Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-16-01259/USCOURTS-ca13-16-01259-0/pdf.json

Parties Involved:
Cumberland Pharmaceuticals Inc.
Appellee
Mylan Inc.
Appellant
Mylan Institutional LLC
Appellant

Document Text:

United States Court of Appeals 

for the Federal Circuit ______________________ 

CUMBERLAND PHARMACEUTICALS INC.,

Plaintiff-Appellee

v.

MYLAN INSTITUTIONAL LLC, MYLAN INC.,

Defendants-Appellants

______________________ 

2016-1155, 2016-1259

______________________ 

Appeals from the United States District Court for the 

Northern District of Illinois in No. 1:12-cv-03846, Judge 

Rebecca R. Pallmeyer.

______________________ 

Decided: January 26, 2017

______________________ 

LAURA POLLARD MASUROVSKY, Finnegan, Henderson, 

Farabow, Garrett & Dunner, LLP, Washington, DC, 

argued for plaintiff-appellee. Also represented by 

DANIELLE ANDREA DUSZCZYSZYN, MARK J. FELDSTEIN, 

JASON LEE ROMRELL. 

NICOLE W. STAFFORD, Wilson, Sonsini, Goodrich & 

Rosati, PC, Austin, TX, argued for defendants-appellants. 

Also represented by ROBERT DELAFIELD; ADAM WILLIAM 

BURROWBRIDGE, Washington, DC; ELHAM FIROUZI 

STEINER, San Diego, CA; NANCY L. ZHANG, Palo Alto, CA.

______________________ 

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Before MOORE, REYNA, and TARANTO, Circuit Judges.

TARANTO, Circuit Judge. 

Cumberland Pharmaceuticals, Inc. owns U.S. Patent 

No. 8,399,445, which describes and claims acetylcysteine 

compositions substantially free of chelating agents. It is 

listed in the Food and Drug Administration’s Approved 

Drug Products with Therapeutic Equivalence Evaluations

(the Orange Book) as covering Cumberland’s chelatingagent-free formulation of Acetadote®, an intravenous 

antidote for overdoses of acetaminophen. When Mylan 

Institutional LLC filed an abbreviated new drug application to market its own chelating-agent-free acetylcysteine

formulation, Cumberland brought this patentinfringement action in the Northern District of Illinois

against Mylan Institutional LLC and Mylan Inc. (hereafter “Mylan,” individually or jointly). Mylan stipulated to 

infringement but asserted invalidity on two grounds: 

derivation of the claimed invention from someone at the 

FDA and obviousness. The district court rejected both 

challenges after a bench trial. In particular, the court 

found that Mylan proved neither (1) that anyone at the 

FDA conceived of the claimed invention before the patentnamed inventor nor (2) that there was a reasonable 

expectation that the claimed formulations, without any 

chelating agents, would succeed. Cumberland Pharm., 

Inc. v. Mylan Institutional LLC, 137 F. Supp. 3d 1108, 

1121–22, 1127 (N.D. Ill. 2015). We affirm. 

I 

A 

At the priority date relevant here (August 24, 2005), 

acetylcysteine was known in the art as an antidote for 

acetaminophen overdoses. ’445 patent, col. 1, lines 20–34. 

It also was known to have a stability problem: heavy 

metal ions, whether inherent in the formulation or found 

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as contaminants, catalyze the oxidation of acetylcysteine 

in solution, causing it to degrade. Id., col. 1, lines 39–40; 

see Cumberland, 137 F. Supp. 3d at 1112 n.2. A prior-art 

response to the stability problem was to include edetate 

disodium (EDTA or edetate) in an acetylcysteine formulation. ’445 patent, col. 1, line 45, through col. 2, line 4.

EDTA, a chelating agent, surrounds and binds to heavy 

metal ions, preventing them from acting as catalysts that 

oxidize acetylcysteine. Id. Such EDTA-containing formulations of acetylcysteine were considered safe, despite 

potential negative side effects. Id., col. 2, lines 14–27. 

Cumberland’s ’445 patent declares: “It has been surprisingly found that an aqueous composition containing 

acetylcysteine, sterilized water, and a pH-adjusting agent, 

is stable without the addition of a chelating agent.” Id., 

col. 2, lines 48–50. The patent claims such compositions. 

Every claim in the patent requires a “stable” composition 

that is “free of chelating agents,” id., col. 9, line 16, 

through col. 10, line 53, and the district court construed 

the term to mean “[l]acking one or more chelating agents,” 

Cumberland, 137 F. Supp. 3d at 1112.

B 

The facts central to the dispute over the ’445 patent’s 

validity date from 2002, when the FDA was considering 

Cumberland’s application for permission to market the 

original EDTA-containing formulation of Acetadote®, a 

formulation previously approved in other countries. On 

December 10, 2002, the FDA sent Cumberland a letter, in 

which the FDA gave Cumberland the following instructions (among others): “[2c.] Provide scientific and regulatory justification for the inclusion of Edetate as a 

component in the drug product. In addition, provide a 

description of the pharmacological properties for Edetate 

in this drug product.” J.A. 12837. Six days later, representatives of the FDA and Cumberland spoke by telephone. Notes of the call state: “Regarding item 2(c), the 

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Division explained that data should be provided to support any justification for the inclusion of Edetate, since a 

non-trivial amount is included in the formulation.” J.A. 

12899.

On December 20, 2002, Cumberland formally responded to the FDA in a letter written by Leo Pavliv, who 

was the Cumberland official responsible for Acetadote®

and who is the named inventor on the ’445 patent.1 The 

letter explained that EDTA was included to stabilize the 

formulation and stated: “If no or lower concentrations of 

edetate are capable of ensuring product stability, lowering 

or removing edetate would raise questions of how the 

safety and efficacy of the product would be effected.” J.A. 

14783. Mr. Pavliv ultimately testified at trial that, shortly after writing this letter, he had the idea of testing the 

stability of an acetylcysteine formulation without EDTA.

On March 5, 2003, Cumberland asked the FDA to 

schedule a call for further discussion of its December 20, 

2002 response. With respect to question 2c, Cumberland

proposed to discuss the following: “Cumberland believes 

the use of Edetate as a component in the drug product is 

justified both from a scientific as well as a regulatory 

point of view. Does FDA agree?” J.A. 11343. There is no 

written record of the occurrence or content of the requested call. At trial, however, Mr. Pavliv testified that the 

call took place; that FDA representatives indicated on the 

call that they were not prepared to say whether they 

considered EDTA’s inclusion justified; and that Mr. Pavliv 

then stated his idea to perform a stability study. Accord-

 

1 Although the letter is signed by Amy Rock of 

Cumberland’s department of regulatory affairs, both Mr. 

Pavliv and Dr. Rock testified that it was Mr. Pavliv who 

drafted the December 20th response and Cumberland’s 

Acetadote® correspondence to the FDA more generally. 

See Cumberland, 137 F. Supp. 3d at 1114 n.3.

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ing to Mr. Pavliv, at least one FDA representative on the 

call approved of his idea to do a study and asked him to 

put the proposal in writing.

Cumberland did so in a July 21, 2003 letter, stating: 

“As requested by FDA, upon product approval [i.e., upon 

FDA approval of the EDTA-containing formulation], 

Cumberland Pharmaceuticals intends to initiate studies 

to determine the impact on product stability of both 

decreasing and completely removing edetate disodium 

from the formulation.” J.A. 14916. The FDA issued its 

Chemistry Review of the EDTA-containing formulation on 

January 9, 2004. That document states: “The sponsor 

reported that, as requested by the FDA upon drug approval, an independent study will be initiated to determine the impact on drug product stability of both 

decreasing and completely removing the amount of edetate sodium.” J.A. 12968; see id. at 12969 (referring twice 

more to Cumberland’s commitment to a post-approval 

study). The FDA approved the EDTA-containing product

on January 23, 2004, J.A. 11334–37, with the approval 

letter reminding Cumberland of its commitment to “evaluate the potential benefit of Edetate disodium on the 

stability of the drug product,” the study to “include a 

comparison of the current concentration of Edetate to a 

formulation with a lower concentration and no concentration of Edetate.” Id. at 11336. 

Cumberland then arranged by contract for testing to 

be done by Bioniche Pharma Group, “Mylan’s predecessor 

company.” Cumberland, 137 F. Supp. 3d at 1116. The 

protocol, proposed by Mr. Pavliv and approved by the 

FDA without change, included testing a formulation that 

turned out to be the claimed invention, i.e., a formulation 

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containing neither EDTA nor any other chelating agent.2 

On November 18, 2004, three months into the study, 

Mr. Pavliv received encouraging stability data. On August 24, 2005, having received further encouraging stability data (for a longer period), Cumberland filed its 

application for what became U.S. Patent No. 8,148,356, 

the parent of the ’445 patent at issue here. 

Cumberland gave the FDA the final results of the stability study, containing data for thirty-six months, on 

August 13, 2008. It then set about securing approval to 

market an EDTA-free version of Acetadote®. The FDA

approved that product in January 2011. 

C 

On December 19, 2011, Mylan filed an abbreviated 

new drug application seeking permission to market a 

generic version of Cumberland’s EDTA-free acetylcysteine 

product. Shortly thereafter, on February 27, 2012, Cumberland filed the divisional application that became the 

’445 patent. When the ’356 patent issued on April 3, 

2012, Mylan sent Cumberland a certification pursuant to 

21 U.S.C. § 355(j)(2)(A)(vii)(IV) that the ’356 patent was 

either invalid or not infringed by Mylan’s proposed product. 

On May 17, 2012, Cumberland sued Mylan for infringement of the ’356 patent pursuant to 35 U.S.C. 

§ 271(e)(2)(A). The ’445 patent issued on March 19, 2013, 

and Cumberland then amended its complaint to add 

allegations of infringement of the ’445 patent. On August 

4, 2014, Mylan stipulated to infringement of claims 1–14 

of the ’445 patent should they be held valid and enforcea-

 

2 Although several patent claims are at issue in this 

case, the issues have been litigated in such a way as to 

make it appropriate to use the singular “invention.”

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ble. Cumberland withdrew its claims regarding the ’356 

patent on September 28, 2014.

At the bench trial, Mylan argued that (1) the ’445 patent had been derived from someone at the FDA, on the 

theory that it was someone at the FDA, not Mr. Pavliv, 

who first had the idea to remove EDTA from the prior-art 

formulation, and (2) the invention would have been obvious in light of certain prior-art communications from the 

FDA. The district court held that (1) Mylan had not 

proved that anyone at the FDA conceived of the invention 

before Cumberland’s inventor did, Cumberland, 137 F. 

Supp. 3d at 1121–22, and (2) there was no reasonable 

expectation that a formulation without any chelating 

agents would be successful, given the prevailing skilledartisan view that chelating agents were necessary to 

prevent degradation of acetylcysteine, id. at 1127. The 

court entered a final judgment of validity and infringement on November 17, 2015. We have jurisdiction under

28 U.S.C. § 1295(a)(1).

II 

“While the ultimate question of whether a patentee 

derived an invention from another is one of fact, the 

determination of whether there was a prior conception is 

a question of law, which is based upon subsidiary factual 

findings.” Price v. Symsek, 988 F.2d 1187, 1190 (Fed. Cir. 

1993) (citations omitted). Obviousness is a question of 

law based on underlying questions of fact. Allergan, Inc. 

v. Sandoz Inc., 726 F.3d 1286, 1290 (Fed. Cir. 2013). We

review the district court’s conclusions of law de novo and 

its findings of fact for clear error. Id.

A 

Mylan’s derivation challenge invokes the rule that an 

applicant is not entitled to a patent if “he did not himself 

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invent the subject matter sought to be patented.” 35 

U.S.C. § 102(f) (2006).3 More specifically, it invokes the 

familiar requirement that a challenger asserting this 

ground show that there was a “prior conception of the 

claimed subject matter and communication of the conception” to the named inventor. Price, 988 F.2d at 1190; see 

Creative Compounds, LLC v. Starmark Labs., 651 F.3d 

1303, 1313 (Fed. Cir. 2011); Eaton Corp. v. Rockwell Int’l 

Corp., 323 F.3d 1332, 1344 (Fed. Cir. 2003); Gambro 

Lundia AB v. Baxter Healthcare Corp., 110 F.3d 1573, 

1576 (Fed. Cir. 1997) (“To show derivation, the party 

asserting invalidity must prove both prior conception of 

the invention by another and communication of that 

conception to the patentee.”). The conception requirement 

of derivation borrows from the conception standard for 

prior invention. Creative Compounds, 651 F.3d at 1313 

(relying on the conception analysis from a discussion of 

priority earlier in the opinion as sufficient in the discussion of derivation). Conception is keyed to the claimed 

invention: “A conception must encompass all limitations 

of the claimed invention.” Singh v. Brake, 317 F.3d 1334, 

1340 (Fed. Cir. 2003); see Taurus IP, LLC v. DaimlerChrysler Corp., 726 F.3d 1306, 1323 (Fed. Cir. 2013);

Slip Track Sys., Inc. v. Metal-Lite, Inc., 304 F.3d 1256, 

 

3 The quoted version of 35 U.S.C. § 102 applies to 

this case. The application that became the ’445 patent 

was filed on February 27, 2012, and claims priority to 

August 2005. The application has never contained a 

claim having an effective filing date on or after March 16, 

2013 (the effective date of the statutory changes enacted 

in 2011), or a reference under 35 U.S.C. §§ 120, 121, of 

365(c) to any patent or application that ever contained 

such a claim. See Leahy-Smith America Invents Act, Pub. 

L. No. 112-29, § 3(n)(1), 125 Stat. 284, 293 (2011); Fleming v. Escort Inc., 774 F.3d 1371, 1374 n.1 (Fed. Cir. 

2014).

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1263 (Fed. Cir. 2002); Brown v. Barbacid, 276 F.3d 1327, 

1336 (Fed. Cir. 2002). Conception requires more than “a 

general goal or research plan”; it requires a “definite and 

permanent,” “specific, settled idea,” namely, the idea 

defined by the claim at issue. Burroughs Wellcome Co. v. 

Barr Labs., Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994); see 

REG Synthetic Fuels, LLC v. Neste Oil Oyj, 841 F.3d 954,

962 (Fed. Cir. 2016). 

In inventorship disputes, “the inventors named on the 

issued patent are presumed to be correct” and “a person 

seeking to add his name ‘must meet the heavy burden of 

proving its case by clear and convincing evidence.’” Shum 

v. Intel Corp., 633 F.3d 1067, 1083 (Fed. Cir. 2010) (quoting Eli Lilly & Co. v. Aradigm Corp., 376 F.3d 1352, 1358 

(Fed. Cir. 2004)). We apply the same approach in the 

derivation context here. Amax Fly Ash Corp. v. United 

States, 514 F.2d 1041, 1047–48 (Ct. Cl. 1975), cited with 

approval in Hess v. Advanced Cardiovascular Sys., Inc., 

106 F.3d 976, 980 (Fed. Cir. 1997).

In this case, as the derivation issue was litigated, it 

suffices to focus on the fact that the required complete 

conception had to include the specific idea to remove 

EDTA from Acetadote® (or a similar product that met all 

the other ’445 claim elements) and not add another chelating agent. It was that idea which Mylan had to show, 

by clear and convincing evidence, was conceived by someone at the FDA and communicated to Mr. Pavliv. See 

Amax Fly Ash Corp., 514 F.2d at 1048.

The district court found that Mylan did not carry that 

burden. After considering the “surprising paucity of 

direct evidence,” Cumberland, 137 F. Supp. 3d at 1120, 

the district court concluded that while “the evidence does 

not establish a precise date of conception by Pavliv,” 

“Mylan has failed to persuade the court that anyone other 

than Pavliv ever conceived of a ‘definite and permanent 

idea’ of an EDTA-free Acetadote formulation,” id. at

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1121–22. Given the claim language requiring that the 

product be “free of chelating agents,” ’445 patent, col. 9, 

lines 20–21, not just EDTA, and the district court’s several references to that particular claim requirement, Cumberland, 137 F. Supp. 3d at 1112–13 (discussing the claim 

limitation “free of chelating agents”); id. at 1123–24 

(same), we think it clear that the district court’s finding

refers to a formulation of Acetadote® that simply removes 

EDTA, without adding another chelating agent in its 

place. The court thus found that Mylan did not prove that 

an FDA person conceived of that formulation, or communicated it to Cumberland, before Mr. Pavliv thought of it. 

The evidence supports the finding. The court could 

properly view the FDA’s December 10, 2002 letter, which

simply requested justification for the inclusion of EDTA in 

the drug product, as not showing the prior conception

needed here. J.A. 12837 (“[2(c):] Provide scientific and 

regulatory justification for the inclusion of Edetate as a 

component in the drug product. In addition, provide a 

description of the pharmacological properties for Edetate 

in this drug product.”). A different view is not required by 

the notes of the December 16, 2002 call, which add only 

that the FDA wanted data to support the justification. 

J.A. 12899 (“Regarding item 2(c), the Division explained 

that data should be provided to support any justification 

for the inclusion of Edetate, since a non-trivial amount is 

included in the formulation.”). A request for justification 

of the inclusion of EDTA, supported by data, is not the 

same as a suggestion to remove it, let alone to remove it

and not replace it with another chelating agent.

Mylan argues that the request for data to support the 

inclusion of EDTA required Cumberland to undertake 

research that would have inevitably led it to the invention. That is not enough for derivation. We have held 

that derivation is not proved by showing conception and

communication of an idea different from the claimed 

invention even where that idea would make the claimed 

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idea obvious. Gambro Lundia, 110 F.3d at 1577–78. We 

also have made clear that a “general goal or research 

plan” does not constitute the “definite and permanent 

idea” required for conception, Burroughs Wellcome, 40 

F.3d at 1228, and that a “bare hope” of a result “never 

before . . . achieved” (here, the claimed “stable” compound) 

is not sufficient for conception, Hitzeman v. Rutter, 243 

F.3d 1345, 1356–57 (Fed. Cir. 2001). See Cumberland, 

137 F. Supp. 3d at 1121. The kind of general research 

suggestion at issue here, whatever its role in an obviousness analysis, does not establish the conception required 

for derivation.

The evidence dating from after December 2002 likewise does not compel a finding contrary to the district 

court’s. In particular, even when documents go beyond 

discussing a study of whether EDTA’s inclusion is justified and mention removing EDTA, they do not make clear 

either that all chelating agents were to be avoided or that 

even the EDTA-removal idea (whether or not a substitute 

was to be added) came from someone other than Mr. 

Pavliv. All of those documents postdate the conversation 

Mr. Pavliv had with FDA representatives, in which, he 

testified, he was the one who introduced the idea of testing an EDTA-free product.

Thus, several Cumberland documents, starting with 

the July 21, 2003 letter quoted above, J.A. 14916, refer to 

the FDA as having “requested” the study. But that language can be read as focusing on the FDA’s request for a 

study implementing the idea already suggested by 

Mr. Pavliv. See J.A. 11263 (Cumberland’s Apr. 19, 2004 

proposed study protocol) (“As part of a post approval 

marketing commitment, the FDA requested Cumberland 

investigate whether EDTA has a beneficial impact on 

stability and if so whether the level could be reduced.”); 

J.A. 11311 (Cumberland’s Aug. 13, 2008 final report from 

stability study) (“The FDA expressed a potential safety 

concern with EDTA in the formulation and as such, 

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requested Cumberland investigate whether EDTA provided a stability benefit or could be reduced or removed from 

the product.”); J.A. 11360 (Cumberland’s May 10, 2011 

draft clinical study protocol for EDTA-free Acetadote®) 

(“The FDA expressed a potential safety concern with 

EDTA in the formulation of Acetadote and requested that 

the manufacturer investigate whether EDTA provided a 

stability benefit or could be reduced or removed from the 

product.”); J.A. 11693 (Cumberland’s May 18, 2012 citizen 

petition) (“From the outset, FDA wanted Cumberland to 

investigate reducing or removing EDTA from Acetadote® 

because the agency was concerned with the safety of 

EDTA. The agency should not now approve an ANDA for 

Acetadote® that relies on the discontinued formulation 

that is less safe than the EDTA-free formulation that 

FDA specifically requested Cumberland investigate 

developing, and that is currently on the market.”). 

Indeed, the FDA’s January 9, 2004 Chemistry Review, 

after stating that “[t]he sponsor reported that, as requested by FDA . . . , an independent study will be initiated to 

determine the impact on drug product stability of both 

decreasing and completely removing the amount of edetate sodium,” J.A. 12968, adds that the study was “applicant proposed,” J.A. 12969. As that document confirms, it 

is entirely possible for Cumberland to have first proposed 

the idea of studying EDTA removal, as Mr. Pavliv testified, and for the FDA to have “requested” that Cumberland actually perform that study. And, as with the 

December 2002 communications, none of these documents 

establish that the FDA specifically conceived of removing 

EDTA from the prior-art Acetadote® without adding any 

other chelating agents, as required by the claim language. 

Mylan gets no further help in reversing the district 

court’s finding from the FDA’s reliance on Cumberland’s

commitment to perform the study in approving the EDTAcontaining product in 2004. It simply does not follow from 

the fact that the study ultimately became a commitment 

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recited in the 2004 FDA approval that it was someone at

the FDA who originally proposed the study, let alone 

conceived of the invention eventually claimed in the ’445 

patent. The district court could properly find that the 

study requirement in the Approval Letter did not specify 

that Cumberland must test an EDTA-free formulation of 

acetylcysteine without adding any other chelating agents. 

Cumberland, 137 F. Supp. 3d at 1123 (“Most importantly, 

the reference to Cumberland’s commitment to study the 

removal of EDTA from Acetadote nowhere specifies that 

the exact same drug formulation without EDTA must be 

used.”). The study requirement, in total, reads:

Commit to evaluate the potential benefit of Edetate disodium on the stability of the drug product. 

The study shall include a comparison of the current concentration of Edetate to a formulation 

with a lower concentration and no concentration 

of Edetate. Generate stability data from the new 

proposed formulations including compatibility 

stability with infusion bags.

J.A. 11336. As the district court explained: “‘A formulation’ could contain, for instance, a chelating agent other 

than EDTA. This composition would be free of EDTA and 

satisfy the study requirement, but would not be ‘free of 

chelating agents,’ . . . which every claim of the ’445 patent 

requires.” Cumberland, 137 F. Supp. 3d at 1123–24 

(citation omitted). Consistent with this conclusion, Cumberland provided testimony that there were many possible ways to meet this commitment, including adding other 

chelating agents or testing without the claimed “airtight 

container” containing inert gas, and there was documentary evidence that it was Mr. Pavliv who came up with 

the precise protocol that amounted to a reduction to 

practice of the ’445 patent’s invention. 

Mylan does not contend that anyone at the FDA, rather than Mr. Pavliv, drafted the study protocol that 

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resulted in the claimed invention (though it does point out 

that the protocol Mr. Pavliv chose was the same protocol 

used to confirm the stability of EDTA-containing Acetadote®). Instead, Mylan takes the position that the 

communications between the FDA and Cumberland, 

which all require “removing or reducing” EDTA from “the” 

formulation or “the” drug product, must refer to the 

approved EDTA-containing product; thus, according to 

Mylan, the study requirement is not open to an interpretation that would allow a relevant skilled artisan to do 

anything other than arrive at the claimed invention, free 

of chelating agents. But the use of the definite article 

need not do so much work as to direct a skilled artisan to 

remove EDTA, add nothing else, and test the resulting 

formulation in exactly the manner to lead to the invention. Indeed, Mylan’s theory would appear to prove too 

much: Cumberland’s December 20, 2002 letter referred to 

the effect on “the product” if it turned out that “no or 

lower concentrations of edetate are capable of ensuring 

product stability,” and Cumberland’s July 21, 2003 letter 

also refers to “completely removing edetate disodium from 

the formulation.” J.A. 14783, 14916 (emphases added). If 

reference to removing EDTA from “the” formulation is 

enough, we do not see why Cumberland’s evidence would 

not suffice to show that Mr. Pavliv, the author of the 

December 20, 2002 and July 21, 2003 letters, first conceived of the invention. 

For those reasons, we affirm the district court’s determination that Mylan did not clearly and convincingly 

show that Mr. Pavliv derived the invention of the ’445 

patent from someone at the FDA. 

B 

We also affirm the district court’s rejection of Mylan’s 

obviousness challenge. Mylan relies for this challenge on 

the EDTA-containing Acetadote® and its package insert—

which, Mylan asserts, include or teach all of the elements 

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of the invention except the removal of EDTA—together 

with several references that allegedly bridge the gap to 

reach the claimed chelating-agent-free version of an 

acetylcysteine product. Specifically, Mylan relies on

(a) the FDA’s January 9, 2004 Chemistry Review and 

January 23, 2004 Approval Letter, each of which, it 

asserts, motivates removal of EDTA by stating Cumberland’s commitment to study EDTA’s role; and (b) U.S. 

Patent Pub. No. 2004/0022873 to Guilford, which describes intravenous acetylcysteine formulations for treating bioterror exposures.4 Those contentions, we conclude, 

do not undermine the district court’s rejection of Mylan’s

obviousness challenge. 

“A party seeking to invalidate a patent on the basis of 

obviousness must demonstrate by clear and convincing 

evidence that a skilled artisan would have been motivated 

to combine the teachings of the prior art references to 

achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in 

doing so.” Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 

688 F.3d 1342, 1360 (Fed. Cir. 2012) (internal quotation 

marks and citations omitted). The presence or absence of 

a reasonable expectation of success is a question of fact. 

See Intelligent Bio-Systems, Inc. v. Illumina Cambridge 

Ltd., 821 F.3d 1359, 1366 (Fed. Cir. 2016); PAR Pharm., 

Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 

2014); Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 

1289 (Fed. Cir. 2006).

“The reasonable expectation of success requirement 

 

4 The parties have stipulated that the Approval 

Letter and package insert were publicly available no later 

than February 2, 2004, and that the Chemistry Review 

was publicly available as of October 1, 2004. J.A. 14923. 

The parties accept that the priority date for the ’445 

patent is August 24, 2005.

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refers to the likelihood of success in combining references 

to meet the limitations of the claimed invention.” Intelligent Bio-Systems, 821 F.3d at 1367. Here, stability is an 

express claim requirement. The district court in this case 

wrote: “the court’s review of the evidence supports the 

conclusion that persons of ordinary skill in the art would 

have assumed that EDTA, or some other chelating agent, 

was necessary to maintain stability in an acetylcysteine 

formulation.” Cumberland, 137 F. Supp. 3d at 1125. It 

added: “Given that all prior acetylcysteine formulations 

contained EDTA, and given that the prior art taught that 

EDTA or another chelating agent was necessary to stabilize the formulation, the court rejects the argument that 

the Approval Letter or Chemistry Review, which contained the EDTA study commitments, would reasonably 

lead to a stable acetylcysteine formulation.” Id. at 1126. 

Though not using the exact phrase, “reasonable expectation of success,” the court thus found that the hypothetical 

relevant skilled artisan would not have reasonably expected a chelating-agent-free intravenous acetylcysteine 

formulation to succeed in being stable, a claim requirement. Id. at 1125. 

That finding is not clearly erroneous. Considerable 

evidence supports the finding that relevant skilled artisans believed that chelating agents were necessary to 

sequester metal contaminants and prevent oxidative 

degradation of acetylcysteine and that such artisans had 

no reasonable expectation of stability without such an 

agent. J.A. 14507 (U.S. Patent No. 5,700,653 to Lu, 

explaining how EDTA can alleviate acetylcysteine’s 

“notorious instability in solution”); J.A. 14509 (Lu patent, 

referring to an experiment “carried out to confirm that, as 

known in the art, [acetylcysteine] in a solution of creatine 

kinase buffer will become unstable in the buffer solution, 

but that the presence of EDTA can provide some limited 

stability”); J.A. 8666, 8723 (Dr. Kent, expert for Mylan, 

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testifying that acetylcysteine’s thiol groups are prone to 

oxidation); J.A. 9298, 9304, 9323–25 (Dr. Byrn, expert for 

Cumberland, testifying that a person of ordinary skill 

would understand that EDTA was necessary to prevent 

oxidation and would be concerned about removing it); see 

also J.A. 13324 (Hamlow, observing that “data show that 

acetylcysteine solution containing the chelating agent 

EDTA is well protected from oxidative degradation”). As 

late as 2011, Mylan’s own scientists expressed concern

that the removal of EDTA would make the product more 

vulnerable to oxidation. E.g., J.A. 14346 (email noting the 

“risk” that “removing EDTA will open up sensitivity to 

heavy metals at low ppm levels in solution” and proposing 

experiments to determine sources and effects of heavy 

metals in the proposed product); J.A. 14487–88 (email to 

vial supplier requesting data for how much iron could 

leech from the glass into solution because of concern that 

the “product may be sensitive to oxidation”); J.A. 14562

(meeting agenda stating: “Iron in Glass may cause an 

issue with EDTA removal. Set up tests to confirm glass 

being chosen is acceptable.”). 

Mylan offered evidence tending to show that there is 

no need to chelate trace metal ions because degradation 

may be effectively avoided by an inert vial atmosphere 

together with modern manufacturing practices that leave 

very low levels of metal contaminants. But Mylan’s 

evidence did not compel a finding that relevant skilled 

artisans would have reasonably expected success for those 

reasons in 2005. The district court had sufficient evidence 

to find otherwise. In addition to the already-cited evidence, we note the pre-2005 references indicating that 

even very small amounts of metal and oxygen could result 

in degradation. J.A. 13574 (Kasraian et al.5 stating: “In 

 

5 Kasra Kasraian et al., Developing an Injectable 

Formula Containing an Oxygen-Sensitive Drug: A case 

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many cases, minimizing oxygen alone is not sufficient to 

prevent autoxidation, because trace levels of oxygen may 

be enough to initiate this reaction”); J.A. 13459 (Waterman6 stating: “Trace metals are almost ubiquitous in 

dosage forms, and since they are often catalysts rather 

than consumed, they can affect rates even at low levels”).

Finally, there is no clear error in the district court’s 

finding that Guilford did not provide either a motivation 

to remove EDTA or a reasonable expectation of success. 

Cumberland, 137 F. Supp. 3d at 1126. Although Guilford 

did not disclose a chelating agent in its formulation of 

acetylcysteine, it also did not publish stability data. To 

the extent that a person of ordinary skill could infer that 

the Guilford formulation was stable, there was testimony 

explaining that a person of ordinary skill would not 

expect it to remain stable as the concentration of acetylcysteine was raised to the level required by the ’445 

patent. See id.

III

For the foregoing reasons, we affirm the district 

court’s judgment.

AFFIRMED

 

Study of Danofloxacin Injectable, 4 Pharmaceutical Dev. 

& Tech. 475 (1999).

6 Kenneth C. Waterman et al., Stabilization of 

Pharmaceuticals to Oxidative Degradation, 7 Pharmaceutical Dev. & Tech. 1 (2002).

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