from the United States District Court for the Northern
District of Illinois in No. 1:11-cv-01285, Judge Amy J. St.
F. Fleming, Haug Partners LLP, New York, NY, argued for
plaintiff-cross-appellant. Also represented by Edgar Haug,
Shannon Bloodworth, Perkins Coie, LLP, Washington, DC, argued
for defendants-appellants. Also represented by Dan L.
Bagatell, Hanover, NH; David Lee Anstaett, Autumn N. Nero,
David R. Pekarek Krohn, Madison, WI.
Dyk, Wallach, and Hughes, Circuit Judges.
Medicines Company ("Medicines") is the owner of
U.S. Patent Nos. 7, 582, 727 ("the '727
patent") and 7, 598, 343 ("the '343
patent"). In response to an Abbreviated New Drug
Application ("ANDA") submitted by Mylan, Inc.
("Mylan"), Medicines filed suit in the United
States District Court for the Northern District of Illinois
alleging that Mylan's ANDA infringed claims 1-3, 7-10,
and 17 of the '727 patent, and claims 1-3 and 7-11 of the
'343 patent. Mylan counterclaimed seeking a declaration
that the asserted claims were invalid.
district court held on summary judgment that the asserted
claims of the '343 patent were not infringed because
Mylan did not satisfy the "efficient mixing"
limitation of those claims. After conducting a bench trial,
the court held that the asserted claims of the '727
patent were infringed because those claims did
not include an "efficient mixing"
that both the '727 and '343 patents include a
"batches" limitation that requires batch
consistency, which, according to the patents in suit, is
achieved through efficient mixing. Efficient mixing is
therefore required by the asserted claims of both patents. We
further construe efficient mixing as defined by Example 5 of
the patents' specification. We therefore reverse the
district court's judgment of infringement with respect to
the '727 patent, and affirm its summary judgment of
noninfringement with respect to the '343 patent. We do
not address the validity of the patents in suit.
'727 and '343 patents are directed to pharmaceutical
formulations-or "batches"-of the drug bivalirudin
produced through a process that consistently minimizes
impurities. Bivalirudin is a synthetic peptide used to
prevent blood clotting in patients undergoing cardiac
catheterization. This clinical application arises from the
drug's ability to act as a reversible inhibitor of
thrombin, a key enzyme in the cascade of biochemical
reactions responsible for the formation of blood clots.
Bivalirudin's pharmacological properties were known in
the art, well before the filing of the patents in suit, and
were covered by a patent owned by Medicines that expired in
2015, U.S. Patent No. 5, 196, 404.
claimed inventions of the '727 and '343 patents are
directed to minimizing impurities in batches of bival-irudin
that have been compounded with a base. See '727
patent, col. 2 ll. 19-22; '343 patent, col. 2 ll. 19-22.
Bival-irudin as an active ingredient is typically distributed
or sold as a dry powder that must be compounded with a base,
before being reconstituted in a clinical setting and
administered to a patient as an intravenous injection.
Reconstitution involves dissolving the drug (in dry powder
form) in an aqueous solvent such as water or saline. Because
dissolving bivalirudin by itself (without a base) results in
an acidic solution not suitable for injection, commercial
forms of bivalirudin compound bivalirudin with a base, which
increases the pH of the reconstituted drug to a clinically
received approval from the Food & Drug Administration
("FDA") to market a base-compounded bivalirudin
drug product in 2000, and has sold the approved product since
2001 under the tradename ANGIOMAX®, well before the
critical date of the patents in suit. In approving
ANGIOMAX®, the FDA required Medicines to limit the level
of "Asp9-bivalirudin"-an impurity generated during
the compounding process that shortens bivalirudin's shelf
life-to less than 1.5 percent. Asp9-bivalirudin is formed
when the ninth amino acid of bivalirudin's peptide chain
converts from asparagine to aspartic acid. Consequently,
Medicines was required to reject any ANGIOMAX® batch
determined to have an Asp9 level higher than 1.5 percent.
See United States v. Barr Labs., Inc., 812 F.Supp.
458, 471-72 (D.N.J. 1993); 21 C.F.R. § 211.165(f).
2001 and 2005, Medicines and its contract manufacturer, Ben
Venue Laboratories ("BVL"), produced and sold
numerous batches of compounded bivalirudin having Asp9 levels
of less than 1.5 percent. Although the "old compounding
process, " Medicines Co. v. Mylan Inc., 72
F.Supp.3d 837, 850 (N.D. Ill. 2014), used by Medicines and
BVL to produce ANGIOMAX® "resulted in variable and
sometimes high levels of Asp9 impurities, " id.
at 847, the overriding majority of these batches in fact had
Asp9 levels below 0.6 percent (the level specified in the
asserted claims). As the district court observed, "79 of
87 prior art ANGIOMAX® batches had Asp9 levels at or
below about 0.6% and [Medicines] sold dozens of these batches
prior to the critical date." Id. at 864.
and 2006, however, Medicines produced two batches of
ANGIOMAX® with Asp9 levels above the 1.5 percent limit
specified by the FDA. After failing to solve the problem of
inconsistent batches internally, Medicines retained a
consultant, Dr. Gary Musso, who together with Dr. Gopal
Krishna, an employee of Medicines at the time, identified the
compounding process used by BVL as the source of the problem.
Drs. Krishna and Musso are the named co-inventors of the
'727 and '343 patents.
process of compounding bivalirudin generally involves three
steps: (1) forming a bivalirudin solution by dissolving the
drug in an aqueous solution; (2) mixing the bivalirudin
solution with a pH-adjusting solution containing a base; and
(3) removing solvents to yield the final compounded drug
product. See Medicines, 72 F.Supp.3d at 843. The
'727 and '343 patents explain that in mixing the
pH-adjusting solution into the bivalirudin solution,
"concentrated sites in the compounding solution that
have much higher pH levels" are formed. See,
e.g., '727 patent, col. 9 ll. 20-22. These localized
"hot spots" catalyzed the degradation of
bivalirudin to Asp9-bivalirudin, resulting in undesirable
high levels of the impurity in some instances. See,
e.g., id. col. 9 l. 19.
on this principle, Drs. Krishna and Musso developed an
improved, "efficient mixing" process for mixing the
pH-adjusting solution with the bivalirudin solution that
minimized the formation of these hotspots. See
Medicines, 72 F.Supp.3d at 848. This improved
"efficient mixing" process resulted in batches that
consistently satisfied the FDA's 1.5 percent limit on the
level of Asp9-bivalirudin. Moreover, based on Drs. Krishna
and Musso's experiments, Medicines discovered that the
Asp9 level of batches compounded using the improved
"efficient mixing" process never exceeded 0.6
percent. See id. at 848-49.
batch consistency of bivalirudin drug products compounded
using "efficient mixing" is the invention disclosed
and claimed by the patents in suit, which were filed on the
same day and share nearly identical specifications. See
Medicines Co. v. Mylan Inc., 2012 WL 3234282, at *2
(N.D. Ill. Aug. 6, 2012).
Representative claim 1 of the '727 patent provides:
1. Pharmaceutical batches of a drug product comprising
bivalirudin . . . wherein the batches have a pH adjusted by a
base, said pH is about 5-6 when reconstituted in an aqueous
solution for injection, and wherein the batches have a
maximum impurity level of Asp9-bivalirudin that does not
exceed about 0.6% as measured by HPLC.
'727 patent, col. 25 ll. 56-64 (emphasis added).
Representative claim 1 of the '343 patent provides:
1. Pharmaceutical batches of a drug product comprising
bivalirudin . . . prepared by a compounding process
(i) dissolving bivalirudin in a solvent to form a first
(ii) efficiently mixing a pH-adjusting solution with the
first solution to form a second solution, wherein the
pH-adjusting solution comprises a pH-adjusting solution
(iii) removing the solvent and pH-adjusting solution solvent
from the second solution;
wherein the batches have a pH adjusted by a base, said pH is
about 5-6 when reconstituted in an aqueous solution for
injection, and wherein the batches have a maximum
impurity level of Asp9-bivalirudin that does not exceed about
0.6% as measured by HPLC.
'343 patent, col. 27 ll. 13-31 (emphasis added).
emphasized claim limitation is common to both patents, and we
refer to this shared limitation as the "batches
limitation." The term "pharmaceutical batches"