In a precedential decision delivered recently, the Federal Circuit shot down arguments from Neptune Generics, LLC, Mylan Laboratories Ltd., and Fresenius Kabi USA, LLC that the Patent Trial and Appeals Board (PTAB) erred in not finding Eli Lilly’s patent covering the vitamin regimen for chemotherapy drug Alimta^® invalid as obvious.

The claims of U.S. Patent No. 7,772,209, which is owned by Eli Lilly & Co., generally cover a method for administering the chemotherapy agent pemetrexed disodium to a patient through first administering effective amounts of folic acid and a methylmalonic acid lowering agent and then administering an effective amount of the chemotherapy agent. According to the ʼ209 patent, the initial administration of folic acid and a methylmalonic lowering agent (such as vitamin B12) reduces the serious side effects of the chemotherapy agent. The ʼ209 patent explains that “[s]urprisingly and unexpectedly, we have now discovered that certain toxic effects such as mortality and nonhematologic events, such as skin rashes and fatigue, caused by antifolates, as a class, can be significantly reduced by the presence of a methylmalonic acid lowering agent, without adversely affecting therapeutic efficacy.”

The claims of the ʼ209 patent were targeted by the trio of appellants, among others, in a number of Inter Partes Reviews (IPRs). Briefly, a first IPR challenged all of the claims in the ʼ209 patent as obvious over five references (including European Patent Application No. 0 595 005 A1 (EP005)), a second IPR challenged all of the claims as obvious over three of the same five references as in the first IPR (again, including EP005), and a third IPR challenged all of the claims as obvious over EP005 combined with a 1999 article. The challenges were based on the premise that the prior art already taught pre-treatment with folic acid before pemetrexed administration and any combination with vitamin B12 was obvious-to-try based on a suggestion of vitamin deficiency associated with pemetrexed disodium. Despite the numerous petitions and different approaches to invalidity, the PTAB found that, while it was known in the prior art that pretreatment with folic acid reduces the toxicity of an antifolate (of which pemetrexed disodium is one), there was no reason prior to the invention to pretreat with a combination of vitamin B12 and folic acid prior to administration of the chemotherapy agent. In addition, the PTAB noted that the skepticism of others, including the FDA, supported a conclusion of nonobviousness. 

Appellants’ multi-prong approach on appeal included an argument that the PTAB’s finding was not supported by substantial evidence because it did not consider the entirety of the teachings in EP005. More specifically, according to appellants, EP005 discloses administration of folic acid and vitamin B12 to lower homocysteine levels for all purposes and, thus, a skilled artisan would have been motivated to administer an MMA lowering agent, such as vitamin B12, in addition to folic acid. However, the Federal Circuit explained that, due to the lack of even a general discussion of antifolates and only general mention of certain cancers in EP005, “substantial evidence supports the Board’s finding that EP005 did not provide information as to how pretreatment with folic acid and vitamin B12 would impact toxicity effects.” 

The second prong of appellants’ argument focused on the PTAB’s purported error in not considering statements made by Eli Lilly to the FDA about the clinical trials of pemetrexed. More specifically, appellants argued that Eli Lilly had “inform[ed] the FDA that the prior art suggested that pretreating with folic acid and B12 was a no-risk, predictable way to lower pemetrexed-induced fatalities by lowering pretreatment homocysteine levels.” Appellants argued that, even if the communications between the FDA and Eli Lilly are not in the prior art, they at least reflect the background knowledge of a skilled artisan and are indicators of the level of ordinary skill in the art. However, the Federal Circuit was not persuaded that the PTAB had erred in not reading the cited references in view of Eli Lilly’s statements to the FDA because the timing of any statements to the FDA occurred more than five months after the critical date and were “made through the lens of what [Eli Lilly] had invented.”  Expounding further, the Federal Circuit indicated that, while evidence of a third-party opinion of impossibility might be entitled to more weight in the context of nonobviousness, the FDA’s concerns about Eli Lilly’s recommendation to supplement pemetrexed administration with vitamins during clinical trials were within the range of a third-party opinion that can constitute skepticism even if the FDA only considered it “risky.”

In concluding its affirmation of the PTAB’s decision, the Federal Circuit reminded appellants that subject matter eligibility is not properly before the court in an appeal from an IPR decision (even if, as argued by appellants that the claims were so clearly ineligible that the court should reject the claims as a matter of law). More particularly, the Federal Circuit noted that the ground of patent eligibility arises under 35 U.S.C. § 101, which is not a proper invalidity challenge in an IPR and, thus, the court was precluded from addressing the issue on appeal of an IPR.

So what are the key takeaways from this decision? First and foremost, it is important not to overlook the importance of secondary considerations—evidence of industry skepticism is a useful tool to show nonobviousness. Second, skepticism comes in many forms and is not necessarily required to be in the form of a third-party opinion of impossibility, infeasibility, or unworkability. Indeed, testimony that third parties were “worried” or “surprised” may be sufficient to establish skepticism so as to support a conclusion of nonobviousness.