Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-14-01184/USCOURTS-ca13-14-01184-0/pdf.json

Parties Involved:
Cadence Pharmaceuticals Inc.
Appellee
Exela Holdings Inc.
Appellant
Exela PharmSci Inc.
Appellant
Exela Pharma Sciences LLC
Appellant
SCR Pharmatop
Appellee

Document Text:

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, Chicago, IL, argued for all plaintiffs-appellees. Plaintiffappellee 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, Holland & Knight, LLP, New York, NY.

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JEFFREY STEPHEN WARD, Merchant & Gould PC, Madison, WI, argued for defendants-appellants. Also represented 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 construction 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 explains that in aqueous solutions, acetaminophen decomposes 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 

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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 essentially of acetaminophen dispersed in an aqueous 

medium containing a buffering agent and at least 

one member of the group consisting of a free radical scavenger and a radical antagonist.

The ’218 patent claims priority to a French application 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 brackets and the disputed terms highlighted): 

1. A method for preparing an aqueous solution

with an active [principle of phenolic] nature susceptible to oxidation, which is paracetamol, while 

preserving for a prolonged period, comprising deoxygenation 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 optionally the aforementioned aqueous solution with 

an active principle is topped with an inert gas atmosphere 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 optionally 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 

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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 certification 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 infringing 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 pursuant 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 appeals 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 obviousness, 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 

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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 determination of law, and [we] review that construction de novo.”) 

(quoting Teva, 135 S. Ct. at 841) (internal citations removed). 

“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. Scientific 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 

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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 definition 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 concentration’ 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 specification and cites applicants’ statements in the prosecution 

history. Cadence disputes Exela’s arguments and responds 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 limited 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.

 

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We agree with the district court that the plain and ordinary meaning of “buffering agent” is “an agent that 

helps the formulation resist change in pH.” We see nothing 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 discussed 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 district 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 infringement 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.

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C. The ’218 Patent

Exela argues first that the district court erred in holding that Exela’s process infringed the asserted claims of 

the ’218 patent under the doctrine of equivalents, contending that reducing the amount of dissolved oxygen to 

below 2 ppm before acetaminophen is added is substantially 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 challenges 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 solution” 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” required 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 deoxygenates a solvent and only then adds an active ingredient. 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 

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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 bubbling 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 conclusion is confirmed by the district court’s finding and Exela’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 responsible 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 argument that this scope of equivalents would vitiate a limitation 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. GameTech 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 winning combination.” 472 F.3d 1338, 1345 (Fed. Cir. 2006). 

Cadence responds that deoxygenating prior to adding the 

active ingredient is insubstantially different from deoxygenating after and that reference to “vitiation” is inappropriate. 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 “vitiates” a claim limitation is nothing more than a 

conclusion that the evidence is such that no reasonable jury could conclude that an element of an 

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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 otherwise 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 threshold 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 element is also a conclusion that should not be used to 

overlook the factual analysis required to establish whether 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 substantiality 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 

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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 conclude 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 infringement of these claims is also affirmed.

2. Claim Construction of the Vacuum Stoppering Step

The district court concluded that the phrase “optionally 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 ‘optionally’ 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 stoppering 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 disavowal 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 defendants stating: “defendants’ position is that the vacuum 

limitation is not optional, notwithstanding that it follows 

the ‘and optionally’ language phrase. I understand English language construction. And if it weren’t for the 

prosecution history, we wouldn’t be making this argument.”). 

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 limitation 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 unmistakable disavowal of the unambiguous recitation of the vacuum stoppering step as being optional. Exela contends 

that the vacuum stoppering step is mandatory, not optional, because applicants argued that step in distinguishing 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 “mandatory,” 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 subject 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 Obviousness 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 pertinent art”; and “[s]uch secondary considerations as commercial 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 Cadence 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 deoxygenating 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. 

 

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34, and the teaching of the Palmieri article that deoxygenating 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 “technical[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 committed 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 reducing dissolved oxygen to trace levels. Exela also contends 

that the district court’s findings as to secondary considerations 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 inapposite as it deals with compounds that degrade via a differCase: 14-1184 Document: 53-2 Page: 16 Filed: 03/23/2015
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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 initially 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 Examiner’s Reasons for Allowance), the Patent Office is “‘presumed 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 presumed to be valid, 35 U.S.C. § 282, so defendants must 

prove invalidity by clear and convincing evidence. Microsoft 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 primarily 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 specification that: “. . . in contrast to what has been reported in the 

literature, the breakdown of acetaminophen first involves 

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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 discussing Example II, testified that the experiments he performed 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 acetaminophen 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] primarily 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 effective 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 degradation 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 acetaminophen solution to below 2 ppm with a reasonable expectation 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 

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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 deoxygenated 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 BristolMyers 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

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