Cadence Pharmaceuticals Inc. v. Exela Pharma Sciences LLC ( 2015 )

United States Court of Appeals
for the Federal Circuit
______________________
CADENCE PHARMACEUTICALS INC.
SCR PHARMATOP,
Plaintiffs-Appellees
v.
EXELA PHARMSCI INC., EXELA HOLDINGS INC.,
EXELA PHARMA SCIENCES LLC,
Defendants-Appellants
______________________
2014-1184
______________________
Appeal from the United States District Court for the
District of Delaware in No. 1:11-cv-00733-LPS, Judge
Leonard P. Stark.
______________________
Decided: March 23, 2015
______________________
KENNETH G. SCHULER, Latham & Watkins LLP, Chi-
cago, IL, argued for all plaintiffs-appellees. Plaintiff-
appellee Cadence Pharmaceuticals Inc. also represented
by MARC NATHAN ZUBICK, EMILY C. MELVIN; STEPHEN P.
SWINTON, DARRYL HUGH STEENSMA, San Diego, CA;
RICHARD P. BRESS, GABRIEL BELL, Washington, DC;
PARKER TRESEMER, Costa Mesa, CA. Plaintiff-appellee
SCR Pharmatop represented by CHARLES A. WEISS, Hol-
land & Knight, LLP, New York, NY.
2 CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA
SCIENCES LLC
JEFFREY STEPHEN WARD, Merchant & Gould PC, Mad-
ison, WI, argued for defendants-appellants. Also repre-
sented by WENDY M. WARD; CLARENCE EDWARD POLK, JR.,
Polk & Chintapalli, PLLC, Ashburn, VA,; SATISH
CHANDRA CHINTAPALLI, Cary, NC.
______________________
Before REYNA, LINN, and WALLACH, Circuit Judges.
LINN, Circuit Judge.
In this Hatch-Waxman Act litigation, Exela PharmSci
Inc., Exela Holdings, Inc. and Exela Pharm Sciences, LLC
(collectively “Exela”) appeal the district court’s construc-
tion of certain claim terms of U.S. Patents No. 6,028,222
(the “’222 patent”) and No. 6,992,218 (the “’218 patent”),
Cadence Pharm., Inc. v. Paddock Labs. Inc., 886 F. Supp.
2d 445 (D. Del. 2012), and its rulings that Exela infringed
certain asserted claims of both patents and failed to prove
invalidity as to the ’218 patent. Cadence Pharm., Inc. v.
Exela Pharma Scis., LLC, No. 11-733-LPS, 2013 U.S.
Dist. LEXIS 166097 (D. Del. Nov. 14, 2013). For the
reasons set forth infra, we affirm.
I. BACKGROUND
A. The Patents-In-Suit
SCR Pharmatop and Cadence Pharmaceuticals, Inc.
(collectively “Cadence”) are the owner and exclusive
licensee, respectively, of the ’222 and ’218 patents. These
patents are directed to aqueous phenol formulations—
particularly acetaminophen (sometimes referred to as
“paracetamol”). ’222 patent abstract; ’218 patent abstract,
col.1 ll.32–33.
The ’222 patent issued on February 22, 2000. It ex-
plains that in aqueous solutions, acetaminophen decom-
poses into potentially toxic products. See ’222 patent col.1
ll.16–22, ll.45–48. The ’222 patent is directed at avoiding
this decomposition by adding a free-radical capturing
CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA 3
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agent and a buffer. Id. abstract. Claim 1 of the ’222
patent is the only independent claim, and recites (with
the disputed term highlighted):
1. A stable, liquid formulation consisting essen-
tially of acetaminophen dispersed in an aqueous
medium containing a buffering agent and at least
one member of the group consisting of a free radi-
cal scavenger and a radical antagonist.
The ’218 patent claims priority to a French applica-
tion filed on June 6, 2000. The ’218 patent discloses a
method for obtaining stable acetaminophen formulations
by deoxygenating solutions with an inert gas to achieve
oxygen concentrations below 2 parts-per-million
(“ppm”). ’218 patent abstract, col.1 ll.32–33. Claim 1 of
the ’218 patent is the only independent claim, and recites
(with the edits from the certificate of correction in brack-
ets and the disputed terms highlighted):
1. A method for preparing an aqueous solution
with an active [principle of phenolic] nature sus-
ceptible to oxidation, which is paracetamol, while
preserving for a prolonged period, comprising de-
oxygenation of the solution by bubbling with at
least one inert gas and/or placing under vacuum,
until the oxygen content is below 2 ppm, and op-
tionally the aforementioned aqueous solution with
an active principle is topped with an inert gas at-
mosphere heavier than air and placed in a closed
container in which the prevailing pressure is
65,000 Pa maximum, and the oxygen content of
the aqueous solution is below 2 ppm, and optional-
ly the deoxygenation of the solution is completed
by addition of an antioxidant.
B. History of the Dispute
Cadence Pharmaceuticals Inc. markets an injectable
acetaminophen product, which is approved by the Food
4 CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA
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and Drug Administration (“FDA”) and is distributed
under the name Ofirmev®. The FDA’s Approved Drug
Products with Therapeutic Equivalence Evaluations
(better known as the “Orange Book”) lists the ’222
and ’218 patents in connection with Ofirmev®.
Exela filed an Abbreviated New Drug Application
(“ANDA”) with the FDA, seeking approval of a generic
equivalent of Ofirmev®. The ANDA included a certifica-
tion pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) (2012)
(commonly referred to as a “Paragraph IV certification”)
stating that the ’222 and ’218 patents were invalid and
not infringed. In response, Cadence sued Exela for in-
fringing claims 1, 3, 4, 5, 9, 10, 12 and 16–18 of the ’222
patent and claims 1, 3, 4 and 19 of the ’218 patent pursu-
ant to 35 U.S.C. § 271(e)(2) (2012).
The district court found the ’222 patent not invalid
and literally infringed and the ’218 patent not invalid and
infringed under the doctrine of equivalents. Exela ap-
peals both of the district court’s infringement decisions
and its validity decision as to the ’218 patent. It does not
appeal the district court’s validity decision as to the ’222
patent. We have jurisdiction pursuant to 28 U.S.C.
§ 1295(a)(1) (2012).
II. DISCUSSION
A. Standard of Review
In reviewing questions of claim construction and obvi-
ousness, we review underlying factual determinations for
clear error and ultimate determinations de novo. Teva
Pharm. USA, Inc. v. Sandoz, Inc., 135 S. Ct. 831, 841
(2015) (claim construction); Allergan, Inc. v. Apotex Inc.,
754 F.3d 952, 961 (Fed. Cir. 2014) (citing Novo Nordisk
A/S v. Caraco Pharm. Labs., Ltd., 719 F.3d 1346, 1354
(Fed. Cir. 2013)) (obviousness). Because the district
court’s claim constructions were based solely on the
intrinsic record, the Supreme Court’s recent decision in
CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA 5
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Teva does not require us to review the district court’s
claim construction any differently than under the de novo
standard we have long applied. Fenner Invs., Ltd. v.
Cellco P’ship, --- F.3d ----, ----, available at 2015 WL
570730 (Fed. Cir. Feb. 12, 2015) (“When the district court
reviews only evidence intrinsic to the patent . . . , the
judge’s determination will amount solely to a determina-
tion of law, and [we] review that construction de novo.”)
(quoting Teva, 135 S. Ct. at 841) (internal citations re-
moved).
“Infringement, either literal or under the doctrine of
equivalents, is a question of fact that we review for clear
error when tried without a jury.” Ultra-Tex Surfaces, Inc.
v. Hill Bros. Chem. Co., 204 F.3d 1360, 1363 (Fed. Cir.
2000) (citing Insituform Techs., Inc. v. Cat Contracting,
Inc., 161 F.3d 688, 692 (Fed. Cir. 1998)). “A factual
finding is clearly erroneous if, despite some supporting
evidence, we are left with the definite and firm conviction
that a mistake has been made.” Ferring B.V. v. Watson
Labs., Inc.-Fla., 764 F.3d 1401, 1406 (Fed. Cir. 2014)
(citing United States v. U.S. Gypsum Co., 333 U.S. 364,
395 (1948) and Alza Corp. v. Mylan Labs., Inc., 464 F.3d
1286, 1289 (Fed. Cir. 2006)). Whether the doctrine of
equivalents would vitiate a claimed element is a question
of law that we review de novo. Cordis Corp. v. Bos. Scien-
tific Corp., 561 F.3d 1319, 1330 (Fed. Cir. 2009) (citing
Pfizer, Inc. v. Teva Pharm. USA, Inc., 429 F.3d 1364, 1379
(Fed. Cir. 2005)).
B. The ’222 Patent
1. Claim Construction
Exela’s appeal regarding the ’222 patent turns on
claim construction. “Claim terms are generally given
their plain and ordinary meanings to one of skill in the
art when read in the context of the specification and
prosecution history.” Golden Bridge Tech., Inc. v. Apple
Inc., 758 F.3d 1362, 1365 (Fed. Cir. 2014) (citing Phillips
6 CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA
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v. AWH Corp., 415 F.3d 1303, 1315–17 (Fed. Cir. 2005)
(en banc)). A patentee can act as his own lexicographer,
but, to do so, “‘a patentee must clearly set forth a defini-
tion of the disputed claim term other than its plain and
ordinary meaning’ and must ‘clearly express an intent to
redefine the term.’” Hill-Rom Servs., Inc. v. Stryker Corp.,
755 F.3d 1367, 1371 (Fed. Cir. 2014) (quoting Thorner v.
Sony Computer Entm’t Am. LLC, 669 F.3d 1362, 1365
(Fed. Cir. 2012)).
The district court construed the term “buffering
agent” in claim 1 to mean “[a]n agent that helps the
formulation resist change in pH.” Cadence, 886 F. Supp.
2d at 456. The court refused to construe the term to
require, as Exela urged, that the buffering agent be
present “in an effective concentration to resist material
changes in pH,” because “nothing in the patent limits the
scope of the claimed buffering agent to an ‘effective con-
centration’ or one that resists ‘material changes in pH.’”
Id. 1
On appeal, Exela continues to urge that a “buffering
agent must be present in a sufficient concentration to
prevent a material change in pH.” Op. Br. at 60. In
support, it points to embodiments described in the specifi-
cation and cites applicants’ statements in the prosecution
history. Cadence disputes Exela’s arguments and re-
sponds that the plain and ordinary meaning of “buffering
agent” does not include specific efficacy and concentration
limitations.
1 Exela also asserted that a “buffering agent” is lim-
ited to “a weak acid and its conjugate base[] or a weak
base and its conjugate acid.” See Cadence, 886 F. Supp.
2d at 456. It does not appeal the district court’s rejection
of this aspect of its proposed construction.
CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA 7
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We agree with the district court that the plain and or-
dinary meaning of “buffering agent” is “an agent that
helps the formulation resist change in pH.” We see noth-
ing in the intrinsic record to warrant adding requirements
of effective concentration or resistance to material change.
The statement in the specification that the concentration
of the buffer “may be” between 0.1 and 10 mg/ml is not
limiting, because even if “all of the embodiments dis-
cussed in the patent” included a specific limitation, it
would not be “proper to import from the patent’s written
description limitations that are not found in the claims
themselves.” Flo Healthcare Solutions, LLC v. Kappos,
697 F.3d 1367, 1375 (Fed. Cir. 2012) (citing Silicon
Graphics, Inc. v. ATI Techs., Inc., 607 F.3d 784, 792 (Fed.
Cir. 2010)). Moreover, the fact that during prosecution
applicants added the term “buffering agent” in response
to a rejection does not show that the phrase requires a
minimum concentration or resistance to material change.
The addition of that phrase shows only that a buffering
agent is necessary.
For the foregoing reasons, we conclude that the dis-
trict court correctly construed the term “buffering agent”
simply as “an agent that helps the formulation resist
change in pH.”
2. Infringement
Exela’s appeal of the district court’s finding of in-
fringement of the ’222 patent is based on its proposed
claim construction, which we have now rejected. Because
the district court’s finding that the sodium ascorbate
present in Exela’s formulation as an antioxidant met the
buffering agent limitation, as correctly construed, we
affirm the district court’s finding that claim 1 is infringed.
As Exela does not assert independent non-infringement
bases for dependent claims 3–5, 9, 10, 12 and 16–18, we
also affirm the district court’s finding of infringement of
these claims.
8 CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA
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C. The ’218 Patent
Exela argues first that the district court erred in hold-
ing that Exela’s process infringed the asserted claims of
the ’218 patent under the doctrine of equivalents, con-
tending that reducing the amount of dissolved oxygen to
below 2 ppm before acetaminophen is added is substan-
tially different from reducing the dissolved oxygen content
after acetaminophen is added. Exela next argues that the
district court erred in finding infringement based on its
construction of the so-called “vacuum stoppering step” of
claim 1 as being merely optional. Finally, Exela challeng-
es the district court’s finding that Exela failed to show by
clear and convincing evidence that the asserted claims of
the ’218 patent were obvious. We address each of these
arguments in turn.
1. Infringement Under the Doctrine of Equivalents
The district court construed the terms “aqueous solu-
tion” and “solution” in claim 1 of the ’218 patent as “[a]
composition containing water as a solvent and an active
ingredient susceptible to oxidation.” Cadence, 886 F.
Supp. 2d at 459. The district court thus concluded that
the claimed step of “deoxygenation of the solution” re-
quired that an active ingredient already be dissolved. In
other words, the district court interpreted the claim to
directly cover only the method of first dissolving an active
ingredient to form a solution and then deoxygenating the
solution. Exela’s accused process, by contrast, first deox-
ygenates a solvent and only then adds an active ingredi-
ent. Accordingly, the district court found that Exela did
not literally infringe claim 1. See Cadence, 2013 U.S.
Dist. LEXIS 166097, at *63–64.
Nevertheless, the district court found that Exela’s
ANDA formulation infringed claim 1 under the doctrine of
equivalents. See id. at *64. It found that the timing of
the addition of the active ingredient did not matter and
CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA 9
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ruled that the differences between the claimed steps and
Exela’s method were insubstantial. See id. at *64–66.
Exela argues that the district court clearly erred in
finding that there was no substantial difference between
deoxygenating before or after forming the solution. Exela
contends that Cadence’s expert’s testimony on this point
was conclusory and improperly compared Exela’s process,
which did not involve stoppering under vacuum, with a
process that did. Cadence disputes that there was clear
error and contends that its expert’s testimony supports
the district court’s decision as does the fact that Exela’s
formulation achieves similar stability to the formulation
described in the ’218 patent.
We agree with Cadence and find no clear error in the
district court’s finding of infringement under the doctrine
of equivalents. The district court relied on the testimony
of Cadence’s expert, Dr. Orr, “that adding acetaminophen
before or after the deoxygenation step would have no
impact on the stability of the final product.” Id. at *65.
Dr. Orr explained that this was so because “in both cases
you’re trying to deoxygenate your solution. In both cases,
you’re employing bubbling to do that. And the results
that you achieve under this prolonged period of—of bub-
bling is still a solution of less than two parts per million.”
This testimony supports the district court’s finding that
changing the timing of the deoxygenation step was an
insubstantial difference. The correctness of this conclu-
sion is confirmed by the district court’s finding and Exe-
la’s accession that its formulation is, in fact, stable. See
id. Exela’s speculation that other differences between its
formulation and the claimed formulation may be respon-
sible for stability is insufficient to create a definite and
firm conviction that the district court made a mistake.
The district court also did not accept Exela’s argu-
ment that this scope of equivalents would vitiate a limita-
tion of the claim. See Cadence, 2013 U.S. Dist. LEXIS
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166097, at *66–67. Exela challenges that determination
and contends that deoxygenating after adding the active
ingredient is the “antithesis” of deoxygenating before
adding the active ingredient and that because such a
substitution would “vitiate” the claimed limitation, there
can be no finding of equivalence. It maintains that the
facts here are analogous to Planet Bingo, LLC v. Gam-
eTech International, Inc., where we held that determining
a winning combination after a game started could not be
equivalent to a claim that recited “a predetermined win-
ning combination.” 472 F.3d 1338, 1345 (Fed. Cir. 2006).
Cadence responds that deoxygenating prior to adding the
active ingredient is insubstantially different from deoxy-
genating after and that reference to “vitiation” is inappro-
priate. According to Cadence, the finding of vitiation in
Planet Bingo was premised on the fact that the difference
in timing was substantial.
Exela’s reliance on Planet Bingo is misplaced. Planet
Bingo’s holding was based on a finding that a combination
determined before a game was substantially different,
factually, from a combination determined after the game
started. See Brilliant Instruments, Inc. v. GuideTech,
LLC, 707 F.3d 1342, 1347 (Fed. Cir. 2013) (explaining the
rationale for Planet Bingo as “two elements likely are not
insubstantially different when they are polar opposites”);
Deere & Co. v. Bush Hog, LLC, 703 F.3d 1349, 1356 (Fed.
Cir. 2012) (same). Exela’s understanding of Planet Bingo
(Fed. Cir. Dec. 13, 2006) is also expressly at odds with this
court’s holding in DePuy Spine, Inc. v. Medtronic Sofamor
Danek, Inc., 469 F.3d 1005 (Fed. Cir. Nov. 20, 2006),
decided just a few weeks before Planet Bingo. DePuy
Spine explained:
A holding that the doctrine of equivalents cannot
be applied to an accused device because it “viti-
ates” a claim limitation is nothing more than a
conclusion that the evidence is such that no rea-
sonable jury could conclude that an element of an
CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA 11
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accused device is equivalent to an element called
for in the claim, or that the theory of equivalence
to support the conclusion of infringement other-
wise lacks legal sufficiency.
469 F.3d at 1018–19, cited with approval in Voda v.
Cordis Corp., 536 F.3d 1311, 1325 n.5 (Fed. Cir. 2008);
U.S. Philips Corp. v. Iwasaki Elec. Co. Ltd., 505 F.3d
1371, 1378–79 (Fed. Cir. 2007) and Abbott Labs. v. Andrx
Pharm., Inc., 473 F.3d 1196, 1212 (Fed. Cir. 2007).
Exela fundamentally misunderstands the doctrine of
claim vitiation. “Vitiation” is not an exception or thresh-
old determination that forecloses resort to the doctrine of
equivalents, but is instead a legal conclusion of a lack of
equivalence based on the evidence presented and the
theory of equivalence asserted. We have repeatedly
reaffirmed this proposition. See VirnetX, Inc. v. Cisco
Sys., Inc., 767 F.3d 1308, 1323 (Fed. Cir. 2014); Ring &
Pinion Serv. Inc. v. ARB Corp. Ltd., 743 F.3d 831, 836
(Fed. Cir. 2014); Charles Mach. Works, Inc. v. Vermeer
Mfg. Co., 723 F.3d 1376, 1380 (Fed. Cir. 2013); Brilliant
Instruments, 707 F.3d at 1347; Bush Hog, 703 F.3d at
1356; Voda, 536 F.3d at 1325 n.5; U.S. Philips Corp., 505
F.3d at 1378–79; Abbott Labs, 473 F.3d at 1212; DePuy
Spine, 469 F.3d at 1018–19. Characterizing an element of
an accused product as the “antithesis” of a claimed ele-
ment is also a conclusion that should not be used to
overlook the factual analysis required to establish wheth-
er the differences between a claimed limitation and an
accused structure or step are substantial vel non. The
determination of equivalence depends not on labels like
“vitiation” and “antithesis” but on the proper assessment
of the language of the claimed limitation and the substan-
tiality of whatever relevant differences may exist in the
accused structure. See Graver Tank & Mfg. Co. v. Linde
Air Prods. Co., 339 U.S. 605, 610–12 (1950) (finding that a
welding process that used manganese, a non-alkaline
metal, could be equivalent to the claimed “alkaline earth
12 CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA
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metal,” even though an alkaline metal can formally be
described as the “antithesis” of a non-alkaline metal). But
see Moore U.S.A., Inc. v. Standard Register Co., 229 F.3d
1091, 1106 (Fed. Cir. 2000) (“it would defy logic to con-
clude that a minority—the very antithesis of a majority—
could be insubstantially different from a claim limitation
requiring a majority, and no reasonable juror could find
otherwise”).
Since a reasonable trier of fact could (and, in fact, did)
conclude that Exela’s process is insubstantially different
from that recited in the claims, the argument that a claim
limitation is vitiated by the district court’s application of
the doctrine of equivalents is both incorrect and inapt.
Therefore, we affirm the district court’s determination of
infringement of claim 1. Because Exela does not assert
any independent bases for not infringing dependent
claims 3, 4 and 19, the district court’s finding of infringe-
ment of these claims is also affirmed.
2. Claim Construction of the Vacuum Stoppering Step
The district court concluded that the phrase “optional-
ly topped with an inert gas . . . and placed in a closed
container in which the prevailing pressure is 65,000 Pa
maximum” (the “vacuum stoppering step”) indicates that
the vacuum stoppering step is optional, because “[t]he
language of claim 1 plainly indicates that the word ‘op-
tionally’ applies to both the first and second clauses,
which are connected by the word ‘and.’” Cadence, 886 F.
Supp. 2d at 464. According to the district court, whatever
statements were made during prosecution “do not rise to
the level of an explicit disclaimer.” Id. at 464–65.
On appeal, Exela contends that the vacuum stopper-
ing step is mandatory, relying on the language of the
claim, the specification and the prosecution history.
Cadence responds that the plain language of the claim
unambiguously recites that the vacuum stoppering step is
optional and that Exela waived any argument to the
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contrary. Cadence also argues that the prosecution
history does not contain a clear and unmistakable disa-
vowal of claim scope.
We conclude, as did the district court, that the step of
stoppering under vacuum is optional. The plain and
ordinary meaning of “optionally . . . topped . . . and
placed” is that both the topping and placing steps are
optional. Indeed, defendants appear to have originally
conceded this point. See J.A. 10379 (counsel for defend-
ants stating: “defendants’ position is that the vacuum
limitation is not optional, notwithstanding that it follows
the ‘and optionally’ language phrase. I understand Eng-
lish language construction. And if it weren’t for the
prosecution history, we wouldn’t be making this argu-
ment.”).
The conclusion that vacuum stoppering is optional is
supported by the specification, which does not describe
vacuum stoppering as one of “the four parameters that
have to be taken into consideration as essential for
preservation.” ’218 patent col.6 ll.29–30. Indeed, the
specification contains examples that exhibit prolonged
stability even without vacuum stoppering. Id. col.7 ll.1-
18. While some examples may work better than others,
the specification’s observation that stoppering under
vacuum “constitutes a distinct advantage,” id. col.5 ll.9–
10, cannot be read to imply that the invention is limited
to such embodiments. Cf. Plantronics, Inc. v. Aliph, Inc.,
724 F.3d 1343, 1350 (Fed. Cir. 2013) (“‘The patentee is
entitled to the full scope of his claims, and we will not
limit him to his preferred embodiment or import a limita-
tion from the specification into the claims.’”) (quoting
Kara Tech. Inc. v. Stamps.com Inc., 582 F.3d 1341, 1348
(Fed. Cir. 2009)).
As for the prosecution history, the district court found
insufficient reason to depart from the unambiguous plain
and ordinary meaning of the claims themselves in reciting
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the vacuum stoppering step as optional. We agree. We
are not persuaded that the portions of the prosecution
history cited by Exela amount to a clear and unmistaka-
ble disavowal of the unambiguous recitation of the vacu-
um stoppering step as being optional. Exela contends
that the vacuum stoppering step is mandatory, not op-
tional, because applicants argued that step in distinguish-
ing the prior art during prosecution. While the vacuum
stoppering step was mentioned in applicants’ argument,
the only factor in the reference that applicants noted in
comparing the reference to the claims was the degree to
which the level of oxygen was reduced. Specifically,
applicants described the oxygen level of the reference by
noting that “[t]he residual oxygen concentration present
in the solution after bubbling of the nitrogen is on the
order of 2 ppm . . . and this is not a satisfactory order.”
U.S. Pat. App. No. 10/332,060 Remarks of Mar. 18, 2005,
at 8 (emphasis added). Applicants then argued that “[i]n
contrast thereto, Applicants’ bubbling with nitrogen is
reduced to below 2 ppm.” Id. (emphasis added). Granted
that applicants also noted the vacuum stoppering step as
a factor in providing a stable solution, but there is no
clear indication that the vacuum stoppering step was the
“contrast” that applicants were trying to make over the
cited reference. And certainly no indication that the
vacuum stoppering step should be understood as “manda-
tory,” despite the clear language of the claim. At bottom,
the language of claim 1 is unambiguous that the vacuum
stoppering step is optional, and the prosecution history
does not reflect a clear and unmistakable disavowal of the
plain and ordinary meaning of that language.
Accordingly, we conclude that in claim 1 of the ’218
patent, the vacuum stoppering step is optional and not
mandatory. We thus affirm the district court’s finding of
infringement and need not address Cadence’s alternate
ground for affirmance based on its asserted construction
of the term “aqueous solution.”
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3. Obviousness
A patent is invalid “if the differences between the sub-
ject matter sought to be patented 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 to which said subject
matter pertains.” 35 U.S.C. § 103(a) (2006). 2 Obvious-
ness is a question of law, based on underlying factual
determinations including: “the scope and content of the
prior art”; “differences between the prior art and the
claims at issue”; “the level of ordinary skill in the perti-
nent art”; and “[s]uch secondary considerations as com-
mercial success, long felt but unsolved needs, failure of
others, etc.” Graham v. John Deere Co., 383 U.S. 1, 17
(1966).
At the district court, Exela contended that the ’218
patent was obvious over the ’222 patent in view of A.
Palmieri, Effect of Dissolved Oxygen Levels on Oxidative
Degradation of Pyrogallol, 67 J. Pharm. Sci. 1338 (Sept.
1978) (the “Palmieri article”). Exela claimed, and Ca-
dence did not dispute, that the only difference between
the asserted claims of the ’218 patent and the disclosure
of the ’222 patent is that the ’222 patent did not disclose
decreasing the oxygen content to below 2 ppm (as recited
in claim 1) or even lower levels (as recited in certain
dependent claims). Cadence, 2013 U.S. Dist. LEXIS
166097, at *99–100, 101 n.30. Exela argued that deoxy-
genating below 2 ppm would have been obvious based on
the disclosure of the ’222 patent that the stability of
acetaminophen solutions depends, inter alia, on “removal
of oxygen dissolved in the carrier,” ’222 patent col.2 ll.33–
2 Because the application that led to the ’218 patent
was filed prior to March 16, 2013, the America Invents
Act’s (“AIA”) amendments to § 103 do not apply. See
§ 3(n)(1) of the AIA, Pub. L. No. 112-29.
16 CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA
SCIENCES LLC
34, and the teaching of the Palmieri article that deoxy-
genating pyrogallol solutions to below 0.05 ppm leads to
increased stability.
The district court found that it would not have been
obvious to combine the Palmieri article with the ’222
patent, because pyrogallol degrades by oxidation while
acetaminophen degrades primarily by hydrolysis and
because deoxygenation to levels below 2 ppm was “tech-
nical[ly] difficult[].” Id. at *105. The district court also
addressed secondary considerations, which it found to
support a conclusion of non-obviousness. See id. at *111.
According to the district court, Ofirmev®—which the
district court found to be made by a process equivalent to
that claimed in the ’218 patent—fulfilled a long-felt need,
was a commercial success, was licensed and was praised
in the industry. See id. at *92–99. The court also found
that the ’218 patent exhibited unexpected results as to
stability as compared to the ’222 patent. See id. at *109–
11.
On appeal, Exela argues that the district court com-
mitted clear error in failing to recognize that the ’222
patent’s Example II suggests that hydrolysis is not the
primary degradation pathway and in failing to recognize
that the Palmieri article teaches the importance of reduc-
ing dissolved oxygen to trace levels. Exela also contends
that the district court’s findings as to secondary consider-
ations relating to Cadence’s distribution of Ofirmev® are
not probative of non-obviousness because the claims of
the ’218 patent recite deoxygenating after the addition of
an active ingredient whereas in Ofirmev® the solvent is
deoxygenated before. It also claims that any secondary
considerations lack a nexus to the novel features of
the ’218 patent. Finally, it contends that the unexpected
results are only a matter of degree.
Cadence responds that the Palmieri article is inappo-
site as it deals with compounds that degrade via a differ-
CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA 17
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ent mechanism and that Exela failed to prove that skilled
practitioners would have been motivated to combine
the ’222 patent with the Palmieri article. According to
Cadence, the secondary considerations further support a
finding of non-obviousness.
Exela bears a difficult burden in this case on the
question of obviousness. First, since the Examiner initial-
ly rejected the claims of the ’218 patent for essentially the
same reasons as defendants now raise, see Cadence, 2013
U.S. Dist. LEXIS 166097, at *100 n.29 (quoting the Exam-
iner’s Reasons for Allowance), the Patent Office is “‘pre-
sumed to have properly done its job’” when it ultimately
allowed the ’218 patent. PowerOasis, Inc. v. T-Mobile
USA, Inc., 522 F.3d 1299, 1304 (Fed. Cir. 2008) (quoting
Am. Hoist & Derrick Co. v. Sowa & Sons, Inc., 725 F.2d
1350, 1360 (Fed. Cir. 1984)). Second, patents are pre-
sumed to be valid, 35 U.S.C. § 282, so defendants must
prove invalidity by clear and convincing evidence. Mi-
crosoft Corp. v. i4i Ltd. P’ship, 131 S. Ct. 2238, 2242
(2011). Third, we will only overturn the district court’s
underlying factual determinations if we believe they are
clearly erroneous.
Exela has not met its burden. The district court found
the teachings of the ’222 patent and the cited Palmieri
article lacking, as do we. The district court found that
skilled artisans understood acetaminophen to be primari-
ly degraded via hydrolysis. Cadence, 2013 U.S. Dist.
LEXIS 166097, at *104 (crediting Kenneth A. Connors et
al., Chemical Stability of Pharmaceuticals 18–19 (1979)
and the testimony of Dr. Elder). Exela argues that the
district court was wrong in failing to appreciate that
the ’222 patent discloses that acetaminophen is in fact
subject to oxidation, followed by hydrolysis. It points
specifically to the hypothesis in the ’222 patent specifica-
tion that: “. . . in contrast to what has been reported in the
literature, the breakdown of acetaminophen first involves
18 CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA
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an ox[i]dative process followed by hydrolysis,” ’222 patent
col.10 ll.41–45.
The district court correctly rejected Exela’s argument.
At trial, one of the inventors, Francois Dietlin, in discuss-
ing Example II, testified that the experiments he per-
formed confirmed that degradation of acetaminophen
resulted from hydrolysis, followed thereafter by oxidation.
Moreover, Cadence’s expert, Dr. Edmond Elder, testified
that the primary degradation mechanism in acetamino-
phen is hydrolysis. This is consistent with the discussion
of the prior art in the ’222 patent that notes the reason
“paracetamol in aqueous solution is unstable [is] primari-
ly correlate[d] with hydrolysis.” Id. at col.1 ll.30–31.
Finally, we note that Dr. Palmieri, testifying as Exela’s
expert, admitted that deoxygenation would not be effec-
tive to prevent hydrolytic degradation. See Cadence, 2013
U.S. Dist. LEXIS 166097, at *104.
The district court thus was correct in concluding that
it would not have been obvious to combine the Palmieri
article with the ’222 patent, because the Palmieri article
addressed the degradation of pyrogallol—which degrades
primarily by oxidation—and did not address the degrada-
tion of acetaminophen—which, as noted above—degrades
primarily by hydrolysis. At bottom, we agree with the
district court that Exela has not proven by clear and
convincing evidence that a person of ordinary skill in the
art would have attempted to deoxygenate an acetamino-
phen solution to below 2 ppm with a reasonable expecta-
tion of “preserving [the acetaminophen] for a prolonged
period,” as recited in claim 1.
Regarding secondary considerations, we agree with
the district court that secondary considerations related to
the marketing of Ofirmev® are not per se irrelevant to the
non-obviousness of the claims of the ’218 patent, despite
the fact that the claims do not literally cover Ofirmev®.
As discussed above, supra at p. 9, whether a solvent is
CADENCE PHARMACEUTICALS INC. v. EXELA PHARMA 19
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deoxygenated before or after the active ingredient has
been dissolved is an insubstantial difference. Thus, there
is no reason to believe that any secondary considerations
attendant to Ofirmev®, in which the solvent is deoxygen-
ated prior to the addition of the active ingredient, would
not also be present in formulations literally covered by
the claims, i.e., where the solvent is deoxygenated after
the addition of active ingredient.
The district court also did not clearly err in finding
that the process claimed in the ’218 patent achieved
unexpected stability relative to that disclosed in the ’222
patent and in finding that the licensing of the ’218 patent
is probative of non-obviousness. Formulations made
pursuant to the methods described in the ’218 patent were
stable for two years, ’218 patent col.8 ll.11–17, whereas
plaintiff’s expert testified that the formulation taught in
the ’222 patent only achieved several months’ stability.
Even if these results were only somewhat unexpected,
they are still evidence of non-obviousness, albeit less so
than if the results were vastly unexpected. See Bristol-
Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967,
977 (Fed. Cir. 2014) (citing cases). That the ’218 patent
was separately licensed, see Cadence, 2013 U.S. Dist.
LEXIS 166097, at *5–6, is also evidence of a belief that
the ’218 patent was valid.
Based on the foregoing, we conclude that Exela has
not proven that the asserted claims of the ’218 patent are
obvious.
III. CONCLUSION
For the foregoing reasons, we affirm the district
court’s determination that the ’222 and ’218 patents are
infringed and its determination that the ’218 patent has
not been shown to be invalid.
AFFIRMED