Amgen Inc. v. Apotex Inc.

NOTE: This disposition is nonprecedential.
United States Court of Appeals
for the Federal Circuit
______________________
AMGEN INC., AMGEN MANUFACTURING
LIMITED,
Plaintiffs-Appellants
v.
APOTEX INC., APOTEX CORP.,
Defendants-Appellees
______________________
2017-1010
______________________
Appeal from the United States District Court for the
Southern District of Florida in Nos. 0:15-cv-61631-JIC,
0:15-cv-62081-JIC, Judge James I. Cohn.
______________________
Decided: November 13, 2017
______________________
NICHOLAS P. GROOMBRIDGE, Paul, Weiss, Rifkind,
Wharton & Garrison LLP, New York, NY, argued for
plaintiffs-appellants. Also represented by JENNIFER
GORDON, ARIELLE K. LINSEY, STEPHEN ACCURSIO
MANISCALCO, CATHERINE NYARADY, PETER SANDEL, ERIC
ALAN STONE, JENNIFER H. WU; JOHN F. O’SULLIVAN,
ALLEN P. PEGG, JASON STERNBERG, Hogan Lovells US
LLP, Miami, FL; LOIS M. KWASIGROCH, KIMBERLIN L.
2 AMGEN INC. v. APOTEX INC.
MORLEY, WENDY A. WHITEFORD, Amgen Inc., Thousand
Oaks, CA.
BARRY P. GOLOB, Cozen O’Connor, Washington, DC,
argued for defendants-appellees. Also represented by
WILLIAM BLAKE COBLENTZ, AARON S. LUKAS, KERRY
BRENDAN MCTIGUE.
______________________
Before LOURIE, O’MALLEY, and TARANTO, Circuit
Judges.
TARANTO, Circuit Judge.
Amgen Inc. and Amgen Manufacturing Limited (col-
lectively, Amgen) own U.S. Patent No. 8,952,138, which
describes and claims methods of refolding recombinant
proteins expressed in non-mammalian cells, such as
bacteria and yeast. ’138 Patent, col. 1, lines 10–20; col. 2,
lines 52–61. Amgen also holds Biologics License Applica-
tion Nos. 125031 and 103353, approved by the Food and
Drug Administration (FDA), for therapeutic products
made from the recombinant proteins pegfilgrastim
(Neulasta®) and filgrastim (Neupogen®).
Apotex Inc. and Apotex Corp. (collectively, Apotex)
filed abbreviated Biologics License Applications Nos.
761026 and 761027 under 42 U.S.C. § 262(k) of the Bio-
logics Price Competition and Innovation Act (BPCIA),
seeking permission from the FDA to market biosimilar
versions of pegfilgrastim and filgrastim products, and
listing Neulasta® and Neupogen®, respectively, as the
reference products. Apotex and Amgen then engaged in
the information exchange described in the BPCIA, 42
U.S.C. § 262(l)(3). After Apotex provided Amgen with
copies of its applications, Amgen identified the ’138 patent
as a patent that the Apotex-proposed products would
infringe, and Apotex replied by sending Amgen a detailed
statement describing, claim by claim, the factual and
AMGEN INC. v. APOTEX INC. 3
legal basis for its opinion that it did not infringe. Amgen
responded with its contrary, detailed view of infringe-
ment. Amgen eventually filed two infringement suits
against Apotex, one for each of Apotex’s applications,
pursuant to 35 U.S.C. § 271(e)(2)(C), (a) and (g).
The two suits were consolidated. The district court
held a bench trial in July 2016, and it issued findings of
fact and conclusions of law on September 6, 2016. The
court found that Amgen had failed to prove that Apotex’s
proposed commercial marketing of the two products,
pursuant to Apotex’s applications, would infringe the ’138
patent, either literally or under the doctrine of equiva-
lents.
Amgen appeals. We have jurisdiction under 28 U.S.C.
§ 1295(a)(1). We affirm.
I
A
The ’138 patent explains that when recombinant pro-
teins are formed in non-mammalian expression systems,
such as bacterial cells, they can precipitate into limited-
solubility aggregates of misfolded proteins called “inclu-
sion bodies.” ’138 patent, col. 1, lines 20–24. To obtain
properly folded proteins from inclusion bodies, practition-
ers developed various methods to accomplish refolding.
Id., col. 1, lines 36–38. Those methods, the patent ex-
plains, commonly include steps of (1) extracting the
inclusion bodies from the expression system; (2) solubiliz-
ing the inclusion bodies in a solubilization buffer, which
disassembles the inclusion bodies into individual protein
chains and unfolds the proteins; and (3) diluting or wash-
ing the unfolded proteins in a refolding buffer, which
causes the proteins to refold in the proper manner. Id.,col. 1, lines 38–51.
Industry faced a challenge in producing certain re-
folded proteins on an industrial scale. Id., col. 1, lines 55–
4 AMGEN INC. v. APOTEX INC.
60. For larger, complicated molecules (e.g., antibodies
and peptibodies, which often have between 8 and 24
disulfide bonds), the refolding mixture used for the pro-
cess had to be maintained at a relatively low protein
concentration, typically 0.01–0.5 g/L. Id., col. 1, lines 51–
54; col. 2, lines 10–16. As a result, a very large volume of
the mixture was required to produce a large amount of
the desired protein. Id., col. 1, lines 55–60; see also id.,col. 1, lines 64–67.
The ’138 patent purports to solve this problem by us-
ing a carefully controlled reduction-oxidation (redox)
reaction to refold proteins—even large, complicated
protein molecules—at a higher concentration than was
possible in the prior art. Claim 1, the ’138 patent’s only
independent claim, reads as follows:
1. A method of refolding a protein expressed in a
non-mammalian expression system and present in
a volume at a concentration of 2.0 g/L or greater
comprising:
(a) contacting the protein with a refold
buffer comprising a redox component com-
prising a final thiol-pair ratio having a
range of 0.001 to 100 and a redox buffer
strength of 2 mM or greater and one or
more of:
(i) a denaturant;
(ii) an aggregation suppressor; and
(iii) a protein stabilizer;
to form a refold mixture;
(b) incubating the refold mixture; and
(c) isolating the protein from the refold
mixture.
Id., col. 17, lines 47–59.
AMGEN INC. v. APOTEX INC. 5
B
Claim 1, in its preamble (which all agree is limiting),
calls for protein present in “a volume at a concentration of
2.0 g/L or greater.” Id., col. 17, line 49. During claim
construction, Amgen argued that the claimed “volume”
was the volume of protein before, not after, the contact
with the refolding buffer that forms the refold mixture.
Amgen also argued, based on the specification, that the
“refold mixture,” as a matter of claim construction, must
have a protein concentration at or above about 1.0 g/L.
Apotex, for its part, contended that the claim 1 “volume”
refers to the refold mixture, so that the claimed refold
mixture must have a protein concentration of 2.0 g/L or
more. The district court agreed with Amgen on both
points, construing “a protein . . . present in a volume at a
concentration of 2.0 g/L or greater” to mean “a protein as
it existed in a volume before contacting the volume with a
refold buffer” and construing “refold mixture” to have a
“high protein concentration[] . . . at or above about 1 g/L.”
C
For the 1.0 g/L claim requirement, Amgen alleged on-
ly literal infringement, not infringement under the doc-
trine of equivalents. In seeking to prove that Apotex’s
accused processes meet this claim requirement, Amgen
relied at trial on the fact that Apotex’s abbreviated Biolog-
ics License Applications identified an “inclusion body
concentration” of 0.9–1.4 g/L for the refold mixture in its
processes for refolding filgrastim and pegfilgrastim. J.A.
23–24, 5594, 5902. In the BPCIA information exchange
that occurred before this suit was filed, Apotex had sent
Amgen several “pre-litigation” letters, at least one with
respect to the filgrastim application and one with respect
to the pegfilgrastim application. In both letters, Apotex
stated that it did not infringe the ’138 patent because its
“concentration of [filgrastim or filgrastim critical inter-
mediate] in the refold buffer” was limited to 0.9–1.4 g/L
6 AMGEN INC. v. APOTEX INC.
(i.e., the “inclusion body concentration” listed on the
applications).
At trial, however, Apotex’s fact witness, Dr. Jason
Dowd, presented evidence that the maximum concentra-
tion of protein in its refold mixture would actually be
0.708 g/L. Dr. Dowd testified, during cross examination,
that the statements in Apotex’s pre-litigation letters were
factually inaccurate. He explained that the inclusion
bodies in Apotex’s process were not pure protein, but,
rather, were a paste of which about two-thirds was water.
In addition, to resolve any potential ambiguity created by
the numbers presented on the face of its application,
Apotex presented two “batch records” showing the actual
data from the manufacturing process of its filgrastim
product. According to Dr. Dowd, those records showed
that the protein (not the inclusion-body) concentration in
the refold mixture never exceeded about 0.56 g/L. Both
that figure and the 0.708 g/L figure are well below the 1.0
g/L minimum level required under the Amgen-urged and
court-adopted claim construction.
The court ruled in favor of Apotex on this issue. It
found that Amgen had failed to prove by a preponderance
of the evidence that Apotex’s processes would meet the 1.0
g/L requirement of claim 1 of the ’138 patent. For that
reason, the court found, Amgen failed to prove direct
infringement.
On Amgen’s appeal, we affirm that finding. We there-
fore need not and do not reach Amgen’s challenge to the
district court’s other, independent ground for finding no
infringement, which involves the claim term “2mM or
greater.” In particular, we do not decide the correctness
or incorrectness of the district court’s construction of that
claim term.
AMGEN INC. v. APOTEX INC. 7
II
Amgen challenges the district court’s finding of no di-
rect infringement of the ’138 patent on three grounds: (1)
that the district court erred in finding Apotex’s pre-
litigation letters to lack probative value; (2) that the
district court erred in not treating “protein concentration”
as interchangeable with “inclusion body concentration”;
and (3) that the district court erred in not finding the
required 1.0 g/L protein concentration based on what
Apotex’s abbreviated Biologics License Applications
permit. We review the finding of non-infringement for
clear error, Alza Corp. v. Mylan Labs., Inc., 464 F.3d
1286, 1289 (Fed. Cir. 2006), and we decide any legal
issues de novo, Jack Guttman, Inc. v. Kopykake Enters.,
Inc., 302 F.3d 1352, 1356 (Fed. Cir. 2002).
A
Amgen first focuses on the pre-litigation letters sent
by Apotex to Amgen during the information exchange
conducted before the litigation pursuant to the BPCIA.
Amgen does not argue that Apotex is legally bound by its
statements about protein concentration in those letters;
indeed, both in the district court and in this court, Amgen
has disclaimed such an argument. See J.A. 3807; Reply
Br. 17–18. Rather, Amgen argues that the district court,
acting as fact-finder during the bench trial, erred by
disregarding those letters.
We do not question the general legal principle that
Amgen asserts: we agree that a district court cannot
ignore letters sent during the BPCIA’s information ex-
change if properly offered into evidence. Indeed, the pre-
litigation information exchange is part of the BPCIA’s
“carefully calibrated scheme for preparing to adjudicate,
and then adjudicating, claims of infringement.” Sandoz
Inc. v. Amgen Inc., 137 S. Ct. 1664, 1670 (2017). The
purpose of the exchange is “to identify relevant patents
and to flesh out the legal arguments that the[] [parties]
8 AMGEN INC. v. APOTEX INC.
might raise in future litigation.” Id. at 1671. Through
the information exchange, the BPCIA seeks to facilitate
the efficient resolution of patent disputes. The state-
ments in the pre-litigation letters are party admissions
and therefore have some probative weight. The district
court’s statement that the letters “are not probative on
the issue of protein concentration,” J.A. 24 ¶ 39, is there-
fore an overstatement to the extent it suggests that the
letters lack probative value as a matter of law.
We read the district court’s statement in context,
however, to mean only that the letters are not sufficiently
probative to outweigh other evidence presented at trial
indicating that the information in the letters was inaccu-
rate. Indeed, the district court did not ignore the pre-
litigation letters. Rather, it first concluded that the
letters were not binding on Apotex, a conclusion that
Amgen does not dispute, and it then found that the letters
lacked probative value in light of the other evidence
presented at trial. Thus, the court gave the letters their
evidentiary due. We do not believe that the court’s phras-
ing reflects an error in the approach it actually took to
reach its findings or calls the court’s ultimate conclusion
into question.
The letters do not render the finding of fact regarding
the protein concentration clearly erroneous. The district
court found that the letters were “not probative on the
issue of protein concentration” because they were “factual-
ly incorrect,” J.A. 24, and it had a sufficient basis in the
evidence to make that finding. On direct examination,
Dr. Dowd testified that the inclusion bodies produced by
the Apotex process are wet—i.e., a paste. He then testi-
fied that, based on the description of the refolding process
given in Apotex’s abbreviated Biologics License Applica-
tions, the maximum protein concentration that could
occur in Apotex’s process is 0.708 g/L. On cross examina-
tion, when asked about the pre-litigation letters, Dr.
Dowd stated that the letters were factually incorrect.
AMGEN INC. v. APOTEX INC. 9
That is, he reiterated that his calculation of a 0.708 g/L
protein concentration was accurate and that the 0.9–1.4
g/L mentioned in the letter was not. Amgen did not
attempt to challenge the accuracy of Dr. Dowd’s state-
ments regarding the pre-litigation letters during cross-
examination. Amgen also did not present any evidence,
other than the pre-litigation letters themselves, to con-
tradict Dr. Dowd’s statements.
On this record, we conclude that the district court did
not err by crediting Dr. Dowd’s testimony and finding that
the factually inaccurate letters were not probative on the
issue of the protein concentration.
B
Amgen argues, as a matter of claim construction, that
“protein concentration” in the claims of the ’138 patent is
interchangeable with “washed-inclusion-body concentra-
tion.” We review this claim-construction argument, which
rests entirely on intrinsic evidence, de novo. Teva Pharm.
USA, Inc. v. Sandoz, Inc., 135 S. Ct. 831, 841 (2015). We
reject the argument.
Amgen’s argument depends on its equating of inclu-
sion bodies with protein. Only on that basis does Amgen
then treat the concentration of one as necessarily identi-
cal to the concentration of the other. But the specification
pervasively disproves rather than supports the equation
of inclusion bodies with proteins.
The specification repeatedly makes clear that the pro-
teins are not the same as, but instead are “in” or “depos-
it[ed] . . . into” or “disposed in,” the “aggregates” called
“inclusion bodies.” See, e.g., ’138 patent, col. 1, lines 23–
25 (“the precipitation of the expressed proteins in limited-
solubility intracellular precipitates typically referred to as
inclusion bodies”); id., col. 9, lines 44–46 (“Often the cells
will deposit the recombinant proteins into large insoluble
or limited solubility aggregates called inclusion bodies.”);
10 AMGEN INC. v. APOTEX INC.
id., col. 10, lines 43–44 (“disposed in”); id., col. 1, lines 23,
38–44; id., col. 7, line 59–60; id., col. 9, line 50; id., col. 12,
line 61–62. Amgen’s own description reflects that fact.
Appellant’s Br. at 9 (“The misfolded proteins precipitate
within the bacterial cells in aggregates called ‘inclusion
bodies.’” (emphasis added)). The specification also makes
clear that it is individual proteins, disaggregated from the
inclusion bodies, that are refolded. See ’138 patent, col. 1,
lines 35–51 (background describing methods “for obtain-
ing correctly folded proteins from bacterial inclusion
bodies” by, e.g., “solubilizing the inclusion bodies,” “which
unfolds the proteins and disassembles the inclusion
bodies into individual protein chains,” allowing the “re-
folding”); id., col. 2, line 52 (summary: “[a] method of
refolding a protein” (emphasis added)); id., col. 6, lines
13–14 (“the term ‘refolding’ means a process of reintroduc-
ing secondary and tertiary structure to a protein” (em-
phasis added)). Amgen’s description reflects that fact as
well. Appellant’s Brief at 9 (“The inclusion bodies must
be isolated and solubilized so that the incorrectly folded
proteins are unfolded and subsequently refolded to form
the proper three-dimensional conformation.”).
Amgen argues otherwise by first pointing to the
Background of the ’138 patent, which, according to
Amgen, shows that “the patent specification contemplates
that, for purposes of calculating concentration, the pro-
tein . . . and the inclusion bodies are one and the same.”
Appellant’s Brief at 52 (internal quotation marks omit-
ted). But the Background material, quoted above, does
not support that characterization. Indeed, it speaks of
proteins “in” inclusion bodies; it does not equate them.
And it does not mention concentration at all, or give any
indication that the patent contemplates calculating the
concentration from the total mass of the inclusions bodies
rather than from the amount of protein contained in the
inclusion bodies.
AMGEN INC. v. APOTEX INC. 11
Amgen next points to the specification’s description of
an embodiment of the claimed refolding method, which
states that “[w]hen the protein is disposed in inclusion
bodies, the inclusion bodies can be harvested . . . , washed,
concentrated and refolded.” ’138 Patent, col. 10, lines 39–
44. Amgen contends that the passage teaches the folding
and washing of inclusion bodies and therefore must be
equating inclusion bodies with proteins. But even this
passage speaks of a protein “disposed in” inclusion bodies,
thereby recognizing the distinction—as does the usage
throughout the specification cited above. In this context,
we read the second half of the sentence as nothing more
than a somewhat imprecise shorthand reference to a
process that the rest of the patent makes clear involves
refolding the proteins, not the aggregates called “inclusion
bodies.” Accordingly, no inference of equating proteins
with the aggregates of proteins that are inclusion bodies
can fairly be drawn from this passage. And the passage
gives no indication that protein concentration should be
derived from the concentration of inclusion bodies rather
than from the proteins contained within the inclusion
bodies.
Amgen’s final basis for its contention is no more per-
suasive. A specification passage states that “the disclosed
method is particularly useful for proteins expressed in
bacterial expression systems[] . . . in which the protein is
expressed in the form of inclusion bodies.” Id., col. 12,
lines 54–57. But the language of “expressed in the form
of” does not imply interchangeability, but refers instead to
the problem of agglomeration that the method is meant to
help solve: “the precipitation of the expressed proteins in
limited-solubility intracellular precipitates typically
referred to as inclusion bodies,” id., col. 1, lines 22–24,
which must be disassembled to “unfold[] the proteins”
contained in them, id., col. 1, line 43, where doing so at an
industrial scale is challenging. It is not reasonable to
read the particular language Amgen cites to mean, coun-
12 AMGEN INC. v. APOTEX INC.
ter to the specification as a whole, that inclusion bodies
are the proteins inside them, even though there also is
water and other non-protein content inside them. In
particular, that reading is wrong in a context of identify-
ing concentration levels, where the distinction might well
(and does here) matter.
Thus, we reject Amgen’s proposed claim construction
of “protein concentration” as interchangeable with
“washed-inclusion-body concentration.”
C
Amgen argues that the district court’s non-
infringement finding rests on too restrictive a view of
Apotex’s FDA applications. It challenges that view as
contrary to this court’s decision in a Hatch-Waxman Act
case, Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc.,
731 F.3d 1271 (Fed. Cir. 2013), under which, Amgen
argues, the district court here was required to assess
infringement based on the full range of processes that
would be consistent with Apotex’s applications. Apotex
does not challenge the importation of Sunovion’s analysis
into the BPCIA context, but it does dispute Sunovion’s
applicability to the facts of this case. We agree with
Apotex.
Sunovion involved an abbreviated new drug applica-
tion that, on its face, authorized the applicant to engage
in actions that would, in fact, infringe the patent in
question. Sunovion, 731 F.3d at 1274–75. The district
court had granted summary judgment of non-
infringement because the defendant had “certified” that it
did not actually intend to run its process in an infringing
manner and presented evidence of internal manufactur-
ing guidelines showing non-infringement. Id. This court
reversed, reasoning that internal guidelines and a certifi-
cation were insufficient to avoid a finding of infringement
when the application itself authorized the activity that
would infringe. Id. at 1280.
AMGEN INC. v. APOTEX INC. 13
Here, in contrast, the district court had a sufficient
basis for reading Apotex’s applications as not authorizing
processes that infringe, indeed, as constraining the pro-
cesses to non-infringing levels. The district court credited
the testimony of Dr. Dowd, based on the numbers in the
applications, that the maximum protein concentration
possible in the refold mixtures of Apotex’s applications is
0.708 g/L. J.A. 3618–20. Dr. Dowd arrived at this calcu-
lation using the high-end of the “key process parameter”
range for solubilized inclusion bodies, 11.8 mg/mL, and
the minimum 75 percent purity of the target protein (i.e.,
filgrastim or pegfilgrastim) specified by the applications.
Amgen argues that the key process parameters do not
prevent Apotex from infringing the ’138 patent because
they are not absolute limits. But the applications indicate
that close adherence to the key process parameters is
critical to the function of the process. J.A. 6725 (noting
that key process parameters must be “carefully controlled
within a narrow range and are essential for process
performance”); J.A. 6728 (identifying the 11.8 mg/ml
figure as a “qualified upper limit”). Consistent with this
description, Dr. Dowd testified at trial that Apotex needs
to maintain its process within the key process parameters
in order “for the batch to be acceptable,” and that, if those
ranges are exceeded, “the batch would be thrown out.”
J.A. 3622–23. The district court found this testimony
credible. J.A. 26. In light of the evidence, we see no basis
for deeming the district court’s finding as to the con-
straints in Apotex’s applications to be clearly erroneous.
At oral argument in this court, Amgen pointed to the
fact that Apotex’s applications contain a “dash” in the
“Acceptance Criterion” column of the solubilized inclusion
body concentration parameters. See J.A. 5595. Amgen
argued that the lack of an explicit acceptance criterion
means that there is effectively no upper bound for the
concentration of solubilized inclusion bodies—and there-
fore protein—that can be used in the process. But Amgen
14 AMGEN INC. v. APOTEX INC.
has given us no evidence to justify setting aside the
district court’s contrary reading of the applications. The
dash in Apotex’s applications is not on its face an affirma-
tive statement authorizing the infringing levels, contrary
to the other evidence recited above. And Amgen has
pointed us to no evidence that the dash would be under-
stood as such an authorization. In these circumstances,
the content of the applications does not bring this case
within Sunovion.
Even if we did not read the applications as affirma-
tively constraining the processes in the way at issue here,
the most that we could conclude about the applications is
that they are silent on the point. In such a case, this
court’s reasoning in Glaxo, Inc. v. Novopharm, Ltd., 110
F.3d 1562 (Fed. Cir. 1997), is applicable. In Glaxo, the
court looked to extrinsic evidence, such as the samples
and data submitted to the FDA, to resolve a question of
infringement left open by the abbreviated new drug
application. Id. at 1569. In this case, Apotex submitted
batch records of its actual manufacturing process to
resolve any question of infringement left open by Apotex’s
application. Between the two batch records submitted by
Apotex, the maximum protein concentration observed in
the process was roughly 0.56 g/L—even further from
infringing levels than the 0.708 g/L level derived from the
applications. J.A. 3645; J.A. 4512.
Amgen disputes the probative value of the batch rec-
ords, arguing that Apotex failed to provide batch records
for the other 89 times it has run the process. But it was
not Apotex’s burden to prove non-infringement. Glaxo,
110 F.3d at 1567. It was Amgen’s burden to prove that
Apotex’s processes would infringe the ’138 patent. Amgen
presents us with no challenge to a restriction on discovery
or an exclusion of evidence. In these circumstances, we
see no basis in the mere existence of other records for
disturbing the district court’s finding that Amgen failed to
provide adequate evidence to prove infringement.
AMGEN INC. v. APOTEX INC. 15
III
For the foregoing reasons, we affirm the judgment of
the district court.
AFFIRMED