Product Profile: Picoxystrobin

Off-patent companies are Active navigating barriers to gain significant market share with Ingredients picoxystrobin. Azoxystrobin
By Dr. Nigel Uttley
May 2011

Inventor Company Syngenta Syngenta Syngenta BASF BASF Shionogi Bayer CropScience Shionogi Shenyang Research Institute

Mainly Commercialized By Syngenta DuPont Bayer CropScience BASF BASF BASF BASF Arysta LifeScience SumiAgro In development

Picoxystrobin Trifloxystrobin Orysastrobin Pyraclostrobin Dimoxystrobin Fluoxastrobin Metominostrobin Pyrametostrobin

Our first profile, published in February, featured azoxystrobin, which was discovered and developed by ICI (now Syngenta). Azoxystrobin was the first of the highly successful strobilurin class (see table) of products to be commercialized and is now the largest selling fungicide active substance in the world with sales that exceed $1 billion. This month we feature picoxystrobin, also discovered by Syngenta but now commercialized by DuPont. Picoxystrobin was the fourth strobilurin to come to market when it was launched in 2001.

Kresoxim-methyl BASF

As with other strobilurin analogues, Shenyang picoxystrobin inhibits fungal Pyrazoxystrobin Research In development respiration and has both preventative Institute and curative properties, with picoxystrobin exhibiting improved curative properties compared to azoxystrobin in certain crops. Picoxystrobin was initially launched as Acanto by Syngenta for control of yellow, brown and crown rusts, powdery mildew, sooty mold, net and leaf blotch and tan spot on cereal crops, including: wheat, barley and oats in Europe. Picoxystrobins dossier was submitted to the EU review system and was declared complete in 1999. It was included on Annex I as a New Active Substance on Jan. 1, 2004. In 2006, DuPont acquired worldwide rights to picoxystrobin as part of an agreement which also gave Syngenta rights to DuPonts insecticide, Rynaxypyr. DuPont has further developed picoxystrobin for use on soybeans in Latin America and in 2010, DuPont applied for authorization for picoxystrobin as Aproach to the USEPA for use on corn, soybeans, cereals, dry beans, peas and canola. Launch in the US is expected in 2012. DuPont has estimated peak year sales potential for picoxystrobin to be $150 million. Picoxystrobin is currently registered in some 28 countries, including: Argentina, Austria, Belgium, Brazil, Colombia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Hungary, Ireland, Kenya, Latvia, Lithuania, the Netherlands, New Zealand, Norway, Poland, Romania, Slovakia, South Africa, Sweden and the UK. Registration is in progress in the US, Italy and Portugal. Picoxystrobin is marketed as a single ingredient fungicide and also in several mixtures with other fungicides, including: cyproconazole (Furlong, Stinger and Aproach Prima); chlorothalonil (Credo and Plinker); and cyprodinil (Acanto Prima).

Navigating Barriers to Entry Clearly, picoxystrobin is an attractive target AS for off-patent companies but how easy will it be for these companies to gain significant market share? To answer this we need to assess where the major barriers to market entry exist.
The EU recognized that a significant erosion in effective patent terms existed for pharmaceutical. This resulted in insufficient market exclusivity period to recoup the substantial R&D costs and, as a result, Supplementary Protection Certificates (SPCs) were introduced in 1992. SPCs give up to five years additional patent protection to the normal 20 year term and as a result of extensive lobbying by the agrochemical R&D sector SPCs became law for agrochemicals in 1996. In the EU, picoxystrobin is protected by EP0447004 (and some national patents) which expired on 14th January 2008. In Austria, Belgium, Switzerland, Germany, Denmark, Great Britain, Hungary, Ireland, Luxembourg, The Netherlands and Romania, SPCs have been granted which provide additional protection until 2013. In addition to these countries, picoxystrobin is registered in Czech Republic, Estonia, Finland, France, Lithuania, Latvia, Poland, Sweden and Slovakia. SPCs have not been granted for these countries which have been open to generic competition since 2008. However, data protection issues have prevented generic market entry. Picoxystrobin was included into Annex I on 1st January 2004 and the data protection period expires 10 years after this date. The time-line diagram shows the market exclusivity period in the EU for products based on single AS picoxystrobin. Even though in some EU countries there is no existing patent protection, generic competitors would need to generate a full data pack, to negotiate a data compensation agreement or wait until data protection ends in 2014 in order to gain market entry. Many patents to mixture products containing picoxystrobin have been filed but in practice, only three mixture products appear to be of commercial interest:

1. Picoxystrobin + cyproconazole SPCs have been granted in three countries extending

protection to 2013.

2. Picoxystrobin + cyprodinil SPCs have been granted in four countries extending 3.

protection to 2013. Picoxystrobin + chlorothalonil an SPC has been granted in Great Britain extending protection to 2013.

In the US, DuPont has applied for registration of picoxystrobin on a variety of crops, a decision on this is scheduled for May 12, 2012 and, if granted, a 10-year period of data protection will exist. Thus, if the market for picoxystrobin is developed in the US, then generic competitors will have to generate a full data pack or negotiate a data compensation agreement with DuPont. In addition, potential generic competitors will have to carefully analyze the full IPR surrounding picoxystrobin such as secondary patents to: Crystalline form Formulations Processes Intermediates

In 2000, Syngenta expanded its production facility at Grangemouth, Scotland (where azoxystrobin is manufactured) to produce picoxystrobin. When DuPont acquired worldwide rights to picoxystrobin (straight and mixtures) in 2006, it was also agreed that Syngenta would continue to manufacture picoxystrobin for another three years.

The chemistry and technology involved in the manufacture of picoxystrobin is relatively straight forward. The availability of key intermediates is an important consideration when assessing how easy it is for generic companies to manufacture an active substance. In the case of picoxystrobin, two intermediates are key to the process:

1. 2-hydroxy-6 trifluoromethylpyridine this intermediate is not used in the synthesis of 2.

other agrochemicals and sourcing it may be a problem, alternatively generic manufacturers may manufacturer it in-house from 2-chloro-6-methylpyridine 2-methyl benzyl cyanide this intermediate is also used in the synthesis of Nippon Sodas acaricide, fluacrypyrim.

Whilst the markets of the EU and US are closed to generic competition in the short term, a number of other markets such as Brazil, Colombia, New Zealand and South Africa, may be available, and it will be interesting to see if generic competitors use these markets to gain a presence in advance of the EU and US markets opening up.

About the author: Dr Nigel Uttley is founder and director of Enigma Marketing Research, which provides business, market and technical information services targeted at identifying new opportunities in the agrochemical industry. The data used to assemble this Product Profile has been extracted from EMRs multi-client reports New Off-Patent/Generic Agrochemicals and AgriBase. AgriBase, is a comprehensive database covering commercial and development active ingredients. The data on AgriBase includes synthetic pathways, key intermediates, patents, registration data and many other fields. Visit www.enigmamarketingresearch.com for more details and to download a free trial version of AgriBase.

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Developing the technology and offerings to improve sustainable agriculture for a growing world.

DuPont Crop Protection in the Czech Republic

With the conclusion of World War II, DuPont began research and development of crop protection products in the Czech Republic. DuPont launched active ingredients from the uracil chemical group, formulated in products like Venzar (lenacil), Hyvar X (bromacil), Sinbar (terbacil). Another important discovery was Benlate (benomyl), the first fungicide with systemic properties, and the insecticide Lannate (methomyl). Velpar (hexazinone), originally recommended as an ecological substitution of soil neutral herbicides, found a preferred use in forestry at the end of 1980s. In the same period Curzate (cymoxanil), a new potato and grapevine fungicide, came to our market. An essential change in the composition of active ingredients used for cereals was the discovery of the group of sulphonylurea herbicides, of which Glean is a typical representative. Others followed including Granstar, Harmony for cereals, Titus and Refine for corn. Another active ingredient discovered by DuPont was Flusilazole contained in products like Alert S, Cerelux Plus, Capitan 25 EW, Punch. Another a.i. was famoxadone contained in products like Charisma (famoxadone+flusilazole), Tanos 50 WG (famoxadone+cymoxanil).

In 2006 DuPont launched a new product Talius (proquinazid), registered in cereals against powdery mildew. Due to the acquisition of the product Acanto (picoxystrobin), DuPont now has a modern strobilurin, recommended for protection of wheat and barley. DuPont continues the search to develop new compounds for crop protection in agriculture. BASEL, Switzerland and WILMINGTON, Del., Feb. 23 /PRNewswire-FirstCall/ -Syngenta and DuPont today announced an agreement that will broaden each company's crop protection product offer.

-- Syngenta acquires an exclusive worldwide license to develop DuPont's new insecticide Rynaxypyr(TM) in mixtures with its own leading insect control products. Rynaxypyr(TM) is a chemical of the bisamide class

characterized by unique systemic properties and outstanding activity on all major lepidoptera pests. DuPont will continue its commercialization plan for straight Rynaxypyr(TM). -- DuPont Crop Protection acquires worldwide rights to Syngenta's strobilurin fungicide picoxystrobin, sold as Acanto(R), including access to companion products used in mixtures. Acanto(R) is currently marketed in Europe on cereals and will be expanded for use on soybeans in Latin America.

The transactions are subject to certain national regulatory approvals. Financial terms were not disclosed. John Atkin, Chief Operating Officer, Syngenta Crop Protection, said: "This agreement gives Syngenta access to a novel class of chemistry that will set new standards in lepidoptera control. Combinations of Rynaxypyr(TM) with our modern insecticides will provide new broad-spectrum solutions in the global insecticide market estimated at around $7 billion. First launches are targeted for 2009. We shall continue to expand our industry-leading position in fungicides led by Amistar(R) and its range of combination products." James C. Collins, Vice President and General Manager of DuPont Crop Protection, commented: "These agreements further enhance our position in the global fungicide market estimated at around $ 7 billion. With picoxystrobin,

DuPont fills a gap and gains access to major fungicide customers and markets in the EU, Latin America and later in the United States. In insecticides, the

agreement we have reached with Syngenta will allow us to expand and accelerate the market potential for our new cutting edge technology."

Syngenta is a world-leading agribusiness committed to sustainable agriculture through innovative research and technology. The company is a leader in crop protection, and ranks third in the high-value commercial seeds market. Sales in 2005 were approximately $8.1 billion. Syngenta employs more

than 19,000 people in over 90 countries. Syngenta is listed on the Swiss stock exchange (SYNN) and in New York (NYSE: at http://www.syngenta.com. SYT). Further information is available

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Founded in 1802, DuPont puts science to work

by creating sustainable solutions essential to a better, safer, healthier life for people everywhere. Operating in more than 70 countries, DuPont offers a

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