Eli Lilly & Co. v. Hospira, Inc.

• Decision Date: 09 August 2019
• Docket Number: 2018-2126,2018-2127,2018-2128
• Citation: 933 F.3d 1320
• Parties: ELI LILLY AND COMPANY, Plaintiff-Appellee v. HOSPIRA, INC., Defendant-Appellant Eli Lilly and Company, Plaintiff-Appellee v. Dr. Reddy's Laboratories, Ltd., Dr. Reddy's Laboratories, Inc., Defendants-Appellants
• Court: U.S. Court of Appeals — Federal Circuit

933 F.3d 1320

ELI LILLY AND COMPANY, Plaintiff-Appellee

v.HOSPIRA, INC., Defendant-Appellant

Eli Lilly and Company, Plaintiff-Appellee

v.Dr. Reddy's Laboratories, Ltd., Dr. Reddy's Laboratories, Inc., Defendants-Appellants

2018-2126

2018-2127

2018-2128

United States Court of Appeals, Federal Circuit.

Decided: August 9, 2019

Adam Lawrence Perlman, Williams & Connolly LLP, Washington, DC, argued for plaintiff-appellee in 2018-2126 and 2018-2128. Also represented by Galina I. Fomenkova, Dov Philip Grossman, David M. Krinsky, Andrew P. Lemens, Charles McCloud; James Patrick Leeds, Eli Lilly and Company, Indianapolis, IN.

Bradford Peter Lyerla, Jenner & Block LLP, Chicago, IL, argued for defendant-appellant in 2018-2126. Also represented by Yusuf Esat, Sara Tonnies Horton ; Adam G. Unikowsky, Washington, DC.

John C. O'Quinn, Kirkland & Ellis LLP, Washington, DC, argued for defendants-appellants in 2018-2128. Also represented by William H. Burgess, Calvin Alexander Shank; Jeffery B. Arnold, Holland & Knight LLP, Atlanta, GA; Merri C. Moken, Charles A. Weiss, Eric H. Yecies, New York, NY.

Brian Timothy Burgess, Goodwin Procter LLP, Washington, DC, for amicus curiae Actavis LLC in 2018-2128. Also represented by Edwina Clarke, Emily L. Rapalino, Daryl L. Wiesen, Boston, MA; Linnea P. Cipriano, New York, NY.

Before Lourie, Moore, and Taranto, Circuit Judges.

Lourie, Circuit Judge.

Hospira Inc. ("Hospira"), Dr. Reddy’s Laboratories Ltd., and Dr. Reddy’s Laboratories Inc. (collectively, "DRL") appeal from two judgments of the United States District Court for the Southern District of Indiana in two infringement suits brought by Eli Lilly & Company ("Lilly") under the Hatch-Waxman Act, 21 U.S.C. § 355. The district court held in each case that the defendant’s submission of a New Drug Application pursuant to 21 U.S.C. § 355(b)(2) infringed U.S. Patent 7,772,209 (the "’209 patent") under 35 U.S.C. § 271(e)(2). See Eli Lilly & Co. v. Hospira, Inc. , No. 1:16-cv-03460-TWP-MPB, 2018 WL 3008570 (S.D. Ind. June 15, 2018) (" Hospira Decision "); Eli Lilly & Co. v. Dr. Reddy’s Labs., Ltd. , 323 F. Supp. 3d 1042 (S.D. Ind. 2018) (" DRL Decision "); see also Eli Lilly & Co. v. Dr. Reddy’s Labs., Ltd. , No. 1:16-cv-00308-TWP-MPB, 2017 WL 6387316 (S.D. Ind. Dec. 14, 2017) (" DRL Summary Judgment Decision "). Accordingly, the district court entered orders under 35 U.S.C. § 271(e)(4)(A) prohibiting FDA approval of the products at issue until the expiration of the ’209 patent. Eli Lilly & Co. v. Hospira, Inc. , No. 1:16-cv-03460-TWP-MPB (S.D. Ind. June 27, 2018), ECF No. 94; Eli Lilly & Co. v. Dr. Reddy’s Labs., Ltd. , No. 1:16-cv-00308-TWP-MPB, 2018 WL 3616715 (S.D. Ind. July 27, 2018). We decide these appeals together in this combined opinion.¹

We reverse the district court’s finding of literal infringement in the Hospira Decision as clearly erroneous in light of the court’s claim construction of "administration of pemetrexed disodium." Because the district court did not err in its application of the doctrine of equivalents in either decision, we affirm both judgments of infringement. Thus, the Hospira Decision is affirmed-in-part and reversed-in-part, and the DRL Decision is affirmed.

BACKGROUND

Lilly markets the compound pemetrexed

in the form of a disodium salt as Alimta ®, which is indicated, both alone and in combination with other active agents, for treating certain types of non-small cell lung cancer and mesothelioma. Pemetrexed is an antifolate, a class of molecules which, at the time of the invention in 2001, was "one of the most thoroughly studied classes of antineoplastic agents." ’209 patent col. 1 ll. 19–20. Antifolates are structurally similar to folic acid and work by competitively binding to certain enzymes that use folic acid metabolites as cofactors in several steps of de novo nucleotide synthesis. Id. col. 1 ll. 40–41. Unlike folic acid, antifolates do not enable these synthetic steps, but instead inhibit them. Pemetrexed inhibits several of these enzymes, including thymidylate synthase, which methylates deoxyuridine in the final step of deoxythymidine synthesis. Id. col. 1 ll. 59–61. By inhibiting the creation of these nucleotides, antifolates slow down DNA and RNA synthesis, and with it, cell growth and division. Cancer cells tend to grow rapidly, so antifolate therapy affects them disproportionately, but healthy cells can also be damaged.

Pemetrexed

had been known for at least a decade in 2001. Lilly’s U.S. Patent 5,344,932 ("Taylor") disclosed that certain glutamic acid derivatives with pyrrolo[2,3d]pyrimidine heterocyclic ring structures, exemplified by pemetrexed, are "particularly active ... inhibitors of thymidylate synth[ase]," Taylor col. 1 ll. 59–60; see also id. col. 19 l. 37–col. 20 l. 25 (disclosing data indicating that pemetrexed inhibits thymidylate synthase activity in vitro in human cell lines and in vivo in mice). The Taylor patent also disclosed that its compounds could be employed as "pharmaceutically acceptable salt[s]," id. col. 2 l. 35, and that the disodium salt form was particularly advantageous, id. col. 2 ll. 47–48. U.S. Patent 4,997,838 ("Akimoto"), to which Lilly took a license, disclosed a large genus of compounds containing pyrrolo[2,3-d]pyrimidine heterocyclic ring structures and a glutamic acid functional group, and that encompassed pemetrexed. The Akimoto patent discloses nearly fifty exemplary compounds, col. 14 l. 61–col. 16 l. 48, none of which is pemetrexed. Akimoto further discloses that its compounds may be prepared as salts of "pharmaceutically acceptable bases," such as "alkali metals, alkali earth metals, non-toxic metals, ammonium, and substituted ammonium." Id. col. 14 ll. 44–47.

By 2001, Lilly had also published the results of several clinical trials investigating the use of pemetrexed

disodium as a treatment for different types of cancer. See, e.g. , W. John et al., "Activity of Multitargeted Antifolate (Pemetrexed Disodium, LY231514) in Patients with Advanced Colorectal Carcinoma : Results from a Phase II Study," Cancer , 88(8):1807–13 (2000). In the course of conducting these studies, Lilly discovered that pemetrexed disodium caused severe hematologic and immunologic side effects, resulting in infections, nausea, rashes, and even some deaths. See id. ; see also

Neptune Generics, LLC v. Eli Lilly & Co. , 921 F.3d 1372, 1377–78 (Fed. Cir. 2019) (discussing Lilly’s response to adverse clinical data), and

Neptune Generics, LLC v. Eli Lilly & Co. , No. IPR2016-00240, 2017 WL 4466557, at *28–30 (P.T.A.B. Oct. 5, 2017) (same). As the ’209 patent teaches, such side effects are not uncommon among antifolates. See ’209 patent col. 1 ll. 11–14. Some researchers hypothesized that folic acid deficiency caused these side effects and suggested supplementing pemetrexed disodium treatment with folic acid. DRL J.A. 7870 (citing J.F. Worzalla et al., "Role of Folic Acid in Modulating the Toxicity and Efficacy of the Multitargeted Antifolate, LY231514," Anticancer Research , 18:3235–40 (1998)).

The invention of the ’209 patent is an improved method of treatment with antifolates, particularly pemetrexed

disodium, through supplementation with a methylmalonic acid lowering agent and folic acid. Doing so, according to the patent, lessens antifolate toxicity without sacrificing efficacy. See ’209 patent col. 10 ll. 17–53 (reporting that pre-supplementation regimen of vitamin B12 and folic acid in clinical studies substantially reduced pemetrexed-induced toxicity and deaths while delivering a superior chemotherapeutic response rate). The ’209 patent lists preferred antifolates, including some then-existing antifolate therapies, as well as "derivatives described in" several patents including the Akimoto patent, and "most preferred, Pemetrexed Disodium." Id. col. 4 ll. 28–43. Each of the claims of the ’209 patent requires administration of pemetrexed disodium following administration of folic acid and a methylmalonic acid lowering agent, specified in some claims, as well as the Alimta ® label, as vitamin B12. Claim 12 is representative² :

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.

In a parent application, Application 10/297,821 (the "’821 application"), Lilly originally sought broad claims to methods of administering an antifolate in conjunction with a methylmalonic acid lowering agent, with or without folic acid

. The original independent claims 2 and 5 read:

2. (Original) A method of reducing the toxicity associated with the administration of an antifolate to a mammal comprising

administering to said mammal an effective amount of said antifolate in combination with a methylmalonic acid lowering agent.

5. (Original) A method of reducing the toxicity associated with the administration of an antifolate to a mammal comprising

administering to said mammal an effective amount of said antifolate in combination with a methylmalonic acid lowering agent and FBP binding agent.

DRL J.A. 7860. A dependent claim further limited the antifolate to pemetrexed

disodium. Id. at 7861.

Claim 2 was rejected as anticipated by F.G. Arsenyan et al., "Influence of Methylcobalamin

on the Antineoplastic Activity of Methotrexate," Onkol. Nauchn ., 12(10):1299-1303 (1978), which disclosed experiments treating mice with various tumors with a combination of methotrexate, an antifolate, and methylcobalamin, a vitamin B12 derivative. The rest of the pending claims, including Claim 5, were rejected as obvious over a collection of references: U.S. Patent 5,431,925 ("Ohmori") —which taught treatment of chemotherapeutically-induced immunosuppression...