Court Opinion

ID: 4118761
Source: CourtListenerOpinion
Date Created: 2017-01-26 16:01:19.419938+00
Date Added: 2024-06-11T14:37:30.029090
License: Public Domain

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.
                 ______________________
2    CUMBERLAND PHARMACEUTICALS    v. MYLAN INSTITUTIONAL
                                                      LLC

    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 chelating-
agent-free formulation of Acetadote®, an intravenous
antidote for overdoses of acetaminophen. When Mylan
Institutional LLC filed an abbreviated new drug applica-
tion to market its own chelating-agent-free acetylcysteine
formulation,    Cumberland       brought   this    patent-
infringement action in the Northern District of Illinois
against Mylan Institutional LLC and Mylan Inc. (hereaf-
ter “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 patent-
named 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
CUMBERLAND PHARMACEUTICALS       v. MYLAN INSTITUTIONAL    3
LLC

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 formula-
tion. ’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 formu-
lations of acetylcysteine were considered safe, despite
potential negative side effects. Id., col. 2, lines 14–27.
     Cumberland’s ’445 patent declares: “It has been sur-
prisingly 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 instruc-
tions (among others): “[2c.] Provide scientific and regula-
tory 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, repre-
sentatives of the FDA and Cumberland spoke by tele-
phone. Notes of the call state: “Regarding item 2(c), the
4       CUMBERLAND PHARMACEUTICALS   v. MYLAN INSTITUTIONAL
                                                        LLC

Division explained that data should be provided to sup-
port 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 re-
sponded 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, short-
ly 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 request-
ed 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.
CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL    5
LLC

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 ap-
proval, an independent study will be initiated to deter-
mine the impact on drug product stability of both
decreasing and completely removing the amount of ede-
tate 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 “eval-
uate 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 concentra-
tion 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
6       CUMBERLAND PHARMACEUTICALS   v. MYLAN INSTITUTIONAL
                                                       LLC

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 Au-
gust 24, 2005, having received further encouraging stabil-
ity 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 sta-
bility 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, Cum-
berland 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 prod-
uct.
    On May 17, 2012, Cumberland sued Mylan for in-
fringement 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.”
CUMBERLAND PHARMACEUTICALS        v. MYLAN INSTITUTIONAL   7
LLC

ble. Cumberland withdrew its claims regarding the ’356
patent on September 28, 2014.
    At the bench trial, Mylan argued that (1) the ’445 pa-
tent 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 obvi-
ous 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 skilled-
artisan view that chelating agents were necessary to
prevent degradation of acetylcysteine, id. at 1127. The
court entered a final judgment of validity and infringe-
ment 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
8       CUMBERLAND PHARMACEUTICALS   v. MYLAN INSTITUTIONAL
                                                        LLC

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 concep-
tion” 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 discus-
sion 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. Daim-
lerChrysler 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); Flem-
ing v. Escort Inc., 774 F.3d 1371, 1374 n.1 (Fed. Cir.
2014).
CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL    9
LLC

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) (quot-
ing 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 che-
lating agent. It was that idea which Mylan had to show,
by clear and convincing evidence, was conceived by some-
one 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
10   CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL
                                                        LLC

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 sever-
al references to that particular claim requirement, Cum-
berland, 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 commu-
nicated 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 inven-
tion. 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
CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL    11
LLC

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 obvious-
ness analysis, does not establish the conception required
for derivation.
    The evidence dating from after December 2002 like-
wise 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 justi-
fied 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 test-
ing 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 lan-
guage 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,
12   CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL
                                                        LLC

requested Cumberland investigate whether EDTA provid-
ed 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 request-
ed 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 ede-
tate sodium,” J.A. 12968, adds that the study was “appli-
cant 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 testi-
fied, and for the FDA to have “requested” that Cumber-
land 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 EDTA-
containing product in 2004. It simply does not follow from
the fact that the study ultimately became a commitment
CUMBERLAND PHARMACEUTICALS      v. MYLAN INSTITUTIONAL    13
LLC

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 Ede-
    tate disodium on the stability of the drug product.
    The study shall include a comparison of the cur-
    rent 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 formula-
tion’ 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, Cum-
berland provided testimony that there were many possi-
ble ways to meet this commitment, including adding other
chelating agents or testing without the claimed “airtight
container” containing inert gas, and there was documen-
tary 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, ra-
ther than Mr. Pavliv, drafted the study protocol that
14   CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL
                                                        LLC

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 Ac-
etadote®). 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 interpre-
tation 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 inven-
tion. 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 con-
ceived of the invention.
    For those reasons, we affirm the district court’s de-
termination 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
CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL   15
LLC

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 Cumber-
land’s commitment to study EDTA’s role; and (b) U.S.
Patent Pub. No. 2004/0022873 to Guilford, which de-
scribes intravenous acetylcysteine formulations for treat-
ing 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 arti-
san 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.
16   CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL
                                                        LLC

refers to the likelihood of success in combining references
to meet the limitations of the claimed invention.” Intelli-
gent 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 stabi-
lize the formulation, the court rejects the argument that
the Approval Letter or Chemistry Review, which con-
tained the EDTA study commitments, would reasonably
lead to a stable acetylcysteine formulation.” Id. at 1126.
Though not using the exact phrase, “reasonable expecta-
tion of success,” the court thus found that the hypothetical
relevant skilled artisan would not have reasonably ex-
pected a chelating-agent-free intravenous acetylcysteine
formulation to succeed in being stable, a claim require-
ment. Id. at 1125.
    That finding is not clearly erroneous. Considerable
evidence supports the finding that relevant skilled arti-
sans 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,
CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL   17
LLC

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 evi-
dence, 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
18   CUMBERLAND PHARMACEUTICALS     v. MYLAN INSTITUTIONAL
                                                        LLC

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 (Water-
man 6 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 acetyl-
cysteine 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 Pharmaceu-
tical Dev. & Tech. 1 (2002).