Neptune Generics, LLC v. Eli Lilly & Company, 921 F.3d 1372

Background

The ’209 patent (Eli Lilly) claims methods of administering folic acid and a methylmalonic acid (MMA)–lowering agent (e.g., vitamin B12) before pemetrexed to reduce antifolate toxicity; independent claims recite pretreatment with folate and vitamin B12 followed by pemetrexed.
Petitioners (Neptune Generics, Fresenius Kabi, Mylan) requested three IPRs arguing claims 1–22 were obvious over prior art including Niyikiza abstracts, EP005, Savage et al., Rusthoven, and U.S. Patent No. 5,217,974.
The Board found prior art taught that folic acid pretreatment reduces antifolate toxicity but that there was no motivation to add vitamin B12 pretreatment for pemetrexed because MMA (linked to B12 deficiency) was not shown to predict pemetrexed toxicity.
The Board credited expert testimony and prior studies showing homocysteine is elevated in folate deficiency and predictive of pemetrexed toxicity, whereas MMA is elevated only in B12 deficiency and not predictive of pemetrexed toxicity.
The Board also relied on contemporaneous skepticism (notably FDA concerns during clinical trials) as supporting nonobviousness; it declined to treat Lilly’s post-critical-date FDA communications as altering the prior-art baseline.
The Board ruled claims not shown obvious; petitioners appealed, arguing (inter alia) EP005 taught combined folate/B12 pretreatment, Lilly’s FDA statements should bind Lilly, and claims are §101-ineligible.

Issues

Issue	Plaintiff's Argument	Defendant's Argument	Held
Obviousness of independent claims (motivation to add B12)	EP005 and other art taught folic acid + B12 to lower homocysteine; a skilled artisan would be motivated to add B12 to reduce pemetrexed toxicity	Board/Patentee: prior art showed homocysteine (not MMA) correlated with pemetrexed toxicity; MMA (B12 marker) not predictive, so no motivation to add B12	Affirmed: substantial evidence supports Board that art did not motivate adding B12; nonobviousness upheld
Weight of EP005	EP005 broadly teaches lowering homocysteine using folate+B12, so it supports combining vitamins pre-pemetrexed	EP005 is focused on cardiovascular homocysteine effects, not antifolate toxicity; its ‘‘elevated’’ homocysteine threshold differs from pemetrexed-risk levels	Affirmed: Board reasonably found EP005 tangential and not dispositive
Use of Lilly’s FDA communications	Lilly told FDA prior art supported vitamins; these statements reflect skilled-artisan knowledge and should affect IPR analysis	Communications post-date the critical date and are colored by Lilly’s invention; Board properly declined to let them redefine the prior art	Affirmed: Board did not err in excluding those post-critical-date statements from the prior-art baseline
Industry skepticism	Petitioners: FDA allowed trial to continue, so its concerns cannot show meaningful skepticism; skepticism must show impossibility or unworkability	Patentee/Board: a range of third-party doubts (including safety concerns) can constitute skepticism supporting nonobviousness	Affirmed: FDA concerns and others constituted admissible skepticism weighing toward nonobviousness

Key Cases Cited

Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064 (Fed. Cir. 2015) (review: legal questions de novo, underlying facts for substantial evidence)
Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359 (Fed. Cir. 2016) (motivation-to-combine is factual)
Arctic Cat Inc. v. Bombardier Recreational Prods. Inc., 876 F.3d 1350 (Fed. Cir. 2017) (scope and content of prior art are fact questions)
In re Copaxone Consol. Cases, 906 F.3d 1013 (Fed. Cir. 2018) (patentee’s FDA disclosures may be considered in assessing prior art)
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) (avoid hindsight bias in obviousness analysis)
WBIP, LLC v. Kohler Co., 829 F.3d 1317 (Fed. Cir. 2016) (industry skepticism can support nonobviousness)
Circuit Check Inc. v. QXQ Inc., 795 F.3d 1331 (Fed. Cir. 2015) (third-party expressions of worry or surprise can constitute skepticism)