CAFC Affirms Nonobviousness of Vitamin B12 and Folate Administration Prior to Chemotherapy


By: Katie Rubino

On April 26, 2019, the Court of Appeals for the Federal Circuit (CAFC) issued a final decision in Neptune Generics, LLC, Fresenius Kabi USA, LLC, (“Neptune”) v. Eli Lilly & Company (“Eli Lilly”). This case was on appeal from four related inter-partes review (IPR) decisions from the Patent Trial and Appeal Board (PTAB). The case centers around the claims of patent 7,772,209 (’209) owned by Eli Lily. The ‘209 patent relates to administering folic acid and a methylmalonic acid lowering agent (MMA) such as Vitamin B12, before administering premetrexed disodium, a chemotherapeutic agent produced by Eli Lilly.

Premetrexed disodium is indicated for the treatment of pleural mesothelioma and non-small cell lung cancer. Premetrexed disodium is a folate antimetabolite that works by inhibiting enzymes used in purine and pyrimidine synthesis. This prevents the formation of DNA and RNA, which are required for the growth and survival of cancer cells. Patients who are prescribed premetrexed disodium are often recommended to supplement with folic acid to reduce the frequency of adverse effects. Premetrexed disodium can often cause a host of adverse effects including low blood cell counts, fatigue, nausea, vomiting, mucositis, loss of appetite, and skin rash.

This case was first initiated when Neptune filed three petitions for IPR, each alleging that the claims in Eli Lily’s ‘209 patent were obvious. Neptune substantiated obviousness claims by citing different articles that were previously published that examined folate metabolism and toxicity. The PTAB concluded that the claims in the ‘209 patent were not unpatentable for obviousness. The PTAB reasoned that while the prior art explored how pretreatment with folic acid reduced the toxicity associated with administering an antifolate such as premetrexed, there was no reason to pretreat with Vitamin B12 in addition to folic acid. Neptune then appealed this decision to the CAFC.

The CAFC affirmed the decision of the PTAB, finding that the claims in Eli Lily’s ‘209 patent were not obvious. The CAFC found that a person of ordinary skill in the art (POSITA) would not have been motivated to administer an agent such as Vitamin B12 in addition to folic acid. The prior art taught that deficiencies in both Vitamin B12 and folate can lead to elevated levels of homocysteine. However, elevated levels of MMA are correlated with Vitamin B12 deficiencies but not folate. The testimony of Eli Lily’s expert witness further substantiated this finding, highlighting there was no correlation between Vitamin B12 deficiency and premetrexed toxicity.

Neptune then tried to establish other arguments as to why the nonobviousness determination should be reversed. Neptune first argued that the nonobviousness determination should be reversed based on the dependent claims. However, the CAFC rejected this argument, citing that given the affirmation of the independent claims, the dependent claims stood as well. Neptune also argued that the claims were directed towards nonpatentable subject matter under ⸹101. The CAFC also rejected this argument, as an IPR can only be raised for grounds under ⸹102 novelty and ⸹103 nonobviousness, respectively.

To conclude, this case highlights the importance of timing in respect to filing grounds for invalidity in post grant decisions. Petitioners seeking to invalidate a patent for nonpatentable subject matter under ⸹101 must do so by filing a post grant review (PGR) within 9 months of issuance of a patent. After a patent has been issued for nine months, challenges are limited to ⸹102 and ⸹103 only when filing an IPR.