MYLAN INSTITUTIONAL LLC, APICORE U.S. LLC, Plaintiffs-Appellees
AUROBINDO PHARMA LTD., AUROBINDO PHARMA USA INC., AUROMEDICS PHARMA LLC, Defendants-Appellants
from the United States District Court for the Eastern
District of Texas in No. 2:16-cv-00491-RWS-RSP, Judge Robert
W. Stafford, Wilson, Sonsini, Goodrich & Rosati, PC,
Austin, TX, argued for plaintiffs-appellees.
Plaintiff-appellee Mylan Institutional LLC also represented
by David S. Steuer, Palo Alto, CA; Sami Sedghani, San
Garelick Goldstein, Sharma & DeYoung LLP, New York, NY,
for Apicore U.S. LLC. Also represented by Allen Gardner,
Gillam, Smith & Gardner, Tyler, TX.
Sailesh K. Patel, Schiff Hardin LLP, Chicago, IL, argued for
defendants-appellants. Also represented by Cindy Ahn; George
Chih-Lun Yu, San Francisco, CA.
Lourie, Moore, and Reyna, Circuit Judges.
Lourie, Circuit Judge.
Pharma Ltd., Aurobindo Pharma USA Inc., and Auromedics Pharma
LLC (together, "Aurobindo") appeal from a decision
of the United States District Court for the Eastern District
of Texas granting Mylan Institutional LLC's ("Mylan
Inst.") and Apicore U.S. LLC's ("Apicore")
(together, "Mylan") motion for a preliminary
injunction precluding Aurobindo from making, using, selling,
offering to sell, and importing the accused isosul-fan blue
("ISB") product that allegedly infringes three of
Apicore's patents-U.S. Patent 7, 622, 992 ("the
'992 patent"), U.S. Patent 8, 969, 616 ("the
'616 patent"), and U.S. Patent 9, 353, 050
("the '050 patent"). See Mylan
Institutional LLC v. Aurobindo Pharma Ltd., No.
2:16-cv-00491, 2017 WL 497593 (E.D. Tex. Feb. 7, 2017)
("Order Adopting R&R"). Because the
district court did not err in its grant of the preliminary
injunction under the '050 patent, although it did err in
granting the injunction under the '992 and '616
patents, we affirm.
owns, and Mylan Inst. is the exclusive licensee of, the
'992, '616, and '050 patents, which relate to
ISB, a triarylmethane dye used to map lymph nodes. The
'992 and '616 patents (together, "the process
patents") are directed to a process for preparing ISB by
reacting iso-leuco acid with silver oxide in a polar solvent,
followed by reaction with a sodium solution. See,
e.g., '992 patent col.
7 ll. 21-44. The '992 patent further requires
2.0-3.0 equivalents of silver oxide. See id. col. 9
1. 65. Claim 1 of the '616 patent is representative of
the process patents and reads as follows:
A process of preparing N-[4-[[4-(diethyl-amino)phenyl] (2, 5-
disulfophenyl)methylene] -2, 5
-cyclohexadien-1-yhdene]-N-ethylethanaminium, sodium salt
comprising combining a suspension of isoleuco acid of the
in a polar solvent with silver oxide, recovering
isosulfan blue acid, and treating the isosulfan blue acid
with a sodium solution.
'616 patent col. 9 11. 38-64 (emphasis added). Claim 1 of
the '992 patent adds the limitation that 2.0-3.0
equivalents of silver oxide are employed in the process, but
otherwise resembles the claim shown above. See
'992 patent col. 9 11. 41-67.
'050 patent (which the parties refer to as "the
purity patent") is directed to an ISB compound having a
purity greater than 99.0%, as measured by high performance
liquid chromatography ("HPLC"). See
'050 patent col. 9 ll. 54-58. Claim 1 is illustrative and
reads as follows:
A compound N-[4-[[4-(diethylamino)phenyl] (2,
5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt
having a purity of at least 99.0% by HPLC.
Id. col. 9 ll. 55-58 (emphasis added).
1981, Hirsch Industries ("Hirsch") developed a 1%
injectable solution of ISB, which it commercialized under the
trade name Lymphazurin®. Covidien Ltd.
("Covidien"), the successor-in-interest to Hirsch,
held the original new drug application ("NDA") and
was the sole supplier of Lymphazurin® for 30
years. From its inception, Lymphazurin®'s
production had been plagued by difficulties in synthesizing
and purifying ISB. Hirsch's original clinical trials
described the mixture as containing 94.5% ISB as determined
by HPLC, with the remaining 5.5% consisting of "closely
related isomers" produced during synthesis. Mylan
Institutional LLC v. Aurobindo Pharma Ltd., No.
2:16-cv-00491, 2016 WL 7587325, at *2 (E.D. Tex. Nov. 21,
2016) ("Report and Recommendation")
(internal quotation marks omitted).
years following the Food and Drug Administration's
("FDA") approval of ISB, Sigma-Aldrich Corp.
("Sigma") supplied Hirsch and its successors with
ISB that was manufactured by Allied Chemical Corp.
("Allied"). Allied's manufacturing process was
unknown, but analysis of its ISB indicated the presence of
lead, which suggested the use of a lead compound in
synthesis. Sigma developed an isolation process to remove the
unwanted lead, but the ultimate purity of the ISB it sold was
unknown. In 2000, Allied stopped supplying Sigma with ISB
and, while Sigma was looking for a new supplier, Covidien was
forced to notify its customers that it was "completely
out of" Lymphazurin® until it could find
a new supplier for ISB. Id. at *2 (internal
quotation marks omitted). By 2008, Sigma had a new supplier,
Inno-vassynth, which synthesized ISB using ammonium
di-chromate, resulting in residual chromium impurities. Sigma
reported numerous problems with the purity of
Innovassynth's product and eventually developed its own
manufacturing process for ISB sometime around 2010.
was founded in 2003 and began developing an improved process
for synthesizing ISB. In 2004, Apicore partnered with Synerx
Pharma LLC ("Synerx"), Mylan Inst.'s
predecessor, to develop and market a generic version of
Lymphazurin®. In 2007, Apicore filed a patent
application that ultimately led to the process and '050
patents. Based on the claimed process, Synerx (acquired by
Mylan Inst. in 2012) filed an abbreviated new drug
application ("ANDA") seeking FDA approval to market
a generic Lymphazurin®; the FDA approved the
ANDA in 2010. By 2011, ISB sales were a significant portion
of Apicore's revenue and in 2012, Covidien withdrew
Lym-phazurin® from the market for
"reasons other than safety or effectiveness."
Id. at *3 (internal quotation marks omitted). Mylan
Inst. became the sole supplier of the 1% ISB drug product
until 2016, when Aurobindo entered the market.
sought FDA approval for a generic
Lym-phazurin®, informing the FDA that it had
studied a "number of patents" describing ISB
manufacture and selected, inter alia, Apicore's
'992 patent, and that it "considered the process
described [therein] for the initial sample preparation and
further, the optimization of the process." Id.
(internal quotation marks omitted). Auro-bindo acknowledged
to the FDA that it was looking for a reagent "other than
silver oxide." Id. (internal quotation marks
omitted). It eventually selected manganese diox- ide, and its
process resulted in ISB with a 5-10% impurity which could not
be removed by recrystallization. Instead, it used preparatory
HPLC to achieve an ISB purity of greater than 99.5%. Mylan
sued Aurobindo for infringement and sought a preliminary
injunction, which the district court granted.
the district court evaluated the likelihood of success on the
merits and found that Aurobindo likely infringed the process
patents under the doctrine of equivalents. Id. at
*10-12. The court found that the difference in oxidation
strength between silver oxide and manganese dioxide is
"irrelevant" under both the
"function-way-result" ("FWR") and
"insubstantial differences" tests for equivalence,
as applied to the "face of the claims, " because
the claims do not specify a requirement of oxidation
strength. Id. at *11. Further, the court explained
that, even if oxidation strength were relevant, it
"finds manganese dioxide to be a mild oxidant equivalent
to silver oxide in the context of the [process
patents]." Id. The court credited Dr.
Sessler's (Mylan's expert) testimony in light of
record evidence that the silver oxide and manganese dioxide
processes produce crude ISB in similar yields. The court
explained that if manganese dioxide were a substantially
stronger oxidizing agent than silver oxide, a skilled artisan
"would expect different results." Id. at
district court found that Aurobindo did not raise a
substantial question of validity of the '050 patent based
on its arguments that the process patent is invalid: (1)
under § 112 because the "by HPLC" limitation
renders the claims indefinite; (2) under § 103 because
the claims would have been obvious over various combinations
of art; and (3) under § 102 because the claims are
anticipated by Sigma's manufacture and sale of ISB.
issue of indefiniteness, the district court credited
Sessler's testimony and found that "by HPLC"
was a common and well-understood way of designating or
determining purity, as seen in "numerous sources, "
including other patents and the scientific literature.
Id. at *8-9. Thus, the court concluded that
Aurobindo had not raised a substantial question of validity
of the '050 patent under § 112. Id.
district court also rejected Aurobindo's obviousness
argument, finding that Aurobindo did not raise a substantial
question regarding motivation to combine the references or a
reasonable expectation of success. See id. at *22.
The court noted that "a purified compound is not always
prima facie obvious over the [prior art] mixture" if the
process to arrive at the purified compound is itself of
patentable weight. Id. at *18 (citing Aventis
Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293,
1301 (Fed. Cir. 2007)) (internal quotation marks omitted).
The court concluded that Apicore's process leading to the
purified compound claimed in the '050 patent constituted
"an invention of patentable weight itself" and thus
the purity claims would not necessarily have been prima facie
obvious over the prior art mixture of (less pure) ISB and
"closely related isomer" by-products.
Id. at *18, *19 (internal quotation marks omitted).
district court credited Mylan's evidence of secondary
considerations-specifically, long-felt but unmet need,
commercial success, copying/praise of others, and unexpected
results. Id. at *20-22. The court pointed to the
failure of Allied, Sigma, Innovassynth, and others in the art
to "reliably" produce "high-purity" ISB
for 30 years. Id. at *20. And the court emphasized
that Auro- bindo "admitted to the FDA" that it had
copied the '992 patent. Id. at *21. Thus, the
court concluded that Auro-bindo had not raised a substantial
question that the '050 patent is invalid as obvious.
district court also concluded that Aurobindo had not raised a
substantial question that the '050 patent claims were
anticipated under § 102(b) and § 102(g)(2) by
Sigma's manufacture and sale of ISB. See id. at
*13. Aurobindo argued that Sigma had made and sold ISB having
a purity of greater than 99.0% six years before the '050
patent priority date. See id. Aurobindo supported
its position by citing a Sigma Certificate of Analysis, which
indicated that a compound named "Patent Violet Blue,
" with a certain product number and Lot number,
possessed a purity that was 100% by HPLC. Id. The
court rejected Aurobindo's argument, finding that: (1) it
is not clear that, at the time of the Certificate,
Sigma's use of the term "Patent Violet Blue"
referred to ISB because other Sigma documents indicate that
"Patent Violet Blue" referred to several blue dye
compounds with different structures; and (2) the record
established that the Certificate is inaccurate because it
"contradicts numerous other Sigma documents" that
report a different purity for samples from the same Lot.
Id. at *14. Thus, the court concluded that Aurobindo
had not raised a substantial question that the '050
patent is invalid as anticipated. Id.
the district court found that Apicore would be irreparably harmed
without a preliminary injunction and identified four
"hallmark examples" of irreparable harm that are
demonstrated by the record: lost sales; lost R&D; price
erosion; and that Apicore must now directly compete with an