation comprising a core
containing an active substance, e.g., salicylazo-sulfapyridine (SASP) or 5ASA, and a coating comprising (i) a polymer soluble only above pH 5.5,
e.g., Eudragit L, and (ii) a water insoluble polymer, with the objective of
releasing a major part of the active substance in the colon for treating, e.g.,
ulcerative colitis. Ex. 1015, Abstract, 1:514, 1:282:6, 3:34:2, 4:1216.
EP590 discloses tests comparing the release properties of such a colon
release preparation with a conventional preparation, using SASP as a
model substance. Id. at 6:421. In tests in vivo, test preparationseither

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IPR2016-00297
Patent 8,865,688 B2
granular preparations (coated cores containing SASP) or a conventional
tablet (Salazopyrin)were administered [a]fter at least 10 hours fasting.
Id. at 6:237:31, 8:2234. Amounts of SASP and its metabolite (acetyl-5ASA) excreted in urine were then measured. Id. at 6:1113, 8:349:35.
According to EP590, the results of these tests demonstrate that the granular
preparations provide the desired colon release properties. Id. at 6:1521,
10:12.
2. Analysis
Petitioners contend that EP590 discloses a method of administering
granulated mesalamine without food. Pet. 41. Petitioners further contend
that EP590 discloses the same reasoning taught by the 688 Patent for why
granulated mesalamine can be taken without food. Pet. 42. In addition,
Petitioners contend that EP590 teaches that administration of granulated
mesalamine without food lowered the excretion of 5-ASA in the urine,
thereby increasing the application in the large intestine. Pet. 4243.
Patent Owner contends that EP590 does not teach using granulated
mesalamine for the maintenance of remission of UC. Prelim. Resp. 36.
Patent Owner further contends that EP590 addresses SASP and would not be
viewed as relevant to mesalamine because the drugs have different
absorption sites. Id. (citing Ex. 1015, 6:9). In addition, Patent Owner
asserts that EP590 does not indicate that administration with versus without
food had any impact on the release profile as a study with food was not
disclosed. Id. at 37.
Petitioners contention that EP590 discloses a method of
administering granulated mesalamine without food, Pet. 41, is based on
EP590s in vivo tests of SASP and Petitioners assertion that SASP . . .
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IPR2016-00297
Patent 8,865,688 B2
comprises 5-ASA. Pet. 40, 41. That assertion is not supported by EP590,
which teaches that SASP is a chemical precursor to 5-ASA. More
specifically, EP590 teaches that SASP is broken down by bacteria in the
colon to produce sulfapyridine (SP) and 5-amino-salicylic acid (5-ASA).
Ex. 1015, 6:1113; see also Ex. 1006 (Stolk), 200-1 (same);13 Ex. 1026
(Brouwers), 155-2 (same).
On this record, Petitioners contention that EP590 discloses the same
reasoning taught by the 688 Patent for why granulated mesalamine can be
taken without food, Pet. 42, is not sufficiently supported. Petitioners refer
to Example 1 of the 688 patent, id., which evaluates urinary excretion of 5ASA, when granulated mesalamine is administered following an overnight
fast as compared to administration following a high fat meal. Ex. 1001,
14:5867. In contrast, EP590 evaluates urinary excretion of 5-ASA, when a
granular preparation of SASP is administered, as compared to administration
of a conventional tablet formulation. Ex. 1015, 6:1521, 7:3031, 8:229:4,
9:2835. As noted by Patent Owner, Prelim. Resp. 37, EP590 does not
compare urinary excretion following administration with and without food,
as in Example 1 of the 688 Patent.
The record also lacks adequate support for Petitioners assertion that
EP590 teaches that administration of granulated mesalamine without food
lowered the excretion of 5-ASA in the urine. Pet. 4243. First, EP590s
evaluations of urinary excretion of 5-ASA did not involve administration of
granulated mesalamine, but instead administration of granulated SASPa

13

L. Stolk et al., Dissolution Profiles of Mesalazine Formulations in Vitro,

12(5) PHARMACEUTISCH WEEKBLAD SCIENTIFIC EDITION 20004 (1990)
(Stolk).
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Patent 8,865,688 B2
chemical precursor, which as Patent Owner notes, Prelim. Resp. 36, has a
different absorption profile than mesalamine. Compare Ex. 1015, 6:910
(SASP is absorbed to a small extent in the stomach and small intestine),
with Ex. 1025 (Brunner), 1163 (Orally administered mesalazine is rapidly
and almost completely absorbed from the small intestine.). Second, EP590
does not teach that urinary excretion was lowered by administration without
food, but instead teaches that excretion was lowered by administration of a
colon release preparation instead of a conventional tablet formulation.
Ex. 1015, 6:1521, 7:3031, 8:229:4, 9:2835.
Accordingly, on this record, we are not persuaded to institute review
based on EP590 in combination with the 2007 Press Release, Endonurse,
and Davis-1985.
III. CONCLUSION
For the reasons stated above, we institute an inter partes review as set
forth in the Order. At this stage of the proceeding, the Board has not made a
final determination with respect to the patentability of the challenged claims
or any underlying factual or legal issues.
IV. ORDER
It is
ORDERED that, pursuant to 35 U.S.C. 314(a), an inter partes
review of the 688 patent is instituted on the following ground of
unpatentability asserted in the Petition:
Claims 1 and 16 under 35 U.S.C. 103(a) as obvious over the
2007 Press Release, Endonurse, and Davis-1985 in view of
Marakhouski or Brunner.

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FURTHER ORDERED that pursuant to 35 U.S.C. 314(a), inter
partes review of the 688 patent is hereby instituted commencing on the
entry date of this Order, and pursuant to 35 U.S.C. 314(c) and 37 C.F.R.
42.4, notice is hereby given of the institution of trial; and
FURTHER ORDERED that the trial is limited to the ground identified
above and no other ground of unpatentability is authorized.

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PETITIONER:
Zachary Silbersher
zsilbersher@kskiplaw.com
Gaston Kroub
info@kskiplaw.com

PATENT OWNER:
Mary Bourke
mbourke@wcsr.com
Preston Heard
pheard@wcsr.com

32