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New Fungicide discovery-IP Case study: The Curious Case of Inpyrfluxamqrcode

Aug. 28, 2018

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Aug. 28, 2018
Extending patent monopoly beyond technical patent expiry is a well-known strategy by innovator companies. Isomeric forms, salts, derivatives and polymorphs are usually subject matter for such extended patent protection. However, significant compound patent protection beyond technical patent expiry achieved by competitor companies other than the innovator of the technical compound presents a curious case. Inpyrfluxam is one such case wherein compound patent protection beyond technical patent expiry was achieved by Sumitomo, Bayer and Isagro.

Inpyrfluxam is a novel fungicide active ingredient discovered by Sumitomo Chemical, belongs to a class of compounds known as succinate dehydrogenase inhibitors (SDHI) that have a mode of action inhibiting energy production process in pathogenic fungi. Evaluations conducted have ascertained that Inpyrfluxam exhibits high efficacy against a broad range of plant diseases on various crops, such as rice sheath blight, Asian soybean rust, cereal rusts, apple scab, and sugar beet root rot and foliar blight. Inpyrfluxam is expected to offer new solutions capable of controlling such major diseases on important crops. 
It all starts with Sumitomo’s Patent US4742074 filed in 1985, where the Applicant claims the basic moiety, however does not claim difluoromethyl substituent as one of the possible alternatives (Inpyrfluxam has difluoromethyl substituent on the pyrazole ring). 
Then Monsanto filed their Patent US5093347 in 1991, where they specifically claim the compound with difluoromethyl substituent on the pyrazole ring. Patent Specifically claims the compound under discussion (3-Difluoromethyl-1-methyl-N-(1,1,3-trimethylindane-4-yl)pyrazole-4-carboxamide), without any mention of the optical activity of the said molecule.
Later, in 2011, Sumitomo identified a predominantly R enantiomeric mixture (R form/S form ratio in the range of 90/10 to 10,000/1) at which Monsanto's pyrazolecarboxamide fungicide exhibited excellent fungicidal activity and filed a patent application (WO2011162397) globally. Sumitomo's product was named Inpyrfluxam (IUPAC Name: 3-(difluoromethyl)-N-[(R)-2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl]-1-methylpyrazole-4-carboxamide)

Sumitomo's patent is granted in Australia, China, Canada, Europe, Japan, Korea, New Zealand, Russia, Taiwan, Ukraine, US, South Africa, Israel, Mexico; while patent applications are pending in other countries like Argentina, Brazil, Chile, Indonesia, Malaysia, Thailand, Vietnam & India. Patent Application is refused in Colombia.
Sumitomo’s patent is granted in many developed countries, but it will be interesting to see the fate of this patent in developing countries especially India, where the law relating to the grant of patent to isomeric forms is complex.
Isomer patent protection is dealt with in Chapter II of Indian Patents Act and the Chapter is titled “INVENTIONS NOT PATENTABLE”. Section 3(d) of Indian Patents Act is the most debated and controversial section, having a Judgment delivered by Supreme Court of India, to understand its meaning and scope in the famous “Gleevec case” on the issue whether Novartis could patent Gleevec in India. The Supreme Court upheld the Indian patent office's rejection of the patent application.
Section 3(d) of Indian Patents act mentions under heading INVENTIONS NOT PATENTABLE that “the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.
Explanation.—For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy
It will be interesting to see how Sumitomo establishes therapeutic efficacy standard.
Subsequent to this, Sumitomo filed many patents covering combination of Inpyrfluxam with other known active ingredients. 
Quite interestingly, in the year 2013, Bayer CropScience filed a patent application (WO2014083012) claiming (R)-enantiomer of the compound. PCT application has entered national phase in Argentina, Brazil, Canada, China, Europe, Russia & US.
Finally, Isagro brought a further twist in the history of this active when they filed a patent application WO2012084812 in the year 2011, for protecting a fluoro derivative of this compound. This fluoro derivative was named as Fluindapyr (As clearly evident from structure, the only difference this molecule has, is an additional fluoro group at 7 position). Isagro’s Patent is granted in Australia, Brazil, Canada, China, Europe, Italy, Japan, Korea, Mexico, US, South Africa, Peru, New Zealand, US, South Africa; while patent applications are pending in other countries like Argentina, Colombia, Chile, Bolivia, Paraguay, Eurasia, Costa Rica, Ecuador, Egypt, Philippines, Guatemala, Honduras, India, Indonesia, Israel, Kenya, Malaysia, Morocco, Dominican Republic, Sri Lanka, Thailand, Tunisia, Ukraine, Vietnam.
Fluindapyr is a new active ingredient that has been shown to be highly effective in controlling Asian soybean rust (ASR) when used in certain premix formulations.
Recently, Arysta reached an agreement with Isagro regarding distribution of Fluindapyr based mixtures for use in soybeans and other row crops in Brazil.
The global fungicides market is growing rapidly and is projected to account sales of USD 16.1 Billion by the end of 2024. The new molecules hold major share in market and article explores the strategies adopted by innovator companies to establish monopoly in market by gaining patent protection for their products.
New molecule discovery is not always about ground breaking studies but simple manifestations of tried and tested scientific procedures.
The above case study illustrates opportunities to non-innovator companies to identify and obtain compound patent protection to variants of the innovator technical molecules with minimal investment on R&D.

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