Court Opinion

ID: 3006757
Source: CourtListenerOpinion
Date Created: 2015-10-02 16:01:08.148625+00
Date Added: 2024-06-11T18:03:13.235146
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                ______________________

      SPECTRUM PHARMACEUTICALS, INC.,
        UNIVERSITY OF STRATHCLYDE,
              Plaintiffs-Appellants

                           v.

                    SANDOZ INC.,
                  Defendant-Appellee
                ______________________

                      2015-1407
                ______________________

    Appeal from the United States District Court for the
District of Nevada in No. 2:12-cv-00111-GMN-NJK, Judge
Gloria M. Navarro.
                 ______________________

               Decided: October 2, 2015
               ______________________

    MARK HARRY IZRAELEWICZ, Marshall, Gerstein & Bo-
run LLP, Chicago, IL¸ argued for plaintiffs-appellants.
Also represented by AMANDA ANTONS, KEVIN M. FLOWERS,
THOMAS IRVING ROSS.

    DEANNE MAYNARD, Morrison & Foerster LLP, Wash-
ington, DC, argued for defendant-appellee. Also repre-
sented by BRIAN ROBERT MATSUI.
                ______________________

 Before LOURIE, WALLACH, and HUGHES, Circuit Judges.
2           SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.

LOURIE, Circuit Judge.
    Spectrum Pharmaceuticals, Inc. (“Spectrum”) appeals
from the decisions of the United States District Court for
the District of Nevada holding claims 1–2 of U.S. Patent
6,500,829 (“the ’829 patent”) invalid as obvious, and
finding claims 5–9 of the ’829 patent not infringed by the
submission of an Abbreviated New Drug Application
(“ANDA”) by Sandoz Inc. (“Sandoz”). Spectrum Pharm.,
Inc. v. Sandoz Inc., No. 2:12-cv-00111, 2015 WL 794674
(D. Nev. Feb. 25, 2015) (“Trial Order”); Spectrum Pharm.,
Inc. v. Sandoz Inc., No. 2:12-cv-00111, 2014 WL 7368845
(D. Nev. Dec. 29, 2014) (“Summary Judgment Order”).
Because the district court did not err in concluding that
claims 1–2 are invalid, and additionally did not clearly err
in finding claims 5–9 not infringed by Sandoz’s ANDA
product, we affirm.
                       BACKGROUND
     Leucovorin is a compound used to ameliorate the toxic
effects of methotrexate, a chemotherapy treatment
(“methotrexate rescue”); to treat folate deficiency; and to
enhance the efficacy of a 5-fluorouracil cancer treatment
(“5-FU combination therapy”). Due to an asymmetric C6
carbon, leucovorin may exist as a 50/50 mixture of two
diastereoisomers, the (6S) and (6R) isomers. The (6S)
diastereoisomer is also known as levoleucovorin or
l-leucovorin, and is the isomer with the desired biological
activity.
     The ’829 patent is directed to pharmaceutical compo-
sitions of substantially pure levoleucovorin. Claim 1 of
the ’829 patent reads as follows:
    1. A pharmaceutical composition for therapeutic
    use which consists essentially of a therapeutically
    effective amount sufficient for the treatment of
    human beings for methotrexate rescue or folate de-
    ficiency, of a pharmaceutically acceptable com-
SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.           3

    pound which is a (6S) diastereoisomer selected
    from the group consisting of (6S) leucovorin (5-
    formyl-(6S)-tetrahydrofolic acid) and pharmaceu-
    tically acceptable salts and esters of (6S) leuco-
    vorin; wherein the compound consists of a mixture
    of (6S) and (6R) diastereoisomers and consists of
    at least 92% by weight of the (6S) diastereoisomer,
    the balance of said compound consisting of the
    (6R) diastereoisomer; in combination with a
    pharmaceutically acceptable carrier.
’829 patent col. 9 ll. 55–67 (emphases added). The written
description states that “a typical daily dose” of the
(6S) isomer for methotrexate rescue would be “up to
150 mg[,] e.g.[,] in the range from 25 to 150 mg,” and that
“a typical daily dose [for treating folate deficiency] for an
adult human is generally in the range from 2 to 25 mg.”
Id. col. 5 ll. 15–19, 21–24. Claim 2 depends from claim 1,
with the additional limitation that the composition “con-
sists of greater than 95% by weight of the (6S) diastereoi-
somer.” Id. col. 10 ll. 1–3 (emphasis added).
    Claim 5 of the ’829 patent reads as follows:
    5. A pharmaceutical composition for therapeutic
    use for the treatment of human beings compris-
    ing:
        a pharmaceutically acceptable composition
        which is a (6S) diastereoisomer selected
        from the group consisting of (6S) leuco-
        vorin (5-formyl-(6S)-tetrahydrofolic acid)
        and pharmaceutically acceptable salts and
        esters of (6S) leucovorin, wherein the
        composition consists of a mixture of (6S)
        and (6R) diastereoisomers and consists of
        at least about 92% by weight of the (6S)
        diastereoisomer, the balance of said com-
        position consisting of the (6R) diastereoi-
        somer; and
4           SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.

       a pharmaceutically acceptable carrier; and
       said composition being of a quantity at
       least sufficient to provide multiple doses of
       said mixture of (6S) and (6R) diastereoi-
       somers in an amount of 2000 mg per dose.
Id. col. 10 ll. 10–24 (emphases added). Claims 6–9 depend
from claim 5 and contain additional limitations not at
issue in this appeal.
    During prosecution of the application that became the
’829 patent, the examiner rejected the application’s claims
as anticipated by or obvious over an article disclosing an
enzymatic synthesis technique by which 0.91 grams of l-
leucovorin had been synthesized. J.A. 4872–77 (office
action detailing rejection over Lilias Rees et al., Asymmet-
ric Reduction of Dihydrofolate Using Dihydrofolate Reduc-
tase and Chiral Boron-Containing Compounds, 42
Tetrahedron 117–136 (1986) (“Rees”)). The applicants
responded by adding new claims, including what later
issued as claims 5–9, and by emphasizing the specific
claim limitations relating to quantities of the specified
mixture, which were allegedly not disclosed by the prior
art. J.A. 4901–05. After a final office action rejecting the
claims, the applicants appealed to the U.S. Patent and
Trademark Office’s Board of Patent Appeals and Interfer-
ences (“the Board”), again emphasizing that the quantity
limitations could not be met by Rees. J.A. 4971, 4993–98.
The patent eventually issued with the University of
Strathclyde listed as the assignee.
    Spectrum, as the exclusive licensee of the ’829 patent,
holds the approved New Drug Application for a levoleuco-
vorin formulation, and accordingly listed the patent as
claiming the drug product in the U.S. Food and Drug
Administration (“FDA”) publication, Approved Drug
Products with Therapeutic Equivalence Evaluations
(commonly known as the “Orange Book”). Spectrum’s
SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.          5

product, Fusilev®, is indicated for the three uses de-
scribed earlier.
    Sandoz submitted an ANDA in October 2011, seeking
approval from the FDA for a drug product that will be
imported in the form of single-use vials with 175 mg or
250 mg of levoleucovorin, indicated for methotrexate
rescue at doses of 7.5–75 mg per dose (“the ANDA prod-
uct”). Its ANDA contained a certification that the ’829
patent was invalid or would not be infringed by the ANDA
product. See 21 U.S.C. § 355(j)(2)(A)(vii)(IV).
     After receiving notice of that certification, Spectrum
filed a timely patent infringement suit in January 2012,
alleging that Sandoz’s ANDA submission infringed the
’829 patent under 35 U.S.C. § 271(e)(2). The asserted
claims were directed to pharmaceutical compositions
comprising a mixture of (6S) and (6R) isomers, with at
least 92% or 95% of the (6S) isomer. The patent discloses,
but does not claim, a process for purifying the (6S) isomer
from a 50/50 mixture using a chiral auxiliary group.
    The district court construed the term “said composi-
tion being of a quantity at least sufficient to provide
multiple doses of said mixture of (6S) and (6R) diastereoi-
somers in an amount of 2000 mg per dose” as having its
plain and ordinary meaning. Spectrum Pharm., Inc. v.
Sandoz Inc., No. 2:12-cv-00111, 2013 WL 6865692, at
*18–20 (D. Nev. Dec. 31, 2013) (emphases added). The
court elaborated that the plain meaning required the
composition to contain “enough of the (6S)/(6R) mixture to
provide two or more doses of, at minimum, 2000 mg per
dose.” Id.
    After construing the claims, the district court granted
Sandoz’s motion for summary judgment of noninfringe-
ment of claims 5–9. Summary Judgment Order at *1.
Comparing the product described in Sandoz’s ANDA to
the claims of the ’829 patent, the court found that because
the individual vials will contain only up to 250 mg of
6           SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.

levoleucovorin, the approved product would not satisfy the
claim limitation of at least two doses of 2000 mg. Id. at
*5. The court also rejected Spectrum’s argument that an
aggregation of Sandoz’s approved product—that is, the
total amount of levoleucovorin drug product to be import-
ed—would infringe the claims. Id.
     The district court further found that Spectrum was
precluded from asserting infringement under the doctrine
of equivalents because of the inventors’ statements during
prosecution. Summary Judgment Order at *7–8. The
court cited various instances in the prosecution history in
which the applicants had distinguished Rees by empha-
sizing that the application claims (that issued as claims
5–9) had “more stringent quantity limitations” than claim
1. Id. at *7. As a result, the court found “a clear and
unmistakable surrender of subject matter covering phar-
maceutical composition quantities less than what is
required to provide two or more doses of, at minimum,
2000 mg per dose of the mixture.” Id. at *8. Because
Spectrum did not raise a genuine issue of material fact as
to literal infringement or infringement under the doctrine
of equivalents of claims 5–9, the court granted summary
judgment of noninfringement of those claims.
    Sandoz stipulated to infringement of claims 1 and 2,
and the district court subsequently conducted a bench
trial only on the validity of those claims. The court found
that the prior art disclosed: (i) leucovorin as a mixture of
(6R) and (6S) diastereoisomers; (ii) that the therapeutic
usefulness of leucovorin derives wholly from the (6S)
isomer; and (iii) a rationale for investigating a purified
(6S) isomer product for use in 5-FU combination therapy.
Trial Order at *6–8, *13–14. The court also found that
preparations of purified (6S) isomer by an enzymatic
synthesis method and by separation methods had been
publicly reported before the ’829 patent’s priority date.
Id. at *6–7. In particular, the court analyzed two related
prior art references that disclosed a process for separating
SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.           7

the diastereoisomers using the solubility differential of
the (6S) and (6R) isomer salts, i.e., fractional crystalliza-
tion. See id. at *11–13 (findings relating to Donna B.
Cosulich, Diastereoisomers of Leucovorin, 74 J. Am.
Chemical Soc’y 4215–16 (1952) and U.S. Patent 2,688,018
(collectively, “Cosulich” or “the Cosulich references”)).
    The district court further found that the process
taught by Cosulich would have “invariably” produced a
mixture containing the (6R) isomer as an impurity, and
that the data in the Cosulich references demonstrated
that Dr. Cosulich also obtained a highly pure (6S) isomer
compound. Trial Order at *10–12. The court concluded
that those facts alone made the subject matter of the
claims prima facie obvious in light of the prior art. The
court also rejected Spectrum’s argument that using the
Rees method would not have produced sufficient quanti-
ties of the (6S) isomer, because the applicants had sub-
mitted a declaration during prosecution stating that the
reaction could have been scaled up to produce about 500
grams of the (6S) isomer per year. Id. at *15–16.
    The district court then found that Spectrum did not
rebut the prima facie case of obviousness because it failed
to prove any nexus between what was claimed and the so-
called secondary factors, much less prove a long-felt need
or successful licensing. Id. at *25–27. In particular, the
court found that the only “distinguishing feature” of the
claims compared to the prior art was “the small presence
of the unwanted (6R) isomer,” and that Spectrum did not
prove a nexus between that amount and any secondary
consideration. Id. at *25. Moreover, as leucovorin was
not used in 5-FU combination therapy until much later
than the claimed uses (and thus the effect of the
(6R) isomer was not previously a concern), the court found
that no nexus was shown between the claims and the
asserted long-felt need. Id. The court found that even if
there were a nexus and a long-felt need, the invention
would not have satisfied the need because substantially
8           SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.

pure levoleucovorin is clinically interchangeable with the
prior art leucovorin. Id. at *26. The district court also
rejected Spectrum’s proof of commercial success. Trial
Order at *26–27. The court thus concluded that the
evidence as a whole showed that claims 1 and 2 were
invalid as obvious. Id. The district court accordingly
entered final judgment in favor of Sandoz.
    Spectrum timely appealed to this court. We have ju-
risdiction pursuant to 28 U.S.C. § 1295(a)(1).
                       DISCUSSION
    On appeal from a bench trial, we review a district
court’s conclusions of law de novo and its findings of fact
for clear error. Golden Blount, Inc. v. Robert H. Peterson
Co., 365 F.3d 1054, 1058 (Fed. Cir. 2004). A factual
finding is only clearly erroneous if, despite some support-
ing evidence, we are left with the definite and firm convic-
tion that a mistake has been made. United States v. U.S.
Gypsum Co., 333 U.S. 364, 395 (1948); see also Polaroid
Corp. v. Eastman Kodak Co., 789 F.2d 1556, 1559 (Fed.
Cir. 1986) (“The burden of overcoming the district court’s
factual findings is, as it should be, a heavy one.”).
    At the summary judgment stage, we review the grant
of summary judgment under the law of the regional
circuit in which the district court sits, here the Ninth
Circuit. Classen Immunotherapies, Inc. v. Elan Pharm.,
Inc., 786 F.3d 892, 896 (Fed. Cir. 2015). Applying the law
of the Ninth Circuit, we review a district court’s grant of
summary judgment de novo. Burke v. Cty. of Alameda,
586 F.3d 725, 730 (9th Cir. 2009). Summary judgment is
appropriate when, drawing all reasonable inferences in
favor of the nonmovant, there is “no genuine dispute as to
any material fact and the movant is entitled to judgment
as a matter of law.” Fed. R. Civ. P. 56(a); see Anderson v.
Liberty Lobby, Inc., 477 U.S. 242, 255 (1986).
SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.           9

    This appeal raises questions of validity and infringe-
ment, but, unlike most such appeals, does not challenge
the district court’s claim construction. As we find no
reason to disturb the district court’s claim construction in
these cases, we will only address the issues raised.
                       I. Invalidity
     We first address Spectrum’s argument that the dis-
trict court erred in holding claims 1 and 2 of the ’829
patent invalid as obvious.
     Patents are presumed to be valid, and overcoming
that presumption requires clear and convincing evidence.
35 U.S.C. § 282; Microsoft Corp. v. i4i Ltd. P’ship, 564
U.S. __, 131 S. Ct. 2238, 2242 (2011). A patent claim is
invalid as obvious if an alleged infringer proves that the
differences between the claims and the prior art are such
that “the subject matter as a whole would have been
obvious at the time the invention was made to a person
having ordinary skill in the art.” 35 U.S.C. § 103(a)
(2006). 1
     Obviousness is ultimately a conclusion of law prem-
ised on underlying findings of fact, including the scope
and content of the prior art, the differences between the
claimed invention and the prior art, and the level of
ordinary skill in the pertinent art. KSR Int’l Co. v. Tele-
flex Inc., 550 U.S. 398, 427 (2007); Graham v. John Deere
Co., 383 U.S. 1, 17–18 (1966). “The presence or absence of
a motivation to combine references in an obviousness
determination is a pure question of fact.” Alza Corp. v.
Mylan Labs., 464 F.3d 1286, 1289 (Fed. Cir. 2006). In
addition to common knowledge or teachings in the prior

   1   Because the ’829 patent was filed before the effec-
tive date of the America Invents Act, the earlier, pre-Act
version of § 103(a) applies. See Leahy–Smith America
Invents Act, Pub. L. No. 112-29, 125 Stat. 284, 293 (2011).
10          SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.

art itself, a “design need or market pressure or other
motivation” may provide a suggestion or motivation to
combine prior art elements in the manner claimed. Rolls
Royce, PLC v. United Techs. Corp., 603 F.3d 1325, 1339
(Fed. Cir. 2010); accord KSR, 550 U.S. at 420. These
principles are relevant here.
    Spectrum asserts that the district court improperly
used hindsight to provide a reason or motivation to modi-
fy the prior art pure (6S) isomer compound to obtain a
slightly impure compound. Even though one of skill in
the art admittedly could have added some (6R) isomer to
contaminate the 100% pure (6S) isomer disclosed by Rees
to produce the claimed substantially pure compound,
Spectrum argues that none of the record evidence sup-
plied a logical motivation to do so.
    Sandoz responds that the district court correctly
found that one of skill would have been motivated to
make substantially pure (6S) leucovorin starting with the
50/50 mixture to have a more effective pharmaceutical
treatment, and would have reasonably expected to suc-
ceed in doing so. Sandoz contends that it had no burden
to show a motivation to contaminate the prior art pure
(6S) isomer compound, because the court’s analysis began
with the 50/50 mixture and rejected Spectrum’s argu-
ments on the inoperability of the prior art. Moreover,
Sandoz argues, the court found no patentable difference
between the claimed substantially pure compound and
the prior art pure compound, which presented a prima
facie case of obviousness that Spectrum failed to rebut.
    Most issues relating to purified diastereoisomers or
enantiomers involve the question whether a pure, re-
solved compound would have been obvious over the corre-
sponding mixture. See, e.g., Aventis Pharma Deutschland
GmbH v. Lupin, Ltd., 499 F.3d 1293, 1301–03 (Fed. Cir.
2007); see also Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d
1075, 1086–90 (Fed. Cir. 2008); Forest Labs., Inc. v. Ivax
SPECTRUM PHARMACEUTICALS, INC.     v. SANDOZ INC.           11

Pharm., Inc., 501 F.3d 1263, 1269 (Fed. Cir. 2007); In re
Adamson, 275 F.2d 952, 953–54 (CCPA 1960); In re
Anthony, 414 F.2d 1383, 1386 (CCPA 1969). This case is
unusual in involving a slightly different question, namely,
whether a substantially pure compound would have been
obvious when both the 50/50 mixture and the pure com-
pound were known in the art. We agree with the district
court that the claimed substantially pure compound
would have been obvious over both the 50/50 mixture and
the pure (6S) isomer compound in the prior art.
    First, the district court did not clearly err in finding
that one of skill would have been motivated to modify the
prior art 50/50 mixture to make the claimed mixture. If it
is known that the desired activity all lies in one isomer,
surely, it is better, and there is generally motivation, to
try to obtain the purest compound possible. See Aventis,
499 F.3d at 1301 (“[A] purified compound is not always
prima facie obvious over the mixture; . . . [h]owever, if it is
known that some desirable property of a mixture derives
in whole or in part from a particular one of its compo-
nents, . . . the purified compound is prima facie obvious
over the mixture even without an explicit teaching that
the ingredient should be concentrated or purified.”). A
physician would not likely want to administer a contami-
nant or a less pure material to a patient if one could use a
pure material. Thus, there is always in such cases a
motivation to aim for obtaining a pure, resolved material.
    Conversely, if the pure material is known, no reason
has been shown why one would want to have an impure
material. Although one may not be motivated to obtain
an impure material and, in effect, it therefore can be
argued to have been nonobvious—which is Spectrum’s
position here, that the 92–95% pure material was nonob-
vious over the known pure material—that position, de-
spite its superficial appeal, is not persuasive. As the
district court correctly decided, because the desirable
properties of the prior art 50/50 mixture are attributable
12          SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.

to only one component, and the slightly impure mixture—
one that contains the substantially pure (6S) isomer in an
amount of at least 92–95%—has not been shown to pos-
sess unexpected advantages over the prior art pure mate-
rial, the less-than-pure material, and any others of
similar concentration, cannot be found to have been
nonobvious.
    We also agree with the district court that, given the
50/50 mixture, there would have been a motivation to
pursue the goal of obtaining either pure or the clinically
interchangeable substantially pure (6S) isomer. A person
of skill knew that the desired activity of leucovorin came
from the (6S) isomer, which therefore provided a motiva-
tion to purify the (6S) isomer, even without an explicit
teaching. Although the claimed compounds are not 100%
pure, they are described as “substantially pure” and as
not patentably different from pure material.
    The evidence showed that “numerous other research
groups had responded to the motivation to obtain a pure
isomer and were pursuing purified (6S) leucovorin prior to
the priority date for the ’829 patent,” and, as the district
court noted, “[i]n short time, many succeeded.” Trial
Order at *14–15 (citation omitted). As in Aventis, here
there was no need to find an express teaching to prove
sufficient motivation to modify the prior art to arrive at
the claimed invention, where various techniques to purify
the isomers were reported in the art and, importantly, it
was known that the (6S) isomer alone provided the thera-
peutic effect.
    In the face of that evidence of obviousness, Spectrum
did not provide any evidence of unexpected results for the
substantially pure compound as compared to the 50/50
mixture or the 100% pure compound. The district court
found that “clinical trials have established that purified
(6S) leucovorin and leucovorin are clinically interchange-
able” and that one of skill in the art “would not have
SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.          13

expected there to be any differences in the biological
properties between purified (6S) leucovorin with or with-
out a small amount of (6R) impurity . . . because small
amounts of the inactive isomer would not be noticeable in
terms of therapeutic effects.” Trial Order at *16.
    The district court also found that the prior art as a
whole enabled one of skill in the art to make and use the
claimed invention. Spectrum asserts that the court made
no explicit finding that Cosulich was enabling, and there-
fore nothing in the record showed that one of skill in the
art had the means to separate the (6S) and (6R) isomers
from a 50/50 mixture. Accordingly, Spectrum argues,
because the ’829 patent enabled one of skill in the art to
produce viable quantities of the substantially pure (6S)
isomer, the claims are directed to both the compound and
the method of making that compound.
    Sandoz responds that the district court made factual
findings that the prior art was enabling because multiple
teams independently developed different methods for
purifying a (6S) isomer compound around the time of the
claimed invention, and that the specification admits that
the prior art methods worked. Sandoz also notes that the
court acknowledged the evidence of failures to repeat the
results of the method disclosed in Cosulich, but did not
find that the purification could not be accomplished.
    Regardless whether the Cosulich references were en-
abling or not, the whole spectrum of prior art available
before the invention was made would have enabled one of
skill in the art to make and use the claimed substantially
pure leucovorin compound. We agree with the district
court’s conclusion on that point.
    Finally, the district court found that the objective in-
dicia did not rebut the prima facie case of obviousness.
Spectrum argues that the district court erred by finding
that, despite the motivation to purify the prior art 50/50
mixture and the knowledge in the art that the (6R) isomer
14          SPECTRUM PHARMACEUTICALS, INC.    v. SANDOZ INC.

was undesirable, there was not a long-felt but unmet
need. Spectrum also asserts that the district court im-
properly used evidence of later clinical studies. Sandoz
responds that such a need does not always exist whenever
there is a motivation to modify the prior art, and that
post-filing evidence is usually required to determine if the
claimed invention satisfied the alleged long-felt need.
    We agree that the district court did not clearly err in
finding that there was no long-felt but unmet need.
Moreover, even if there were a long-felt need, the district
court found that a purified (6S) isomer compound would
not have satisfied that need because it was shown to be
clinically interchangeable with the 50/50 mixture. Id. at
*18. The court also credited expert testimony, including
that of Spectrum’s expert, that the claimed substantially
pure (6S) isomer compound “offers no meaningful differ-
ence” from the pure (6S) isomer compound. Id. at *16. As
a long-felt but unmet need was the only indicium argued
on appeal, we agree with the district court that Spectrum
did not provide evidence of objective indicia of nonobvi-
ousness.
     We owe the district court’s factual findings considera-
ble deference on appeal, and we see no clear error based
on the record before us. Based on those findings, we
affirm the district court’s conclusion that Sandoz proved
by clear and convincing evidence that claims 1 and 2 of
the ’829 patent are invalid as obvious.
                   II. Noninfringement
    We also address the district court’s finding that
claims 5–9 of the ’829 patent would not be infringed by
Sandoz’s ANDA product. The key language at issue in
claim 5, and by extension in dependent claims 6–9, is
“said composition being of a quantity at least sufficient to
provide multiple doses of said mixture of (6S) and (6R)
diastereoisomers in an amount of 2000 mg per dose.” ’829
patent col. 10 ll. 10–24 (emphasis added). Based on its
SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.         15

claim construction, the district court found that Sandoz’s
ANDA product, in vials of 175 mg or 250 mg of levoleuco-
vorin, would not meet the limitation of at least two doses
of 2000 mg each. The court also found that the patent
applicant had explicitly disclaimed smaller dosage
amounts during prosecution. The district court therefore
decided that no genuine issue of material fact on the
infringement question had been raised, finding that
Spectrum had not shown literal infringement and was
estopped from applying the doctrine of equivalents.
     Under the framework of the Hatch–Waxman Act, the
infringement inquiry focuses on a comparison of the
asserted patent claims against the ANDA product that is
likely to be sold following FDA approval. Warner–
Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1365–66
(Fed. Cir. 2003) (citing Glaxo, Inc. v. Novopharm, Ltd.,
110 F.3d 1562, 1567–68 (Fed. Cir. 1997)). The burden of
proving infringement by a preponderance of the evidence
remains on the patentee. Id. Evaluating the grant of
summary judgment of noninfringement requires two
steps: (1) claim construction, where contested, and (2)
comparison of the properly construed claims to the ac-
cused product. Abbott Labs. v. Sandoz, Inc., 566 F.3d
1282, 1288 (Fed. Cir. 2009). The second step of the analy-
sis is a question of fact. Bai v. L&L Wings, Inc., 160 F.3d
1350, 1353 (Fed. Cir. 1998). As such, it is amenable to
summary judgment where no reasonable factfinder could
find that the accused product contains every claim limita-
tion or its equivalent. Id.; see Warner–Jenkinson Co. v.
Hilton Davis Chem. Co., 520 U.S. 17, 29, 39 n.8 (1997).
    Even without literal infringement, a patentee may es-
tablish infringement under the doctrine of equivalents if
an element of the accused product “performs substantially
the same function in substantially the same way to obtain
the same result as the claim limitation.” Pozen Inc. v. Par
Pharm., Inc., 696 F.3d 1151, 1167 (Fed. Cir. 2012) (cita-
tion omitted).
16          SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.

    Whether prosecution history estoppel applies, and
thus whether the doctrine of equivalents is available for a
particular claim limitation, is a question of law reviewed
de novo. Intervet Inc. v. Merial Ltd., 617 F.3d 1282, 1290–
91 (Fed. Cir. 2010). That situation arises when an appli-
cant during prosecution either makes an argument evinc-
ing a “clear and unmistakable surrender” of subject
matter, Elkay Mfg. Co. v. Ebco Mfg. Co., 192 F.3d 973,
979 (Fed. Cir. 1999), or narrows a claim “to avoid the
prior art, or otherwise to address a specific concern . . .
that arguably would have rendered the claimed subject
matter unpatentable,” Warner–Jenkinson, 520 U.S. at 30–
31. The applicant is then estopped from later invoking
the doctrine of equivalents to recapture the surrendered
subject matter. Festo Corp. v. Shoketsu Kinzoku Kogyo
Kabushiki Co., 535 U.S. 722, 734 (2002). The patentee
bears the burden of rebutting the application of prosecu-
tion history estoppel. Id. at 740–41.
    Spectrum asserts that the claims do not require that
the end product be distributed or administered in the
packaged dosage. Because Sandoz stipulated to future
importation of more than 10 grams of its product, Spec-
trum argues that such importation will literally infringe
the claims. Spectrum also asserts that the court erred in
finding that prosecution history estoppel applied. Spec-
trum insists that the applicants did not surrender cover-
age of aggregate quantities of the mixture. Moreover,
Spectrum argues, claim 5 was added by amendment in
addition to, not in place of, the original claims, and was
not amended to relinquish any claim scope.
    Sandoz responds that the district court rejected Spec-
trum’s argument during claim construction that the “2000
mg per dose” limitation could be satisfied by multiple
doses as long as they added up to 4000 mg total, because
that ignored the “per dose” language in the claim. Sandoz
also contends that Spectrum is barred from asserting
infringement under the doctrine of equivalents because of
SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.         17

the statements of disclaimer made during prosecution
that were described as defining a significant aspect of the
invention. Even without the disclaimer, Sandoz argues
that amendment-based estoppel would apply because
those claims were added with the dosage limitation to
overcome an obviousness rejection based on Rees.
     Viewing the record in the light most favorable to
Spectrum and drawing all reasonable inferences in its
favor, we do not find the evidence in the record sufficient
to prove infringement. The product that is likely to be
sold following FDA approval is what Sandoz’s ANDA
describes: single-use vials with 175 mg or 250 mg of
substantially pure levoleucovorin, indicated only for
methotrexate rescue at doses between 7.5 mg and 75 mg
per dose, which would be far less than at least two doses
of 2000 mg each. We discern no clear error in the district
court’s finding that Sandoz’s approved product would not
meet the dosage claim limitation, and thus would not
literally infringe claims 5–9.
     Moreover, by claim amendments and distinguishing
statements on the prior art during prosecution, Spectrum
is now estopped from invoking the doctrine of equivalents
to prove infringement. When submitting an amendment
with the application claims that eventually issued as
claims 5–9, the applicants asserted that the newly added
claims “include specific limitations as to quantities of
materials,” and distinguished the prior art by pointing to
the “quantities of these specific mixtures specified in the
claims.” J.A. 4904–05. Those claims were also added
following an office action rejecting the previous original
claims as obvious in view of Rees. The applicants again
explicitly highlighted the significance of the dosage limi-
tation during an appeal to the Board, their brief stating
that the claims “require a minimum of four grams,” the
“quantity limitations set forth in the claims” which “de-
fine an aspect of the invention that is of great practical
significance.” J.A. 4996–97. The applicants unequivocal-
18          SPECTRUM PHARMACEUTICALS, INC.   v. SANDOZ INC.

ly argued that Rees, which allegedly only produced exper-
imental quantities, “do[es] not teach, suggest, or other-
wise render obvious the claimed compositions in the
quantity specified” in the application claims that became
claims 5–9. J.A. 4998 (emphasis in original). Those
statements are clear and unmistakable expressions of the
applicants’ intent to surrender coverage of quantities of
the compound in lower doses.
    Accordingly, we agree with the district court that
Spectrum did not sufficiently raise a genuine issue of
material fact as to infringement to defeat the motion for
summary judgment. The court did not clearly err in
finding that Spectrum failed to prove that the approved
product would literally infringe claims 5–9. The court
also did not err in concluding that Spectrum was barred
from invoking the doctrine of equivalents by prosecution
history estoppel. The district court thus did not err in
granting summary judgment of noninfringement.
                       CONCLUSION
    We have considered the remaining arguments and
conclude that they are without merit. For the foregoing
reasons, we conclude that the district court did not err in
holding that claims 1–2 of the ’829 patent are invalid as
obvious under 35 U.S.C. § 103, and we therefore affirm
that decision. We further conclude that the district court
did not err in holding that Spectrum failed to prove by a
preponderance of the evidence that Sandoz’s ANDA
product would infringe claims 5–9 of the ’829 patent, and
we also affirm that decision.
                      AFFIRMED