Federal Circuit: “Batches Limitation” Requires a Process that Achieves Consistency Between Batches of Bivalirudin (Angiomax)

The Medicines Company brought a suit against Mylan for submitting an ANDA for the drug bivalirudin (Angiomax).  The Medicines Company asserted the following two patents against Mylan: 

7,582,727

Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier for use as an anticoagulant in a subject in need thereof, 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.

7,598,343

1. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier, for use as an anticoagulant in a subject in need thereof, said batches 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.

The inventors of these two patents realized that during mixing, certain “hot spots” occurred that increased the impurity level of Asp⁹-bivalirudin, an undesired impurity.  The inventors developed an improved, “efficient mixing” process for mixing the pH-adjusting solution with the bivalirudin solution that minimized the formation of these hotspots. 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, the Asp9 level of batches compounded using the improved “efficient mixing”process never exceeded 0.6 percent.

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. The Federal Circuit held 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:

The batches limitation restricts the claims of the ’727 patent (as well as the ’343 patent) to “batches hav[ing] a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6%.” At the outset, we note that the batches limitation cannot be literally construed to cover individual batches of base-compounded bivalirudin having Asp⁹ levels that “do[] not exceed about 0.6%.” Such a construction would render the claims of the ’727 patent invalid in light of Medicines’ numerous pre-critical-date sales of ANGIOMAX batches having Asp9 levels below 0.6 percent. See Medicines, 72 F. Supp. 3d at 864. Rather, properly construed, what the batches limitation requires is the use of a process that achieves batch consistency. This requirement follows from simply reading the batches limitation against the specification’s definition of the term “batches,” as slightly revised by the district court with the agreement of the parties to clarify that the “batches” must be made by a particular compounding process. See Medicines, 2012 WL 3234282, at *5. That definition limits the “batches” claimed by the patents in suit to either “all batches prepared by a same compounding process,” or “a single batch . . . wherein the levels of [Asp9-bivalirudin] represent levels for all potential batches made by said process.” ’727 patent, col. 5 ll. 24–36 (emphasis added); ’343 patent, col. 5 ll. 24–36. The batches limitation therefore requires a process that achieves consistency between batches produced from the “same compounding process”—i.e., batch consistency.

The Federal Circuit limited the batch claims by the process of making the batches despite the ‘727 Patent lacking the process limitation of “efficient mixing.”

The Medicines Company v. Mylan, Inc. (Fed Cir. April 6, 2017).

http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/15-1113.Opinion.4-4-2017.1.PDF