The Federal Circuit’s decision in Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., 845 F.3d 1357 (Fed. Cir. 2017) attracted much attention for applying the theory of divided infringement in the context of pharmaceutical therapeutic regimen claims. Before the Federal Circuit decision, a scrum of petitioners successfully petitioned for IPR of the Lilly patent, alleging that the claims were obvious in view of a combination of references that included prior art considered by the court in the litigation. Our previous post highlighted the potential for inconsistent results that AIA trials may present relative to district court actions concerning the same patent. In Neptune Generics, LLC. et al., v. Eli Lilly & Co., Case No. IPR2016-00237, Paper 84 (P.T.A.B. Oct. 5, 2017), the Board issued an 88-page final written decision determining that the petitioners failed to establish that the challenged claims were unpatentable, preserving Lilly’s patent position for one of its most lucrative products.

Neptune Generics, LLC successfully petitioned for IPR of claims 1-22 of U.S. Patent No. 7,772,209. The claims are directed to a method of administering pemetrexed (ALIMTA®) requiring co-administration with folic acid and a methylmalonic acid lowering agent (e.g., vitamin B12) to reduce toxicity associated with pemetrexed. Neptune challenged the claims for being obvious in view of a combination of three references, two of which the district court previously determined did not render the claims invalid. The PTAB instituted IPR, noting that Neptune’s challenge combined the prior art differently than the challenge during the district court case, and presented different expert witness testimony. Thereafter, through ten additional IPR petitions, Apotex Inc., Apotex Corp., Wockhardt Bio AG, Teva Pharmaceuticals USA, Inc., and Fresenius Kabi USA, LLC. all successfully moved to join Neptune’s IPR, challenged the same claims based on the same ground of unpatentability over the same art relied upon by Neptune Generics, LLC.

The PTAB determined that administration of folic acid with pemetrexed was obvious in view of the prior art, in contrast to the district court’s finding that co-administration of folic acid and pemetrexed was not obvious over a similar combination of references. Notably, the PTAB relied heavily on the opinion of Neptune’s expert, who did not testify in the district court case. The PTAB held, however, that the Petitioners failed to establish that pretreatment with vitamin B12 was obvious, echoing the district court’s conclusion that the art suffered from a “missing link between vitamin B12 deficiency and pemetrexed toxicity.” With respect to this claim element, the PTAB found Neptune’s expert’s testimony to be “internally inconsistent” as to the proffered motivation for administering vitamin B12. Specifically, Neptune’s expert testified that cancer patients undergoing pemetrexed treatment are more likely to have vitamin B12 deficiencies, thus motivating the artisan to supplement the treatment with vitamin B12. But he further testified, inconsistently according to the PTAB, that administration of even a small amount of vitamin B12 could potentially cause a reduction in the anti-cancer properties of the antifolate drug.

The PTAB further found that secondary considerations, namely skepticism by others, supported the non-obviousness of the claimed method. Lilly submitted correspondence from the FDA issued during clinical trials expressing the FDA’s doubt regarding vitamin pretreatment. In this regard, Lilly recommended supplementation of pemetrexed therapy with folic acid and vitamin B12 after reporting a 7% death rate in patients. The record established that, even in the face of clinical trial deaths, the FDA was not convinced that vitamin supplementation was warranted. Weighing all the evidence, the PTAB concluded that the Petitioners failed to demonstrate by a preponderance of the evidence that the challenged claims were obvious.

The PTAB’s final written decision estops the petitioners from challenging in the pending parallel district court actions the validity of these claims over the prior art addressed in the decision. The deadline for appealing to the Federal Circuit is fast approaching. If appealed, the Federal Circuit will review the PTAB’s legal conclusion regarding non-obviousness de novo, but will review the PTAB’s fact findings for support by substantial evidence in the record. The court’s review standard in this regard is not meaningfully different than how it previously reviewed the district court decision on the same issue. Given that the Federal Circuit considered most of the prior art during the litigation, an affirmance would appear to be likely.