Product Profile: Mesotrione

In 1997, after noticing that very few plants were growing under his bottlebrush plant (Callistemon citrinus), a biologist from Zeneca (which became Syngenta in 1999) identified leptospermone, a natural herbicide. This discovery led Syngenta scientists to undertake a significant research program that resulted in the synthesis of the triketone herbicide, mesotrione. Marketed under the trade name Callisto, mesotrione has become one of Syngenta’s major brands since its launch in 2001, available in more than 50 countries and posting more than $400 million in annual revenue.

Mesotrione works by inhibiting the p-hydroxyphenylpyruvate dioxygenase (HPPD) enzyme, which prevents the biosynthesis of carotenoids. Without carotenoids, light energy destroys chlorophyll and leads to the death of susceptible plants.

Mesotrione is mainly used as a systemic pre- and post- emergence herbicide for the selective contact and residual control of broadleaf weeds in maize. It is absorbed by weeds during emergence or through the treated foliage and is active against a broad spectrum of annual broadleaf weeds including: velvetleaf, redroot/smooth pigweed, common ragweed, common lambsquarters, wild mustard, chickweed, ground ivy, dandelion and clover. It has also been developed for use on berry crops, rhubarb, sorghum, sugar cane, soybeans, millet and turf, and for controlling weeds resistant to glyphosate, ALS-inhibiting and triazine herbicides.

Commercialization of mesotrione began with its launch in the United States, Germany and Austria in 2001. It is now available under various Syngenta trade names — Callisto, Lumax, Lexar, Halex GT, Camix, Calcris, Elumis, Calaris Callisto Xtra and Tenacity — in more than 50 countries, including Austria, Argentina, Belgium, Brazil, Bulgaria, Canada, China, Croatia, Czech Republic, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Netherlands, New Zealand, Mozambique, Poland, Portugal, Romania, Russia, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Turkey, the United Kingdom and the United States.

Syngenta has developed several mixtures of mesotrione, combining it with the herbicides atrazine, S-metolachlor, terbuthylazine and glyphosate as well as the safener, benoxacor.

In 2008, Syngenta acquired the rights to DuPont’s insecticide, chlorantraniliprole and gave some rights to mesotrione to DuPont. In 2010, DuPont launched Realm Q, a mixture of mesotrione and rimsulfuron, in the United States.

Syngenta’s launch of mesotrione-containing products in Japan in 2010 for use on paddy fields — and the April 2011 agreement with Bayer CropScience to co-develop genetically modified HPPD inhibitor herbicide-tolerant soybeans — are testament to the company’s continued efforts to further develop the market for mesotrione.

Barriers to Entry

Mesotrione has been a very successful product and is already an attractive target AS for off-patent companies, but how easy will it be for these companies to gain significant market share? To get that answer, we need to assess where major barriers to market entry exist.

The European Union recognized that a significant erosion in effective patent term existed for pharmaceuticals, which resulted in a market exclusivity period that wasn’t long enough to recoup the substantial R&D costs. As a result, Supplementary Protection Certificates (SPCs) were introduced in 1992. SPCs add as many as five years of additional patent protection to the normal 20-year term. Extensive lobbying by the agrochemical R&D sector helped SPCs become law for agrochemicals in 1996.

The EU patent for mesotrione, EP0186118, expired Dec. 17, 2005, but there remains a complex SPC situation for straight and mixture products of mesotrione. SPCs for straight mesotrione were granted in 10 EU countries, but only Spain’s is still valid (due to expire in 2012).

The main mixture products with SPC protection:

1) mesotrione + (S)-metolchlor + benoxacor, which is protected by EP0840548 (and in France there is a granted SPC which protects this mixture to 2020).

2) mesotrione + (S)-metolachlor + terbuthylazine, which is protected by EP080548 and national patents. For this mixture, six SPCs are relevant. In Italy and Slovenia, there are granted SPCs which will protect the market until 2019; in Slovakia and Belgium, the SPC application was rejected; and in Hungary and Romania, the SPC is still in the application stage.

3) mesotrione + terbuthylazine, which was protected by EP0186118 (it expired in 2005) and the only granted SPC was in the United Kingdom, which expired in 2010.

EP0840548 is still in force but will expire on Nov. 7, 2016, in 18 countries. Thus, while the patent protection for straight mesotrione has expired, there still remains patent protection for mixture products.

In the European Union, the date of Annex I inclusion (for example, date of entry into force) was Jan. 10, 2003, and therefore data protection period expires 10 years after this date. Mesotrione is authorized at the national level in 21 countries — thus an extended market exclusivity period of eight years was achieved through data protection and extended patents. The timeline shows the critical dates for patent, SPC and Annex I data protection expiry.

In other countries, such as South Africa, where patent term extensions do not exist, the market for straight mesotrione has been open to generic competition since 2005. However, the market there is dominated by mixture patents — especially mesotrione plus (S)-metolachlor- — which are still in force and restrict generic competition.

The year of initial registration in the United States was 2001 and therefore a 10-year period of exclusive use for data submitted in support of the registration exists. In the United States, Syngenta has been granted extended data protection for certain minor crop uses until June 4, 2013, and a decision to extend protection for an additional year is pending.

Syngenta manufactures mesotrione in the United States at its Cold Harbor Creek, Alabama plant, which came on-stream in 2001. The chemistry and technology involved in the manufacture of mesotrione are relatively straightforward and use some basic intermediates obtainable from a number of sources.

However, 1-cyano-6-(methylsulfonyl)-7-nitro-9H-xanthen-9-one can be produced as an impurity during the manufacturing of mesotrione and is considered to be of toxicological concern and must remain below 0.0002% (w/w) in the technical product. Thus, the process conditions rather than the actual technologies involved in the synthesis will be the key to whether generic manufacturers will be capable of producing an acceptable product. Chinese suppliers are offering mesotrione that conforms to the tight specification.

Ultimately, mesotrione may be a difficult product for generic manufacturers to target because patents, data protection, and technology issues favor Syngenta maintaining its market share in markets such as the European Union and United States. However, with sales in excess of $400 million per year, mesotrione is an attractive product and it will be interesting to see if generic competitors use markets such as South Africa and Brazil to gain a presence before the EU and US markets open up.

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