Appeals from the United States District Court for the
Southern District of Indiana in Nos. 1:16-cv-03460-TWP-MPB,
1:16-cv-00308-TWP-MPB, Judge Tanya Walton Pratt.
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 syn-thase, 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,
3-d]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 presupplementation 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
representative[2]:
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
with a combination of vitamins ...