Neptune’s IPR petition, IPR2016-00237, was one of many challenges of the ’209 patent—including IPR2016-01190, IPR2016-01335, and IPR2016-01341, which were joined with the present proceeding. The ’209 patent was also the subject of a district court litigation, Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., No. 1:10-cv-1376 (S.D. Ind.). Notably, the Southern District of Indiana had previously rejected invalidity challenges involving some of the same prior art references. The Southern District of Indiana court’s decision upholding the validity of the ʼ209 patent was affirmed by the Federal Circuit.

The claims of the ’209 patent are directed to methods of administering pemetrexed to a patient in need of such treatment—for example, a patient in need of chemotherapeutic treatment. Prior to administration of pemetrexed, the claims provide for administration of folic acid and a methylmalonic acid (e.g., vitamin B12). The patent contains two independent claims—claims 1 and 12. The narrower of the two claims—claim 12—is reproduced below:

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.

The Board instituted the IPR based on a single ground of unpatentability—obviousness in view of a meeting abstract by Niyikiza (“Niyikiza”), U.S. Patent No. 5,217,974 (“the ’974 patent”), and EP 0595005 (“EP ’005”). Niyikiza, which was considered during the federal court litigation, described a clinical study assessing patient characteristics following pemetrexed treatment in 139 cancer patients. Niyikiza reported that methylmalonic acid and homocysteine levels should be measured in patients at the beginning and during treatment. The ’974 patent is directed to methods of improving the therapeutic utility of antifolates by co-administering a folate binding protein. Additionally, the ’974 patent recognizes that folic acid is a preferred folate binding protein. EP ’005 is directed to pharmaceutical preparations comprising vitamin B6, folate, and vitamin B12.

After full briefing and argument, the Board rejected Neptune’s challenge. While the Board concluded that Neptune had established that it would have been obvious to pretreat with folic acid prior to administering pemetrexed sodium to treat cancer, it also concluded that Neptune failed to establish that it would have been obvious to treat with vitamin B12 as well. The Board did not agree with Neptune’s arguments that Niyikiza’s teachings to measure methylmalonic acid levels during cancer treatment would have motivated a skilled artisan to pretreat with vitamin B12. Moreover, the Board found that objective indicia of nonobviousness supported the patentability of the ’209 patent claims. Specifically, the Board relied on evidence of skepticism of others (including the FDA) regarding pretreatment of pemetrexed patients with vitamin B12, which further undermined Neptune’s unpatentability challenge.

While patents challenged in a district court proceeding enjoy a statutory presumption of validity, such a presumption is not present in an IPR proceeding. Even though the legal standard is different, this decision evidences the difficulty in overcoming a decision in a parallel proceeding—particularly after the Federal Circuit has affirmed that decision. In affirming the district court, the Federal Circuit found that there was a “missing link between vitamin B12 deficiency and pemetrexed toxicity.” In the IPR, Neptune was still unable to overcome factual findings relating to the lack of motivation to pretreat pemetrexed patients with vitamin B12. Accordingly, the Board, like the district court and Federal Circuit, denied Neptune’s invalidity challenge.