Pemetrexed - USA

On Apr 26, 2019, Federal Circuit affirmed PTAB’s decision that claims of method of use patent are not obvious.

Neptune Generics, LLC, Fresenius Kabi USA, LLC, and Mylan Laboratories Ltd. (“Petitioners”) appealed the PTAB’s decisions regarding U.S. Patent No. 7,772,209. The ’209 patent is owned by Eli Lilly & Co. and relates to administering folic acid and a methylmalonic acid (“MMA”) lowering agent, such as vitamin B12, before administering pemetrexed disodium to reduce toxic effects of pemetrexed therapy. The Board concluded that the claims were not established to be unpatentable for obviousness. It found that it was known in the prior art that pretreatment with folic acid reduces the toxicity associated with administration of an antifolate, like pemetrexed, but there was not a reason to pretreat with vitamin B12 along with folic acid before administering pemetrexed to treat cancer. It also found that the skepticism of others, particularly the FDA, supported a conclusion of nonobviousness.

Federal Circuit while agreeing said that Board’s findings are based on the prior art’s disclosure of the relationships between various biochemicals and toxicity. Deficiencies in both vitamin B12 and folate can lead to elevated levels of the biomarker homocysteine. In contrast, it found that elevated levels of MMA are correlated only with vitamin B12 deficiencies and not folate deficiencies. Therefore, in patients with a vitamin B12 deficiency, but not a folate deficiency, both MMA levels and homocysteine levels would be elevated, while in patients with just a folate deficiency homocysteine levels would be elevated, but MMA levels would not be elevated. The Board further found that while elevated levels of homocysteine were known to be predictive of pemetrexed toxicity, elevated levels of MMA were understood to not be a predictor of pemetrexed toxicity. Board credited the testimony of Lilly’s expert Dr. Bruce Chabner that a skilled artisan would have understood that there was no observed correlation between vitamin B12 deficiency and pemetrexed-induced toxicity. Federal Circuit said that each step of the Board’s analysis is supported by substantial evidence.

Petitioners argued that one of the prior art, EP’005 teaches the administration of folic acid and vitamin B12 to lower homocysteine levels for all purposes. Therefore, a skilled artisan would have been motivated to pretreat with vitamin B12. But Board correctly found that EP’005 is concerned with the cardiovascular effects associated with elevated homocysteine levels, does not discuss antifolates generally. While EP’005 also states that methotrexate, an antifolate drug like pemetrexed, “induce[s] elevated homocysteine levels,” the Board noted that, in contrast, Niyikiza II explained that pemetrexed specifically did not increase homocysteine levels.

With respect to scepticism, Federal Circuit said that evidence of skepticism of others, particularly the FDA, supported a conclusion of nonobviousness. During Lilly’s clinical trials for pemetrexed, a number of fatalities occurred. In response, Lilly recommended supplementation with folic acid and vitamin B12. The FDA responded that the “medical officer does not support adding vitamins to the ongoing . . . trial & “the addition of vitamins . . . is risky.” Despite the FDA’s concerns, it allowed the trial to continue. Therefore, the Board did not err in finding that skepticism supported a conclusion of nonobviousness.

Federal Circuit finally held that Petitioners’ remaining arguments are unpersuasive & thus affirmed Board’s finding of nonobviousness.