Last week, in Neptune Generics, LLC v. Eli Lilly & Co., the Federal Circuit affirmed a determination by the U.S. Patent and Trademark Office Patent Trial and Appeal Board in an inter partes review that claims 1-22 of U.S. Patent No. 7,772,209 were not unpatentable for obviousness. In affirming the Board's decision, the Federal Circuit found that the Board did not err in conducting its obviousness analysis and that substantial evidence supported the Board's factual findings. The Federal Circuit also noted that the issue of subject matter eligibility was not properly before the Court.
The '209 patent, which is owned by Eli Lilly & Co., is directed to methods of administering folic acid and a methylmalonic acid ("MMA") lowering agent, such as vitamin B12, before administering pemetrexed disodium, a chemotherapy agent, in order to reduce the toxic effects of pemetrexed, an antifolate. Antifolates slow the ability of cells to divide by inhibiting enzymes that the cells use to make the components of DNA and RNA, but as a result, also have toxic effects that can be life threatening. The two independent claims of the '209 patent recite:
1. A method for administering pemetrexed disodium to a patient in need thereof comprising administering an effective amount of folic acid and an effective amount of a methylmalonic acid lowering agent followed by administering an effective amount of pemetrexed disodium, wherein the methylmalonic acid lowering agent is selected from the group consisting of vitamin B12, hydroxycobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-cobalamin perchlorate, azidocobalamin, cobalamin, cyanocobalamin, or chlorocobalamin.
12. An improved method for administering pemetrexed disodium to a patient in need of chemotherapeutic treatment, wherein the improvement comprises:
a) administration of between about 350 μg and about 1000 μg of folic acid prior to the first administration of pemetrexed disodium;
b) administration of about 500 μg to about 1500 μg of vitamin B12, prior to the first administration of pemetrexed disodium; and
c) administration of pemetrexed disodium.
Three petitions seeking inter partes review of the '209 patent were filed by Appellants Neptune Generics, LLC; Fresenius Kabi USA, LLC; and Mylan Laboratories Ltd. The first petition asserted that claims 1–22 of the '209 patent are obvious in view of a 1999 article by Hilary Calvert, a 1998 abstract by Niyikiza et al. ("Niyikiza I"), a 1998 article by Worzalla et al., European Patent Application No. 0 595 005 A1 ("EP005"), and U.S. Patent No. 5,217,974. The second petition asserted that the claims of the '209 patent are obvious in view of Niyikiza I, the '974 patent, and EP005. The third petition asserted that the claims of the '209 patent are obvious over a 1999 article by Rusthoven et al. and EP005. In the IPRs that were instituted, the Board concluded that the claims of the '209 patent were not established to be unpatentable for obviousness. In particular, the Board concluded that while it was known in the art that pretreatment with folic acid reduces the toxicity associated with administration of an antifolate, like pemetrexed, there was no reason to also pretreat with vitamin B12 before administering pemetrexed to treat cancer. The Board also found that the skepticism of others, particularly the FDA, supported a conclusion of nonobviousness.
On appeal, Appellants focused on three references: Niyikiza I, EP005, and another abstract by Niyikiza et al. ("Niyikiza II"). With respect to EP005, Appellants argued that the Board did not consider all that this reference teaches in finding that that the skilled artisan would not have been motivated to administer an MMA lowering agent, such as vitamin B12, in addition to folic acid. In particular, Appellants argued that EP005 discloses administration of folic acid and vitamin B12 to lower homocysteine levels for all purposes. The Federal Circuit, however, found that substantial evidence supported the Board's findings. In particular, the Court determined that substantial evidence supported the Board's findings that elevated levels of homocysteine were known to be predictive of pemetrexed toxicity and elevated levels of MMA were understood not to be predictive of pemetrexed toxicity, that a skilled artisan would have understood that there was no observed correlation between vitamin B12 deficiency and pemetrexed-induced toxicity, and therefore, that the prior art did not provide a motivation for a skilled artisan to administer an MMA lowering agent, such as vitamin B12, in addition to folic acid. With respect to EP005, the Federal Circuit pointed out that the Board had determined that this reference was concerned with the cardiovascular effects associated with elevated homocysteine levels, does not discuss antifolates generally, and only generally mentions certain cancers, explaining that "[g]iven the contrast between the specific, directly applicable teachings of Niyikiza II and the tangential, general statements of 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."
Appellants also argued that the Board erred by not considering statements made by Lilly to the FDA concerning clinical trials of pemetrexed. In particular, Appellants argued that 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," and that Lilly's statements reflected the background knowledge of the skilled artisan and were indicators of the level of ordinary skill in the art. In concluding that the Board did not err in declining to read the cited references in view of Lilly's statements to the FDA, the Federal Circuit noted that the statements were made more than five months after the critical date, and "[a]s the Board found, the views Lilly expressed about the prior art references in its communications are made through the lens of what they had invented."
In finding that claims 1-22 of the '209 patent were not unpatentable for obviousness, the Board determined that the evidence of skepticism of others, particularly the FDA, supported a conclusion of nonobviousness. During clinical trials for pemetrexed, in which a number of fatalities had occurred, Lilly recommended to the FDA that pemetrexed administration be supplemented with folic acid and vitamin B12, and the FDA responded that it did not support adding vitamins to the ongoing trial because the addition of vitamins was "risky." Appellants argued that the Board erred in finding this evidence to be sufficient to support a finding of skepticism because the FDA allowed the trial to continue, and 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 Federal Circuit, however, disagreed with Appellants, stating that their "position is not consistent with our caselaw, which recognizes a range of third-party opinion that can constitute skepticism," and finding that "[w]hile evidence that third parties thought the invention was impossible might be entitled to more weight, that does not mean the Board erred in giving weight to the skepticism evidence here." The Federal Circuit therefore determined that the Board did not err in finding that skepticism supported a conclusion of nonobviousness.
Finally, with respect to Appellants' argument that the claims are not directed to patentable subject matter (asserting that the issue was properly raised because eligibility is a question of law and that there were no factual issues that must be decided in the appeal), the Federal Circuit noted that the ground of patent eligibility arises under § 101, and therefore, that the Court was precluded from addressing the issue on appeal of an IPR. The Federal Circuit therefore affirmed the Board's determination that claims 1-22 of the '209 patent were not unpatentable for obviousness.
Neptune Generics, LLC v. Eli Lilly & Co. (Fed. Cir. 2019)
Panel: Circuit Judges Moore, Wallach, and Hughes
Opinion by Circuit Judge Moore
