AMGEN INC., AMGEN MANUFACTURING, LIMITED, Plaintiffs-Cross-Appellants
HOSPIRA, INC., Defendant-Appellant
Appeals from the United States District Court for the
District of Delaware in No. 1:15-cv-00839-RGA, Judge Richard
Labbe, Marshall, Gerstein & Borun LLP, Chicago, IL,
argued for plaintiffs-cross-appellants. Also represented by
Kevin M. Flowers, Julianne M. Hartzell, Mark Harry
Izraelewicz; Thomas Francis Lavery, Wendy A. Whiteford, Amgen
Inc., Thousand Oaks, CA.
J. Meloro, Willkie Farr & Gallagher LLP, New York, NY,
argued for defendant-appellant. Also represented by Michael
Johnson, Heather M. Schneider.
Moore, Bryson, and Chen, Circuit Judges.
Inc. (Hospira) appeals the District of Delaware's denial
of its motion for judgment as a matter of law (JMOL), or
alternative motion for new trial, upholding the jury's
verdict that: (1) Amgen, Inc. and Amgen Manufacturing,
Ltd.'s (Amgen) U.S. Patent No. 5, 856, 298 (the '298
patent) was infringed and not invalid; (2) fourteen batches
of drug substance for Hospira's erythropoietin biosimilar
drug product were not covered by the Safe Harbor provision of
35 U.S.C. § 271(e)(1); and (3) Amgen had proven it was
entitled to $70 million in damages. Amgen cross-appeals the
district court's denial of its motion for judgment as a
matter of law, and alternative motion for new trial,
upholding the jury's verdict of noninfringement of U.S.
Patent No. 5, 756, 349 (the '349 patent). For the
following reasons, we affirm the district court's
decisions as to each.
patents at issue relate to erythropoietin (EPO) isoforms and
aspects of their production. EPO is a glycoprotein hormone
that regulates red blood cell maturation and production.
Recombinant human EPO is an important therapeutic protein for
the treatment of anemia. Human EPO consists of a polypeptide
of 165 amino acids and a high content of saccharides (or
glycans). It contains various sites for glycosylation, i.e.,
sites where saccharides can be attached to the protein part
of the molecule. Each of these glycosylation sites has the
potential for branching and each branch contains a potential
terminal sialic acid, a negatively-charged molecule. Thus,
each EPO molecule can have different numbers of sialic acids.
Amgen manufactures and markets recombinant human EPO as
claims of the '298 patent claim, inter alia,
methods of producing EPO isoforms having a specific number of
sialic acids per molecule, and methods for obtaining EPO
compositions having a predetermined in vivo specific
activity. According to the '298 patent, each isoform of
EPO has an in vivo activity which correlates to the
number of sialic acids the isoform possesses. '298 patent
at 5:33-46, 5:62- 64.
to this case are certain techniques for separating protein
molecules. The first, isoelectric focusing, "separates
proteins on the basis of charge." '298 patent at
4:65-67. Proteins placed in a pH gradient and subjected to an
electric field will migrate (through attraction toward or
repulsion from the negatively- or positively-charged
electrode) towards the point at which they have no net
charge. Id. at 4:67-5:3. This point is known as the
isoelectric point, or pI. Id. Each band seen on an
isoelectric focusing gel represents molecules that have the
same overall charge and are termed "isoforms."
Id. at 5:4-5:7. The '298 patent describes
"erythropoietin isoforms" as EPO preparations
"having a single pI, and having the same amino acid
sequence." Id. at 5:6-9. A second technique,
ion exchange chromatography, involves separation of proteins
on the basis of charge by application of material containing
the protein "to a column resin under conditions that
permit binding of some or all of the [protein of interest] to
the resin." Id. at 7:3-8. The resin can be
washed with buffers of varying pHs, thereby
"elut[ing]" the proteins based on the charge.
Id. at 7:4-17.
'349 patent is directed to recombinant cells that are
capable of producing EPO at certain rates when grown in
culture. The claims of the '349 patent are directed to
cells that produce certain units of EPO as determined by a
radioimmunoassay, a technique that allows for measuring
protein levels using a radioisotope.
2014, Hospira submitted its Biologics License Application
(BLA) No. 125-545 to the FDA, seeking approval for a
biosimilar to Amgen's Epogen product. Amgen sued Hospira
for infringement of the '298 patent under 35 U.S.C.
§§ 271(a) and 271(e)(2)(C), and for infringement of
the '349 patent under 35 U.S.C. § 271(a). Amgen
asserted that Hospira's manufacture of twenty-one batches
of drug substance for its EPO biosimilar drug product
infringes claims 24 and 27 of the '298 patent and claims
1-7 of the '349 patent. A jury trial was held in
September 2017. The jury found the asserted claims of the
'298 patent not invalid and infringed, and the asserted
claims of the '349 patent not invalid and not infringed.
Of the twenty-one accused drug substance batches, the jury
found seven batches entitled to the Safe Harbor defense. The
jury awarded Amgen $70 million in damages.
district court denied Hospira's post-trial Rule 50(b)
Motion for Judgment as a Matter of Law on issues of
non-infringement and invalidity of the '298 patent, Safe
Harbor, and damages, or in the alternative, for remittitur or
a new trial. The district court also denied Amgen's
renewed motion for JMOL for infringement of the '349
patent, or in the alternative, for a new trial.
appeal, Hospira challenges a myriad of issues, including: (1)
the district court's claim construction; (2) the jury
instructions regarding the Safe Harbor defense; (3) the
jury's findings regarding the Safe Harbor defense and
denial of JMOL on the Safe Harbor issue; (4) the evidentiary
rulings regarding Amgen's damages expert; and (5) the
denial of JMOL of noninfringement and invalidity. On
cross-appeal, Amgen challenges: (1) the district court's
denial of JMOL of infringement of the '349 patent; and
(2) the denial of its motion for a new trial. We have
jurisdiction under 28 U.S.C. § 1295(a)(1).
review a denial of JMOL under the law of the regional
circuit. Energy Transp. Grp. Inc. v. William Demant
Holding A/S, 697 F.3d 1342, 1350 (Fed. Cir. 2012).
"In the Third Circuit, review of denial of JMOL is
plenary." Finjan, Inc. v. Secure Computing
Corp., 626 F.3d 1197, 1202 (Fed. Cir. 2010) (citations
omitted). JMOL is "'granted only if, viewing the
evidence in the light most favorable to the nonmovant and
giving it the advantage of every fair and reasonable
inference, there is insufficient evidence from which a jury
reasonably could find' for the nonmovant."
TransWeb, LLC v. 3M Innovative Props. Co., 812 F.3d
1295, 1301 (Fed. Cir. 2016) (quoting Lightning Lube, Inc.
v. Witco Corp., 4 F.3d 1153, 1166 (3d Cir. 1993));
see also Pitts v. Delaware, 646 F.3d 151, 155 (3d
Cir. 2011). Moreover, where the movant bore the burden of
proof on an issue, JMOL is only granted where "there is
insufficient evidence for permitting any different
finding." Fireman's Fund Ins. Co. v. Videfreeze
Corp., 540 F.2d 1171, 1177 (3d Cir. 1976) (citations
omitted). The decision to grant or deny a new trial is
committed to the discretion of the district court, which
grants a new trial only where "a miscarriage of justice
would result if the verdict were to stand" or where the
verdict "shocks [the] conscience." Williamson
v. Consol. Rail Corp., 926 F.2d 1344, 1352-53 (3d Cir.
Judgment of Infringement and No Invalidity
contends that it is entitled to a judgment of noninfringement
of claim 27 of the '298 patent because: (1) the district
court's claim construction was erroneous, and no
reasonable jury could find infringement under the proper
construction; and (2) even under the district court's
construction, Amgen did not establish Hospira's
infringement of every limitation. Hospira also argues that
under the district court's construction, no reasonable
jury could find claim 27 not invalid over U.S. Patent No. 4,
667, 016 (Lai). As discussed below, we find Hospira's
construction is a question of law we review de novo,
with subsidiary factual findings based on extrinsic evidence
reviewed for clear error. Teva Pharm. USA, Inc. v.
Sandoz, Inc., 574 U.S. 318 (2015).
A method for obtaining an erythropoietin composition having a
predetermined in vivo specific activity comprising preparing
a mixture of two or more erythropoietin isoforms of claim 1.
An isolated biologically active erythropoietin isoform having
a single isoelectric point and having a specific number of
sialic acids per molecule, said number selected from the
group consisting of 1-14, and said isoform being the product
of the expression of an exogenous DNA sequence in a non-human
eucaryotic host cell.
appeal, the parties do not dispute the district court's
finding that, although claim 27 refers to claim 1, it is an
independent claim. Defendant-Appellant's Resp. Br. 14-15;
Plaintiffs-Cross-Appellants' Br. 28. The district court
construed the term "[a]n isolated biologically active
erythropoietin isoform" in claim 1 to mean "a group
of molecules that has a single isoelectric focusing point and
a specific number of sialic acids per molecule, and appears
as a single band on an isoelectric focusing gel (an example
of which is shown in Figure 1 of the '298 patent)."
J.A. 192-93. The district court construed the limitation in
claim 27, "a mixture of two or more erythropoietin
isoforms of claim 1," to mean "a mixture of two or
more of the isolated erythropoietin isoforms of Claim
1." J.A. 174. In denying Hospira's motion for
summary judgment of noninfringement, the district court
explained that "[n]othing in [the claim] language
suggests that the individual isoforms of claim 1 have to be
separately prepared prior to making the mixture."
J.A.169. Accordingly, the final claim construction provided
to the jury included the following sentence: "Claim 27
does not require the individual isoforms of Claim 1 to be
separately prepared prior to making the mixture." J.A.
challenges this last portion of the construction. According
to Hospira, the proper construction of claim 27 requires a
mixture of "isolated" isoforms of claim 1, but the
district court's construction reads out the phrase
"isolated" by stating that the isoforms do not need
to be separately prepared prior to making the mixture.
Hospira argues that this construction contradicts the
intrinsic evidence and the testimony of the inventor Dr.
Strickland, who stated that the purpose of his invention
"was to separate isoforms and then 'recombine'
them or 'mix those fractions back together' to make
EPO compositions with specific in vivo
activity." Defendant-Appellant's Br. 37 (quoting
J.A. 720 at 375:12- 377:18). Hospira contends that under the