Court Opinion

ID: 4464586
Source: CourtListenerOpinion
Date Created: 2019-12-16 17:00:36.909809+00
Date Added: 2024-06-11T14:53:43.028903
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                  ______________________

     AMGEN INC., AMGEN MANUFACTURING,
                    LIMITED,
            Plaintiffs-Cross-Appellants

                             v.

                     HOSPIRA, INC.,
                   Defendant-Appellant
                  ______________________

                   2019-1067, 2019-1102
                  ______________________

    Appeals from the United States District Court for the
District of Delaware in No. 1:15-cv-00839-RGA, Judge
Richard G. Andrews.
                ______________________

               Decided: December 16, 2019
                ______________________

    JOHN LABBE, Marshall, Gerstein & Borun LLP, Chi-
cago, IL, argued for plaintiffs-cross-appellants. Also repre-
sented by KEVIN M. FLOWERS, JULIANNE M. HARTZELL,
MARK HARRY IZRAELEWICZ; THOMAS FRANCIS LAVERY,
WENDY A. WHITEFORD, Amgen Inc., Thousand Oaks, CA.

    THOMAS J. MELORO, Willkie Farr & Gallagher LLP,
New York, NY, argued for defendant-appellant. Also rep-
resented by MICHAEL JOHNSON, HEATHER M. SCHNEIDER.
                ______________________
2                                 AMGEN INC. v. HOSPIRA, INC.

    Before MOORE, BRYSON, and CHEN, Circuit Judges.
MOORE, Circuit Judge.
    Hospira, Inc. (Hospira) appeals the District of Dela-
ware’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 Manufac-
turing, 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 provi-
sion of 35 U.S.C. § 271(e)(1); and (3) Amgen had proven it
was entitled to $70 million in damages. Amgen cross-ap-
peals 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. Pa-
tent No. 5,756,349 (the ’349 patent). For the following rea-
sons, we affirm the district court’s decisions as to each.
                      I. BACKGROUND
                 A. The Asserted Patents
    The patents at issue relate to erythropoietin (EPO)
isoforms and aspects of their production. EPO is a glyco-
protein 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 nega-
tively-charged molecule. Thus, each EPO molecule can
have different numbers of sialic acids. Amgen manufac-
tures and markets recombinant human EPO as Epogen.
    The claims of the ’298 patent claim, inter alia, methods
of producing EPO isoforms having a specific number of
AMGEN INC. v. HOSPIRA, INC.                               3

sialic acids per molecule, and methods for obtaining EPO
compositions having a predetermined in vivo specific activ-
ity. 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.
     Relevant to this case are certain techniques for sepa-
rating 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 isoelec-
tric point, or pI. Id. Each band seen on an isoelectric fo-
cusing 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 prepa-
rations “having a single pI, and having the same amino
acid sequence.” Id. at 5:6–9. A second technique, ion ex-
change 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.
    The ’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.
                  B. Procedural History
    In 2014, Hospira submitted its Biologics License Appli-
cation (BLA) No. 125-545 to the FDA, seeking approval for
4                                 AMGEN INC. v. HOSPIRA, INC.

a biosimilar to Amgen’s Epogen product. Amgen sued Hos-
pira 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 Hos-
pira’s manufacture of twenty-one batches of drug sub-
stance for its EPO biosimilar drug product infringes claims
24 and 27 of the ’298 patent and claims 1–7 of the ’349 pa-
tent. 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 mil-
lion in damages.
    The 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 Har-
bor, 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.
     On appeal, Hospira challenges a myriad of issues, in-
cluding: (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 de-
nial of JMOL on the Safe Harbor issue; (4) the evidentiary
rulings regarding Amgen’s damages expert; and (5) the de-
nial 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).
                      II. DISCUSSION
    We review a denial of JMOL under the law of the re-
gional circuit. Energy Transp. Grp. Inc. v. William Demant
Holding A/S, 697 F.3d 1342, 1350 (Fed. Cir. 2012). “In the
AMGEN INC. v. HOSPIRA, INC.                               5

Third Circuit, review of denial of JMOL is plenary.” Fin-
jan, 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 jus-
tice 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. 1991).
     A. Judgment of Infringement and No Invalidity
     Hospira 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 infringe-
ment 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 arguments un-
availing.
                   i. Claim Construction
   Claim construction is a question of law we review de
novo, with subsidiary factual findings based on extrinsic
6                                 AMGEN INC. v. HOSPIRA, INC.

evidence reviewed for clear error. Teva Pharm. USA, Inc.
v. Sandoz, Inc., 574 U.S. 318 (2015).
    Claim 27 recites:
        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.
    Claim 1 recites:
        An isolated biologically active erythropoi-
        etin 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.
     On 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 mol-
ecules that has a single isoelectric focusing point and a spe-
cific 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 iso-
lated erythropoietin isoforms of Claim 1.” J.A. 174. In
denying Hospira’s motion for summary judgment of nonin-
fringement, 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
AMGEN INC. v. HOSPIRA, INC.                                7

the mixture.” J.A.169. Accordingly, the final claim con-
struction provided to the jury included the following sen-
tence: “Claim 27 does not require the individual isoforms
of Claim 1 to be separately prepared prior to making the
mixture.” J.A. 160.
    Hospira 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 proper construc-
tion, no reasonable jury could find infringement because
Hospira does not mix isolated isoforms, rather all the
isoforms in Hospira’s product elute off the ion exchange col-
umn together.
    Amgen responds that claim 27 is directed to “preparing
a mixture” of isoforms, not “mixing” isoforms. In Amgen’s
view, although “‘preparing a mixture’ could be accom-
plished by preparing isolated isoforms and mixing those
isoforms together, claim 27” is not so limited. Construing
the claim to require “mixing,” Amgen argues, “would ren-
der the term ‘preparing a’ superfluous.” Plaintiffs-Cross-
Appellants’ Br. 27.
    Nothing in the claim language or the specification sug-
gests that it would be proper to limit claim 27 in the man-
ner Hospira proposes. Claim 27 recites “preparing a
mixture of two or more erythropoietin isoforms of claim 1.”
Contrary to Hospira’s arguments, this reference to
“isoforms of claim 1” does not require that the mixture of
8                                 AMGEN INC. v. HOSPIRA, INC.

two or more isoforms of claim 1 be prepared in any partic-
ular way (i.e., by preparing individual isoforms separately
and mixing them together). Indeed, the specification dis-
closes that “mixtures of erythropoietin isoforms” can be
produced by “isolating selected erythropoietin isoforms
simultaneously.” ’298 patent, 6:61–63 (emphasis added).
Such “methods include isolation of individual isoforms by
techniques such as preparative isoelectric focusing or prep-
aration of mixtures of isoforms having a predetermined
number of sialic acids per molecule (for example, greater
than 11) by techniques such as ion exchange chromatog-
raphy or chromatofocusing.” ’298 patent, 6:63–7:3 (empha-
sis added). The specification clearly contemplates the
preparation of mixtures of isoforms in more than one way.
     The intrinsic evidence suggests that the claim is not
limited to methods of preparing individual isoforms sepa-
rately and mixing them together. It is therefore improper
to limit claim 27 to one embodiment based on Dr. Strick-
land’s testimony. See Phillips v. AWH Corp., 415 F.3d
1303, 1318 (Fed. Cir. 2005) (Extrinsic evidence is “less re-
liable than the patent and its prosecution history in deter-
mining how to read claim terms.”). Accordingly, we hold
that the district court did not err in construing claim 27 to
“not require the individual isoforms of [c]laim 1 to be sepa-
rately prepared prior to making the mixture.”
           ii. Amgen’s Evidence of Infringement
    Infringement is a question of fact, “reviewed for sub-
stantial evidence when tried to a jury.” ACCO Brands, Inc.
v. ABA Locks Mfrs. Co., 501 F.3d 1307, 1311 (Fed. Cir.
2007). A factual finding is supported by substantial evi-
dence if a reasonable jury could have found in favor of the
prevailing party in light of the evidence presented at trial.
See Tec Air, Inc. v. Denso Mfg. Michigan Inc., 192 F.3d
1353, 1357–58 (Fed. Cir. 1999).
    Hospira argues that, even under the district court’s
construction, no reasonable jury could have found
AMGEN INC. v. HOSPIRA, INC.                                9

infringement of claim 27 for two separate reasons. First,
although claim 27 references claim 1, Amgen did not men-
tion claim 1 or attempt to prove the limitations of claim 1
at trial. Second, Hospira contends, Amgen’s evidence is in-
sufficient to establish that Hospira’s EPO has a “predeter-
mined in vivo specific activity,” as required by claim 27. In
Hospira’s view, Amgen’s evidence of infringement only
demonstrates that Hospira’s product is biosimilar to
Amgen’s Epogen. Hospira contends that this evidence does
not prove infringement, particularly when Epogen is not
manufactured using the claimed methods of the ’298 pa-
tent. Defendant-Appellant’s Br. 39.
    Amgen responds that the evidence at trial showed Hos-
pira prepared a product containing biologically active EPO,
establishing that the limitations of claim 1 were satisfied.
Amgen further contends that Hospira’s statements in its
BLA show that its EPO falls within a specified range of in
vivo specific activity, a range that was, in Amgen’s view,
“predetermined based on the reference product,” Epogen.
Plaintiffs-Cross-Appellants’ Br. 29.
    Substantial evidence supports the jury’s infringement
verdict. Amgen presented evidence that satisfied the limi-
tations of claim 1. The inventor, Dr. Strickland, testified
that “all EPO isoforms have biological activity.” J.A. 725
at 394:1–2. Amgen’s expert, Dr. Wall, testified that Hos-
pira’s product is produced through expression of an exoge-
nous DNA sequence in a non-human eucaryotic host cell.
J.A. 453 at 277:7–278:5. Amgen also introduced into evi-
dence portions of Hospira’s BLA, which show that Hos-
pira’s EPO is a mixture of two or more EPO isoforms, each
having a single isoelectric focusing point and a specific
number of sialic acids per molecule. J.A. 744–45 at
470:16–475:8 (testimony of Amgen’s expert Dr. Cummings,
discussing J.A. 3690, J.A. 3693, and J.A. 3711). Thus, the
jury heard evidence on whether Hospira’s process met the
limitations of claim 1. Amgen’s failure to mention claim 1
at trial does not negate this evidence. As such, the jury
10                                AMGEN INC. v. HOSPIRA, INC.

reasonably found that Hospira’s process meets the limita-
tions of claim 1.
    As to whether Hospira’s process results in EPO that
has a predetermined in vivo specific activity, Hospira’s
BLA states that 100% of its EPO batches have a specified
range of in vivo activity, i.e., 93–147 U/µg. J.A. 4606.
Amgen’s expert, Dr. Cummings, testified that all of Hos-
pira’s EPO batches have an in vivo specific activity within
a specified range, a range predetermined based on Epogen,
the reference product. J.A. 746. As such, the jury was pre-
sented with substantial evidence that Hospira’s process re-
sulted in EPO “having a predetermined in vivo specific
activity.” ’298 patent at claim 27.
     We conclude that substantial evidence supports the
jury’s verdict of infringement of claim 27. Accordingly, we
affirm the district court’s denial of JMOL.
              iii. Alleged Anticipation by Lai
    “Anticipation is a factual determination that is re-
viewed for substantial evidence when decided by a jury.”
Koito Mfg. Co. v. Turn-Key-Tech, LLC, 381 F.3d 1142, 1149
(Fed. Cir. 2004).
    Hospira argues that under the district court’s errone-
ous claim construction, no reasonable jury could find claim
27 not invalid over Lai. According to Hospira, if all it takes
to “predetermine” a specific activity is to use ion exchange
chromatography to prepare a mixture of active EPO, then
Lai disclosed exactly such a process in its Example 2. De-
fendant-Appellants’ Br. 40 (citing Lai at 5:20–37, 5:59–68).
Hospira argues that Example 2 discloses the use of ion ex-
change chromatography to separate impurities and less bi-
ologically active EPO from more biologically active EPO.
Id.
    Amgen argues that Lai does not expressly disclose EPO
isoforms, selectively eluting EPO molecules, or EPO
isoforms with a predetermined in vivo specific activity. For
AMGEN INC. v. HOSPIRA, INC.                                11

this reason, Amgen contends, Hospira resorted to arguing
inherency to the jury, but failed to show that Example 2
“necessarily and inevitably” produced EPO with a prede-
termined in vivo specific activity. Plaintiffs-Cross-Appel-
lants’ Br. 30 (citing Schering Corp. v. Geneva Pharm., Inc.,
339 F.3d 1373, 1377–78 (Fed. Cir. 2003)). 1
     We agree with Amgen and conclude that substantial
evidence exists for the jury’s finding that Lai does not an-
ticipate claim 27. Lai is directed to processes of efficient
recovery of EPO from a fluid, that is, separating EPO from
non-EPO contaminants. See, e.g., Lai at 3:9–15. Lai spe-
cifically describes the first step of its Example 2 as remov-
ing non-EPO contaminants. Id. at 5:29–31. But, Lai does
not refer to a composition with a predetermined in vivo ac-
tivity, it discloses only that “[b]iologically active” EPO was
eluted. Id. at 5:34. Thus, Lai does not expressly disclose
EPO isoforms with a predetermined in vivo specific activity
(or EPO isoforms at all).
    Moreover, Amgen’s expert, Dr. Cummings, testified
that nothing in Lai “would indicate one to think there’s a
predetermined in vivo activity.” J.A. 1844–46. Notably,
Hospira’s own expert, Dr. Levine, testified that predeter-
mined in vivo specific activity means “a specific subset of
isoforms” and that Lai does not disclose anything about
EPO isoforms. J.A. 1436 at 1128:13–18. Dr. Levine also
admitted that the product of Lai’s method depends on what
is present in the starting material (see id. at 1128:19–24),
supporting the finding that the Lai process does not “nec-
essarily and inevitably” meet the limitations of claim 27.

    1   Hospira does not expressly argue inherency on ap-
peal, but instead argues that the district court’s erroneous
construction encompasses the prior art and therefore the
jury verdict should be vacated. Defendant-Appellant’s Br.
5, 40.
12                                  AMGEN INC. v. HOSPIRA, INC.

    Based on the foregoing, substantial evidence supports
the jury’s finding that Lai does not anticipate claim 27. Ac-
cordingly, we affirm the district court’s denial of JMOL as
to anticipation.
    Because substantial evidence supports the jury’s find-
ing that claim 27 is not invalid and Hospira is liable for
infringement of claim 27 of the ’298 patent, and “[b]ecause
the damages calculation at trial was not predicated on the
infringement of particular claims,” we need not reach the
parties’ arguments regarding claim 24. See TiVo, Inc. v.
EchoStar Commc’ns Corp., 516 F.3d 1290, 1312 (Fed. Cir.
2008).
                         B. Safe Harbor
     35 U.S.C. § 271(e)(1) provides a Safe Harbor defense for
defendants for their otherwise infringing activities by stat-
ing:
     It shall not be an act of infringement to make,
     use, offer to sell, or sell within the United States
     or import into the United States a patented in-
     vention (other than a new animal drug or veter-
     inary biological product (as those terms are used
     in the Federal Food, Drug, and Cosmetic Act and
     the Act of March 4, 1913) which is primarily
     manufactured using recombinant DNA, recom-
     binant RNA, hybridoma technology, or other
     processes involving site specific genetic manipu-
     lation techniques) solely for uses reasonably re-
     lated to the development and submission of
     information under a Federal law which regu-
     lates the manufacture, use, or sale of drugs or
     veterinary biological products.
35 U.S.C. § 271(e)(1).
    On appeal, Hospira challenges the district court’s jury
instructions regarding its Safe Harbor defense. Hospira
also contends that no reasonable jury could have found that
AMGEN INC. v. HOSPIRA, INC.                                13

some, but not all, of Hospira’s drug substance batches were
protected by the Safe Harbor defense. We address each is-
sue in turn.
                    i. Jury Instructions
     We review de novo “[t]he legal sufficiency of jury in-
structions on an issue of patent law,” such as the Safe Har-
bor provision of 35 U.S.C. § 271(e)(1). See Bettcher Indus.,
Inc. v. Bunzl USA, Inc., 661 F.3d 629, 638 (Fed. Cir. 2011)
(citations omitted). A jury verdict based on erroneous in-
structions is set aside only if “the movant can establish that
the instructions were legally erroneous and that the errors
had a prejudicial effect.” Id. at 639 (citations omitted).
    The final paragraph of the Safe Harbor jury instruc-
tions states:
    You must evaluate each of the accused activities
    separately to determine whether the Safe Har-
    bor applies. If you find that an accused activity
    was reasonably related to the development and
    submission of information to the FDA for the
    purpose of obtaining FDA approval, then Hos-
    pira has proved its Safe Harbor defense as to
    that activity. If Hospira has proved that the
    manufacture of a particular batch was reasona-
    bly related to developing and submitting infor-
    mation to the FDA in order to obtain FDA
    approval, Hospira’s additional underlying pur-
    poses for the manufacture and use of that batch
    do not remove that batch from the Safe Harbor
    defense.
J.A. 139.
    Hospira argues that the final sentence of the instruc-
tions improperly focused on Hospira’s intent for manufac-
turing batches of EPO. In Hospira’s view, “the jury
instructions and verdict form improperly focused the jury
on the reasons why each batch of EPO was manufactured,
14                                AMGEN INC. v. HOSPIRA, INC.

not how each batch was used or whether that use was rea-
sonably related to the development and submission of in-
formation to support Hospira’s BLA.” Defendant-
Appellant’s Br. 45–46. According to Hospira, it only had to
prove that the use of the patented invention was reasona-
bly related to submission of information to the FDA, not
the manufacture.
    Amgen responds that Hospira’s infringing acts were
the use of Amgen’s patented methods for making Hospira’s
EPO drug substance. According to Amgen, the jury in-
structions “properly focused the jury on Hospira’s use of the
patented invention, that is, the manufacture of [Hospira’s
EPO] drug substance, and then asked whether each act of
manufacture was for uses reasonably related to seeking
FDA approval.” Plaintiffs-Cross-Appellants’ Br. 37.

    The jury instructions properly articulated the legal
principles underlying the Safe Harbor inquiry. Section
271(e)(1)’s exemption from infringement “extends to all
uses of patented inventions that are reasonably related to
the development and submission of any information under
the FDCA.” Merck KGaA v. Integra Lifesciences I, Ltd.,
545 U.S. 193, 202 (2005) (emphasis removed). The statute
does not exclude “certain information from the exemption
on the basis of the phase of research in which it is devel-
oped or the particular submission in which it could be in-
cluded.” Id. The exemption applies “as long as there is a
reasonable basis for believing” that the use of the patented
invention will produce the types of information that are rel-
evant to an FDA submission. Id. at 207–08. Moreover,
“[e]ach of the accused activities must be evaluated sepa-
rately to determine whether the exemption applies.” Id. at
200.
    Here, the patented inventions are Amgen’s claimed
methods of manufacture. The accused activity is Hospira’s
use of Amgen’s claimed methods of manufacture. The rel-
evant inquiry, therefore, is not how Hospira used each
AMGEN INC. v. HOSPIRA, INC.                              15

batch it manufactured, but whether each act of manufac-
ture was for uses reasonably related to submitting infor-
mation to the FDA. 2 The jury instructions properly asked
whether each act of manufacture, that is, each accused ac-
tivity, was for uses reasonably related to submitting infor-
mation to the FDA. And, contrary to Hospira’s contentions,
the instructions struck the appropriate balance by telling
the jury that Hospira’s additional underlying purposes do
not matter as long as Hospira proved that the manufacture
of any given batch of drug substance was reasonably re-
lated to developing information for FDA submission.
     In sum, reading the instructions as a whole, we con-
clude that it was not legal error to instruct the jury that
“[i]f Hospira has proved that the manufacture of a particu-
lar batch,” that is, Hospira’s use of Amgen’s patented meth-
ods, “was reasonably related to developing and submitting
information to the FDA . . . Hospira’s additional underlying
purposes for the manufacture and use of that batch do not
remove that batch from the Safe Harbor defense.” J.A. 139.
Accordingly, we affirm the district court’s denial of Hos-
pira’s motion for a new trial on Safe Harbor grounds.

     We note that Hospira’s arguments regarding the dis-
trict court’s denial of JMOL are also predicated on the jury
instructions being erroneous. Defendant-Appellant’s Br.
57–60. We have considered these arguments and find them
unpersuasive.

    2   To the extent Hospira suggests that the Safe Har-
bor exemption always applies in the pre-approval context,
see Defendant-Appellant’s Br. 45, we have previously re-
jected that reading of the statute. It is incorrect to “as-
sume[] that all otherwise infringing activities are exempt
if conducted during the period before regulatory approval
is granted.” Amgen Inc. v. Int’l Trade Comm’n, 565 F.3d
846, 852 (Fed. Cir. 2009).
16                                AMGEN INC. v. HOSPIRA, INC.

                  ii. The Jury’s Findings
    Hospira argues that no reasonable jury could have
found that some batches of EPO were not protected by the
Safe Harbor where, as here, all twenty-one batches were
used for the development and submission of information
included in the original BLA filing or in a subsequent filing
necessitated by a Complete Response Letter (CRL) from
the FDA. We review a jury’s factual findings for substan-
tial evidence. Comcast IP Holdings, LLC v. Sprint
Commc’ns Co., 850 F.3d 1302, 1309 (Fed. Cir. 2017).
    At issue are twenty-one batches of EPO Hospira man-
ufactured in 2013, 2014, and 2015. The jury found seven
batches were protected under the Safe Harbor, whereas
fourteen were not. The protected batches include two
batches used for qualifying Hospira’s process to make the
drug and for qualifying alternate equipment (manufac-
tured in 2013) and five batches used for a mandatory pre-
approval inspection by the FDA (manufactured in 2015).
For all other batches, the jury found no Safe Harbor pro-
tection.
    Hospira used the EPO batches at issue for various
types of testing, including biosimilarity, revisions to re-
lease specifications, stability testing, and continued pro-
cess verification (CPV). According to Hospira, each type of
testing was conducted as part of its BLA submission or its
response to the FDA’s CRL. For example, Hospira argues,
biosimilarity testing is required for FDA approval, yet the
jury found that two of the batches used to demonstrate bi-
osimilarity with the reference product were not protected
by the Safe Harbor. Defendant-Appellant’s Br. 48. Hos-
pira similarly argues that revised release specification test-
ing was required for it to properly respond to the FDA’s
CRL, and stability testing was required for FDA approval,
as was a commitment to make the CPV batches. Therefore,
Hospira argues, no reasonable jury could have found that
AMGEN INC. v. HOSPIRA, INC.                                17

certain of these batches were not protected by the Safe Har-
bor.
    Substantial evidence supports the jury’s finding that
the batches at issue were not manufactured “solely for uses
reasonably related to the development and submission of
information” to the FDA. For example, Amgen’s expert,
Dr. Martin-Moe, testified that Hospira was not required to
manufacture additional batches after it made its 2012
batches. J.A. 1484. She also explained that stability test-
ing of Hospira’s 2013 batches was not required but would
be part of a “continuing program for stability that is a post-
approval commitment.” J.A. 1487 at 1333:9–1334:1. She
further explained that CPV is an ongoing process that ap-
plies to batches made for commercial use. J.A. 1486–89.
Hospira’s regulatory witness, Ms. Dianis, admitted that
CPV is not required before FDA approval. J.A. 1087–88.
Further, Hospira’s Senior Director of Analytical R&D,
Dr. Srebalus-Barnes, admitted that Hospira did not man-
ufacture any drug substance batches in response to the
FDA’s CRL and the CRL did not require manufacture of
additional batches. J.A. 1105. Accordingly, the jury rea-
sonably found that certain batches at issue were not pro-
tected under the Safe Harbor. 3
    Moreover, documentary evidence shows that Hospira
planned for “the balance of the material from the 2013 cam-
paign (approximately 50%) and most of the material from
the 2014 and 2015 campaigns [to] serve as commercial

    3   We also reject Hospira’s suggestion that simply
submitting information about a drug substance lot to the
FDA brings the manufacture of that lot within the Safe
Harbor. We have explained that “routine record retention
requirements associated with testing and other aspects of
the commercial production process” are not protected by
the Safe Harbor. Momenta Pharms., Inc. v. Teva Pharms.
USA, Inc., 809 F.3d 610, 620–21 (Fed. Cir. 2015).
18                                 AMGEN INC. v. HOSPIRA, INC.

inventory to support single dose vial launch stock.” J.A.
2392. When it resubmitted its application in late 2015 af-
ter litigation began, Hospira changed the designation of
certain batches from “commercial inventory” to “CPV.”
Compare J.A. 2311–13, with J.A. 4314–18. Hospira argues
that, in denying its motion in limine to exclude this evi-
dence, the district court allowed Amgen to taint the entire
trial with its “commercial theme.” Defendant-Appellant’s
Br. 56. Hospira contends that this “legally irrelevant” evi-
dence was repeatedly put before the jury. Id. at 57. We
find no reversible error in the district court’s ruling regard-
ing this evidence. Hospira’s decision to manufacture its
EPO drug substance “commercial inventory” was not dis-
positive of the Safe Harbor defense, but Amgen is correct
that this evidence was probative of whether Hospira’s use
of Amgen’s patented process was reasonably related to
seeking FDA approval. Plaintiffs-Cross-Appellants’ Br.
47–48. The fact that the jury found some of the “commer-
cial inventory” batches nonetheless protected by the Safe
Harbor defense supports the conclusion that the jury did
not reject the defense simply because Hospira made the
batches for commercial inventory.
    We conclude that the jury’s finding that certain batches
of Hospira’s EPO were not protected by the Safe Harbor is
supported by substantial evidence. We therefore affirm the
district court’s denial of JMOL on Hospira’s Safe Harbor
defense.
                        C. Damages
     Finally, Hospira argues that the jury’s damages award
should be vacated because the district court erred in deny-
ing Hospira’s Daubert motion and allowing Amgen’s ex-
pert, Dr. Heeb, to testify. We review the district court’s
decision to admit expert testimony for abuse of discretion.
Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997). The
jury’s determination of the amount of damages is an issue
of fact, which we review for substantial evidence. Lucent
AMGEN INC. v. HOSPIRA, INC.                               19

Techs., Inc. v. Gateway, Inc., 580 F.3d 1301, 1310 (Fed. Cir.
2009) (citations omitted). A jury’s damages award “must
be upheld unless the amount is grossly excessive or mon-
strous, clearly not supported by the evidence, or based only
on speculation or guesswork.” Id. (citations omitted).
    According to Hospira, the jury’s damages award does
not reflect a “reasonable royalty.” Hospira takes issue both
with the amount of the award and its lump-sum structure.
Dr. Heeb’s opinions, argues Hospira, are erroneously based
on the “value of delay” to Hospira, i.e., the profit Hospira
could earn if it were in a place to launch its EPO as soon as
the patents expired. Hospira contends that this methodol-
ogy is flawed because it requires Hospira to accept all the
risk of the transaction and considers only the benefit to
Hospira, not the harm to Amgen. Further, Hospira argues,
a lump-sum payment that cannot be clawed back gives
Amgen a windfall because at the time of trial, Hospira still
had not received FDA approval or sold any EPO. And, Hos-
pira argues, Dr. Heeb did not account for the reality that
Amgen does not use the ’298 patent to produce Epogen or
any other product. According to Hospira, the “book of wis-
dom” doctrine allows parties to consider after-the-fact
events, like Hospira’s lack of FDA approval, Amgen not
practicing the ’298 patent, and the claw-back provision in
the only other lump-sum agreement in the evidence.
     Amgen contends that the district court did not abuse
its discretion by allowing the jury to hear Dr. Heeb’s opin-
ions. According to Amgen, Dr. Heeb determined what Hos-
pira would have expected to gain from obtaining a license
to manufacture the volume of batches needed to meet its
expected product launch date in 2015, before expiration of
the ’298 patent, and appropriately concluded that the hy-
pothetical negotiators would have been incentivized to ob-
tain the license needed for Hospira’s pre-launch
manufacture. Amgen also argues that Dr. Heeb’s reliance
on a lump-sum royalty structure is supported by the evi-
dence in the record in the context of a method of
20                               AMGEN INC. v. HOSPIRA, INC.

manufacture patent, where the infringing act is not tied to
the sales of the product. And, Amgen contends, Hospira
was permitted to present testimony to the jury that Amgen
did not use the ’298 patent’s inventions. According to
Amgen, although Hospira appeals the district court’s de-
nial of JMOL, Hospira’s damages argument is entirely
about its Daubert challenges to Dr. Heeb’s methodology.
    We see no reversible error. The district court permit-
ted Hospira to cross-examine Dr. Heeb and to present the
testimony of its own damages expert, Dr. Bell. Hospira was
permitted to argue at trial that it had not yet received FDA
approval, and that the amount of damages should be based
on “replacement cost” because Hospira could simply re-
make the product. J.A. 1881–82; see also J.A. 148–51 (in-
struction stating that the jury “may consider events and
facts that occurred after the hypothetical negotiation took
place.”). Dr. Heeb testified that he considered the appro-
priate factors in determining a reasonable royalty and
placed the timing of the hypothetical negotiation in late
2013, before the act of first infringement. See J.A. 778–79;
see also Georgia-Pacific Corp. v. United Plywood Corp.,
318 F. Supp. 1116 (S.D.N.Y. 1970). He also explained that
he considered the gain to Hospira from obtaining a license
to manufacture batches to meet its expected 2015 launch
date, and the harm to Amgen if it entered a license. J.A.
779–85. Finally, Dr. Heeb explained his reasoning for pro-
posing a lump-sum structure for the royalties, including
the fact that in this case, infringement is tied to manufac-
ture and not directly to the sales of the product. J.A. 786.
Accordingly, the district court did not abuse its discretion
in permitting Dr. Heeb to testify.
    In view of Dr. Heeb’s testimony, we also find that sub-
stantial evidence supports the jury’s damages award and
see no reason to vacate it. The jury heard Dr. Heeb testify
at length and propose a reasonable royalty in the range of
between $154 and $170 million. J.A. 788. It also heard the
testimony of Hospira’s expert, Dr. Bell, who proposed a
AMGEN INC. v. HOSPIRA, INC.                             21

reasonable royalty in the range of $4.1 to $4.6 million per
batch. J.A. 1465. In addition, Dr. Heeb explained his rea-
soning for proposing a lump-sum structure. J.A. 786. As
to his proposal of a lump-sum damages amount without a
claw-back provision, Dr. Heeb distinguished the claw-back
provision in the only other lump-sum agreement in the ev-
idence as a “mutually profitable arrangement” instead of a
license from one competitor to another. J.A. 792 at 664:10–
665:13. Dr. Heeb further testified that Amgen would not
be incentivized to “refund[] [any] royalty” to Hospira be-
cause it would not want to offer license terms that would
encourage other competitors to infringe its patent.
J.A. 792–93 at 665:15–666:3. It was not unreasonable for
the jury to choose a damages award within the amounts
proposed by each expert. Accordingly, we affirm the dis-
trict court’s denial of Hospira’s JMOL motion regarding the
jury’s damages award.
                   D. Amgen’s Cross-Appeal
    Amgen also asserted infringement of claims 1–7 of the
’349 patent. Claim 1 is the only independent claim of the
’349 patent. It recites:
    Vertebrate cells which can be propagated in
    vitro and which are capable upon growth in cul-
    ture of producing erythropoietin in the medium
    of their growth in excess of 100 U of erythropoi-
    etin per 106 cells in 48 hours as determined by
    radioimmunoassay, said cells comprising non-
    human DNA sequences which control transcrip-
    tion of DNA encoding human erythropoietin.
    The only disputed issue at trial was whether Hospira’s
cells were capable of producing EPO “in excess of 100 U”
(claims 1 and 4), “in excess of 500 U” (claims 2 and 5), or
“in excess of 1000 U” (claims 3 and 6) of EPO per 106 cells
in 48 hours, “as determined by radioimmunoassay.” ’349
patent at claims 1–7. The jury found that Hospira does not
infringe the asserted claims. The district court denied
22                                AMGEN INC. v. HOSPIRA, INC.

Amgen’s motion for JMOL that Hospira infringed claims
1–7 of the ’349 patent. Amgen appeals.
     Amgen argues that, as part of its BLA submission, Hos-
pira reported to “the FDA that its cells were capable of pro-
ducing EPO ‘in the range of 100 µg per ml [of culture fluid]
or higher’ in a 24-hour period,” as measured by the “dot-
blot” immunoassay. Plaintiffs-Cross-Appellants’ Br. 68
(citing J.A. 2372). Amgen’s expert testified that the value
obtained from Hospira’s dot-blot assay could be converted
from µg/ml to biological units (expressed as Units or U) and
Hospira’s cells were capable of producing 3534 U of EPO
per 106 cells in 48 hours. Id. at 68–69 (citing J.A. 757–760).
Amgen contends that, instead of presenting expert testi-
mony refuting this evidence of infringement, Hospira ar-
gued that the dot-blot assay results were insufficient proof
of infringement because that assay used different stand-
ards and antibodies than those described in the ’349 patent
and because that assay could not be used to calculate the
specific activity of the unpurified EPO produced by the
cells. According to Amgen, Hospira’s failure to offer com-
peting evidence means that no reasonable jury could have
concluded that Amgen failed to meet its burden on infringe-
ment.
    Hospira responds that its expert, Dr. Hamilton, ex-
plained in detail why the dot-blot assay results could not
be correlated to EPO production rates as determined by ra-
dioimmunoassay (RIA). Defendant-Appellant’s Resp. Br.
38. Hospira contends that Dr. Hamilton provided unrebut-
ted testimony that the two tests were not comparable. Id.
at 41 (citing J.A. 1452–54). Further, Dr. Hamilton testified
that the only way µg/ml could be converted into U was if
the EPO was purified out. Hospira argues that Amgen’s
experts did not provide any testimony that the dot-blot as-
say results are similar or comparable to the RIA results.
Thus, according to Hospira, the jury’s verdict is supported
by substantial evidence. We agree.
AMGEN INC. v. HOSPIRA, INC.                                 23

    The jury was presented with testimony from both ex-
perts. Hospira’s expert explained that the dot-blot assay
results could be an overestimation and articulated several
reasons why those results could not be correlated to EPO
production rates as determined by RIA. J.A. 1453–54.
Amgen’s former employee Dr. Egrie, who conducted RIA
testing for Amgen, confirmed the need to use the same
standard to compare the two tests. J.A. 1455. Substantial
evidence thus supports the jury’s finding that Amgen did
not meet its burden of proving infringement. Accordingly,
the district court did not err in denying Amgen’s JMOL mo-
tion on this issue.
    Amgen also argues that the district court erred in deny-
ing it a new trial. According to Amgen, during closing ar-
guments, counsel for Hospira used a demonstrative that
showed the ’349 claim limitation “as determined by [RIA]”
as being within a fence of claimed land, while showing a
“dot blot” outside the fence, thereby improperly arguing
claim construction and influencing the jury. Plaintiffs-
Cross-Appellants’ Br. 73 (citing J.A. 13632). Hospira re-
sponds that its counsel never argued that a dot blot could
not be used as a matter of claim construction. According to
Hospira, it was well within the district court’s discretion to
rule on Amgen’s objection to Hospira’s demonstrative.
     We see no error by the district court, which concluded
that Hospira’s counsel did not argue claim construction to
the jury. J.A. 104–05. It was within the district court’s
discretion to allow the demonstrative at issue and we do
not find any abuse of discretion in the district court’s denial
of a new trial. This is hardly a situation where “a miscar-
riage of justice would result if the verdict were to stand.”
Consol. Rail Corp., 926 F.2d at 1352–53. Accordingly, we
affirm the district court’s denial of a new trial.
                      III. CONCLUSION
    For the foregoing reasons, we affirm the district court’s
decision denying the parties’ respective JMOL motions and
24                                 AMGEN INC. v. HOSPIRA, INC.

motions in the alternative for a new trial. We have consid-
ered the parties’ remaining arguments and find them un-
persuasive.
                        AFFIRMED
                           COSTS
     Each party to bear its own costs.