Addressing secondary considerations of non-obviousness, the US Court of Appeals for the Federal Circuit affirmed a Patent Trial and Appeal Board (PTAB) obviousness decision, finding that skepticism does not need to be premised on whether it would be impossible for the claimed subject matter to work for its intended purpose. Neptune Generics, LLC, Fresenius Kabi USA, LLC v. Eli Lilly & Co., Case Nos. 18-1257, -1258 (Fed. Cir. Apr. 26, 2019) (Moore, J).

Eli Lilly owns a patent directed to reducing toxicity in cancer patients undergoing chemotherapy with pemetrexed, an antifolate. Antifolates inhibit the synthesis of DNA and RNA, which are required for the growth and survival of cancer cells, but can have serious side effects. Folic acid and methylmalonic acid (MMA) inhibitors such as vitamin B12 reduce these side effects. Eli Lilly’s patent claims a method of administering pemetrexed to a patient by administering effective amounts of folic acid and an MMA-lowering agent, such as vitamin B12, followed by administering an effective amount of pemetrexed. The patent also claims improved methods for administering pemetrexed, by administering specific dosages of folic acid and vitamin B12, each of which are administered prior to the first administration of pemetrexed.

Neptune Generics, Fresenius Kabi and Mylan Laboratories (collectively, petitioners) requested inter partes review (IPR) of Eli Lilly’s patent, arguing that the claims of the patent were obvious over several prior art references. After the IPRs were instituted, the PTAB held that the patent claims were not obvious, finding that while the prior art disclosed that pretreatment with folic acid reduced pemetrexed-associated toxicity, the prior art offered no suggestion to pretreat cancer patients with vitamin B12 along with folic acid before administering pemetrexed. The PTAB found that the skepticism of others, particularly the US Food and Drug Administration (FDA), supported a conclusion of non-obviousness. Petitioners appealed.

On appeal, petitioners argued that the PTAB’s non-obvious finding was erroneous based on teaching of the prior art and also in view of Lilly’s statements to the FDA regarding the predictable activity of the claimed combination of folate and B12. On the first point, the Federal Circuit upheld the PTAB’s finding that the cited references failed to support a prima facie case of obviousness since the prior art did not provide information as to how pretreatment with folic acid and vitamin B12 attenuated antifolate toxicity. On the second point, the petitioners argued that the PTAB should have considered Eli Lilly’s statement to the FDA and precluded it from taking contrary positions in the IPR. Specifically, petitioners claimed that Lilly’s statement that “folic acid and B12 [pretreatment] was a no-risk, predictable way to lower pemetrexed-induced fatalities” reflected the background knowledge of the skilled artisan. The Court disagreed, finding that the PTAB did not err by declining to read prior art references in view of Lilly’s statements, which were made to the FDA more than five months after the critical date.

Turing to secondary considerations of non-obviousness, the Federal Circuit found no error in the PTAB’s finding of skepticism based on the FDA’s statement that the patented method was “risky.” Petitioners argued that skepticism must be premised on whether it is “technically infeasible,” “unworkable” or “impossible” that the claimed subject matter would work for its intended purpose. The Court rejected that argument, finding that a range of third-party opinions can constitute skepticism, including if a third-party is “worried” or “surprised.” The Court found the FDA’s concerns of “risk” well within the acceptable range of skepticism. Thus, the Court found that the PTAB did not err in finding that skepticism supported a conclusion of non-obviousness.