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The Medicines Co. v. Mylan, Inc.

United States Court of Appeals, Federal Circuit

April 6, 2017

THE MEDICINES COMPANY, Plaintiff-Cross-Appellant
v.
MYLAN, INC., MYLAN PHARMACEUTICALS INC., BIONICHE PHARMA USA, LLC, Defendants-Appellants

         Appeals from the United States District Court for the Northern District of Illinois in No. 1:11-cv-01285, Judge Amy J. St. Eve.

          Porter F. Fleming, Haug Partners LLP, New York, NY, argued for plaintiff-cross-appellant. Also represented by Edgar Haug, Angus Chen.

          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.

          Before Dyk, Wallach, and Hughes, Circuit Judges.

          Dyk, Circuit Judge.

         The 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.

         The 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" limitation.

         We hold 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.

         Background

         I

         The '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.

         The 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 acceptable level.

         II

         Medicines 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).

         Between 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.

         In 2005 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.

         The 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.

         Based 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.

         This 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 comprising:
(i) dissolving bivalirudin in a solvent to form a first solution;
(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 solvent; and
(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).

         The emphasized claim limitation is common to both patents, and we refer to this shared limitation as the "batches limitation." The term "pharmaceutical batches" ...


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