Product Profile: Azoxystrobin

Editor’s note: Throughout 2011, Nigel Uttley will examine barriers to entry and market opportunities for key active substances with upcoming patent expirations. Learn how research companies marketed their discoveries and where new business can be found.

What will be the key features of the inventor company’s post-patent defense strategy? Will it be so successful that the off-patent active substance (AS) never becomes a true generic product? What are the difficulties facing a generic manufacturer in getting a generic to market?

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A generic manufacturer has to navigate his way through a minefield before he can open the gate to the market. In its path are four key defense strategies used by inventor companies to protect a market post-expiry of the AS:
• Market segmentation
• Synthesis/technology/manufacturing know-how
• Registrations — data protection
• Intellectual Property Rights (IPR)

Discovered and developed by ICI (now Syngenta), the broad-spectrum fungicide azoxystrobin has become the best-selling fungicide AS in the world with sales of more than $1 billion. It was the first of the highly successful strobilurin class of products to be commercialized.

Azoxystrobin’s success is based on its ability to prevent and/or cure all four of the major groups of pathogenic plant fungi: Ascomcetes, Basidiomycetes, Deutoromycetes and Oomycetes, which cause soil-borne and foliar diseases such as rusts, powdery mildew, downy mildew, black rot, scab, anthracnose, white mould, Rhizoctonia limb, peg rot, early and late leaf spot, black sigatoka, botrytis, web blotch and rice blast.

This wide range of activity has been translated through extensive development and trials into products that are registered in about 100 countries. They are used on more than 120 crops such as wheat, grapes, citrus, sunflowers, strawberries, onions, cotton, pecan nuts, peaches, canola, maize, soybeans, rice, brassicas, cucurbits, bananas, potatoes, peanuts, turf and ornamentals.

The discovery of azoxystrobin resulted from a combination of nature’s ingenuity, scientific skills and determination. The strobilurin class of fungicides was discovered in the 1960s and 1970s following the isolation and characterization of fungicidal compounds that are naturally produced by some species of Basidiomycete fungi. These compounds were shown to have a novel mode of action but were not suitable candidates themselves to be commercial fungicide products because they are unstable in sunlight. Using techniques such as structure-activity relationship knowledge, chemists synthesized analogues of the natural products to discover compounds with superior fungicidal properties and stability. ICI first filed patents for strobilurins in 1984 and had synthesized about 1,400 molecules in its search for azoxystrobin, which became the first strobilurin to be commercialized in 1996. By the late 1980s, three strobilurins — azoxystrobin (ICI), trifloxystrobin (Ciba Geigy now Syngenta) and kresoxim-methyl (BASF) — were in development.

Azoxystrobin is marketed by Syngenta as single AS products under several trade names, the major ones for crop protection being: Amistar, Abound, Priori, Quadris, Dynasty for seed treatments, and Heritage for turf.

Despite the launch of other strobilurin products and the growth of strobilurin resistance, especially in cereals in Europe where strobilurin fungicide sales declined from 2002 to 2008, azoxystrobin has managed to continue to grow through expansion into new countries, new crops (in 2010, Syngenta gained approval for azoxystrobin as Priori Xtra for use on sugarcane) and especially through the development of mixture products.

Azoxystrobin is manufactured at Syngenta’s Grangemouth, UK site, which came on-stream in August 1996. The original investment in the facility was $23.8 million, and it had a capacity of 1,500 tpa as AS. The plant has been upgraded by major additional investment of more than $164 million with the latest improvements being completed in 2010, giving the plant a capacity of around 6,000 tpa.

Table 1:    
Examples of early launches of straight azoxystrobin products    
Launch year  Country  Trade Name  Crop example 
1996  Germany  Amistar  Cereals 
1997  Other EU countries  Amistar   
1997  Central America, Brazil, Colombia, Ecuador
and Mexico 
Bankit  Bananas 
1997  US  Heritage  Turf 
1997  US  Abound  Fruit, nuts and vegetables 
1998  Japan  Several  Rice, wheat, beans 

How Can Off-Patents Compete?

Clearly, azoxystrobin is a very successful AS and will be targeted by generic companies, but how easy will it be for these companies to gain market share? We need to look at the minefield to ascertain where the major barriers exist. Patents and data protection issues have to be examined in detail in all national and regional markets.

The EU recognized that a significant erosion in effective patent term existed for pharmaceuticals and this resulted in an 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 of additional patent protection to the normal 20-year term. As a result of extensive lobbying by the agrochemical R&D sector, SPCs became law for agrochemicals in 1996.

In the EU, azoxystrobin is protected by EP0382375, which expired in January 2010. However, in a number of EU countries, SPCs were granted and will expire during 2011. Azoxystrobin gained Annex I inclusion as a new AS under the EU Directive 91/414/EEC in July 1998, and thus the 10 years of data protection has now expired.

The timeline shows the market exclusivity period in the EU for products based on single AS azoxystrobin. From the timeline it can be seen that the market in the EU will soon be open to generic competition. However, this is far from the full picture and it is necessary to look at the secondary patents that may restrict generic competition (Table 2).

Table 2:
Examples of mixture products protected by SPCs
Mixture AS Trade Name SPC expiry year
Chlorothalonil Amistar Opti, Quadris Opti 2015
Cyproconazole Amistar Xtra, Quadris Xtra
and Priori Xtra
2018
Difenoconazole Amistar Top 2015
Folpet Quadris Max 2015
Hexaconazole Amistar Ter 2015
Propiconazole Quilt 2015

In addition to mixture patents, the generic sector will have to consider other secondary patents such as:
• Crystalline form
• Formulations
• Processes
• Intermediates
• Chiral resolution

In the US, a more complex patent situation exists for the AS with patents due to expire only in 2014. In addition, mixture patents exist and there have been extensions to the exclusive-use data protection period for a number of minor crops.

A further post-patent defense strategy has seen Syngenta sign commercial agreements with companies such as Makhteshim-Agan, Rallis and Nufarm to supply azoxystrobin for use in their products.

In 2010, several companies in India and China claimed to manufacture azoxystrobin but it will be interesting to see what percentage of the market they can gain in the next 10 years.