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Amgen Inc. v. Hospira, Inc.

United States Court of Appeals, Federal Circuit

December 16, 2019

AMGEN INC., AMGEN MANUFACTURING, LIMITED, Plaintiffs-Cross-Appellants
v.
HOSPIRA, INC., Defendant-Appellant

          Appeals from the United States District Court for the District of Delaware in No. 1:15-cv-00839-RGA, Judge Richard G. Andrews.

          John Labbe, Marshall, Gerstein & Borun LLP, Chicago, IL, argued for plaintiffs-cross-appellants. Also represented by Kevin M. Flowers, Julianne M. Hartzell, Mark Harry Izraelewicz; Thomas Francis Lavery, Wendy A. Whiteford, Amgen Inc., Thousand Oaks, CA.

          Thomas J. Meloro, Willkie Farr & Gallagher LLP, New York, NY, argued for defendant-appellant. Also represented by Michael Johnson, Heather M. Schneider.

          Before Moore, Bryson, and Chen, Circuit Judges.

          Moore, Circuit Judge.

         Hospira, Inc. (Hospira) appeals the District of Delaware's denial of its motion for judgment as a matter of law (JMOL), or alternative motion for new trial, upholding the jury's verdict that: (1) Amgen, Inc. and Amgen Manufacturing, Ltd.'s (Amgen) U.S. Patent No. 5, 856, 298 (the '298 patent) was infringed and not invalid; (2) fourteen batches of drug substance for Hospira's erythropoietin biosimilar drug product were not covered by the Safe Harbor provision of 35 U.S.C. § 271(e)(1); and (3) Amgen had proven it was entitled to $70 million in damages. Amgen cross-appeals the district court's denial of its motion for judgment as a matter of law, and alternative motion for new trial, upholding the jury's verdict of noninfringement of U.S. Patent No. 5, 756, 349 (the '349 patent). For the following reasons, we affirm the district court's decisions as to each.

         I. Background

         A. The Asserted Patents

         The patents at issue relate to erythropoietin (EPO) isoforms and aspects of their production. EPO is a glycoprotein hormone that regulates red blood cell maturation and production. Recombinant human EPO is an important therapeutic protein for the treatment of anemia. Human EPO consists of a polypeptide of 165 amino acids and a high content of saccharides (or glycans). It contains various sites for glycosylation, i.e., sites where saccharides can be attached to the protein part of the molecule. Each of these glycosylation sites has the potential for branching and each branch contains a potential terminal sialic acid, a negatively-charged molecule. Thus, each EPO molecule can have different numbers of sialic acids. Amgen manufactures and markets recombinant human EPO as Epogen.

         The claims of the '298 patent claim, inter alia, methods of producing EPO isoforms having a specific number of sialic acids per molecule, and methods for obtaining EPO compositions having a predetermined in vivo specific activity. According to the '298 patent, each isoform of EPO has an in vivo activity which correlates to the number of sialic acids the isoform possesses. '298 patent at 5:33-46, 5:62- 64.

         Relevant to this case are certain techniques for separating protein molecules. The first, isoelectric focusing, "separates proteins on the basis of charge." '298 patent at 4:65-67. Proteins placed in a pH gradient and subjected to an electric field will migrate (through attraction toward or repulsion from the negatively- or positively-charged electrode) towards the point at which they have no net charge. Id. at 4:67-5:3. This point is known as the isoelectric point, or pI. Id. Each band seen on an isoelectric focusing gel represents molecules that have the same overall charge and are termed "isoforms." Id. at 5:4-5:7. The '298 patent describes "erythropoietin isoforms" as EPO preparations "having a single pI, and having the same amino acid sequence." Id. at 5:6-9. A second technique, ion exchange chromatography, involves separation of proteins on the basis of charge by application of material containing the protein "to a column resin under conditions that permit binding of some or all of the [protein of interest] to the resin." Id. at 7:3-8. The resin can be washed with buffers of varying pHs, thereby "elut[ing]" the proteins based on the charge. Id. at 7:4-17.

         The '349 patent is directed to recombinant cells that are capable of producing EPO at certain rates when grown in culture. The claims of the '349 patent are directed to cells that produce certain units of EPO as determined by a radioimmunoassay, a technique that allows for measuring protein levels using a radioisotope.

         B. Procedural History

         In 2014, Hospira submitted its Biologics License Application (BLA) No. 125-545 to the FDA, seeking approval for a biosimilar to Amgen's Epogen product. Amgen sued Hospira for infringement of the '298 patent under 35 U.S.C. §§ 271(a) and 271(e)(2)(C), and for infringement of the '349 patent under 35 U.S.C. § 271(a). Amgen asserted that Hospira's manufacture of twenty-one batches of drug substance for its EPO biosimilar drug product infringes claims 24 and 27 of the '298 patent and claims 1-7 of the '349 patent. A jury trial was held in September 2017. The jury found the asserted claims of the '298 patent not invalid and infringed, and the asserted claims of the '349 patent not invalid and not infringed. Of the twenty-one accused drug substance batches, the jury found seven batches entitled to the Safe Harbor defense. The jury awarded Amgen $70 million in damages.

         The district court denied Hospira's post-trial Rule 50(b) Motion for Judgment as a Matter of Law on issues of non-infringement and invalidity of the '298 patent, Safe Harbor, and damages, or in the alternative, for remittitur or a new trial. The district court also denied Amgen's renewed motion for JMOL for infringement of the '349 patent, or in the alternative, for a new trial.

         On appeal, Hospira challenges a myriad of issues, including: (1) the district court's claim construction; (2) the jury instructions regarding the Safe Harbor defense; (3) the jury's findings regarding the Safe Harbor defense and denial of JMOL on the Safe Harbor issue; (4) the evidentiary rulings regarding Amgen's damages expert; and (5) the denial of JMOL of noninfringement and invalidity. On cross-appeal, Amgen challenges: (1) the district court's denial of JMOL of infringement of the '349 patent; and (2) the denial of its motion for a new trial. We have jurisdiction under 28 U.S.C. § 1295(a)(1).

         II. Discussion

         We review a denial of JMOL under the law of the regional circuit. Energy Transp. Grp. Inc. v. William Demant Holding A/S, 697 F.3d 1342, 1350 (Fed. Cir. 2012). "In the Third Circuit, review of denial of JMOL is plenary." Finjan, Inc. v. Secure Computing Corp., 626 F.3d 1197, 1202 (Fed. Cir. 2010) (citations omitted). JMOL is "'granted only if, viewing the evidence in the light most favorable to the nonmovant and giving it the advantage of every fair and reasonable inference, there is insufficient evidence from which a jury reasonably could find' for the nonmovant." TransWeb, LLC v. 3M Innovative Props. Co., 812 F.3d 1295, 1301 (Fed. Cir. 2016) (quoting Lightning Lube, Inc. v. Witco Corp., 4 F.3d 1153, 1166 (3d Cir. 1993)); see also Pitts v. Delaware, 646 F.3d 151, 155 (3d Cir. 2011). Moreover, where the movant bore the burden of proof on an issue, JMOL is only granted where "there is insufficient evidence for permitting any different finding." Fireman's Fund Ins. Co. v. Videfreeze Corp., 540 F.2d 1171, 1177 (3d Cir. 1976) (citations omitted). The decision to grant or deny a new trial is committed to the discretion of the district court, which grants a new trial only where "a miscarriage of justice would result if the verdict were to stand" or where the verdict "shocks [the] conscience." Williamson v. Consol. Rail Corp., 926 F.2d 1344, 1352-53 (3d Cir. 1991).

         A. Judgment of Infringement and No Invalidity

         Hospira contends that it is entitled to a judgment of noninfringement of claim 27 of the '298 patent because: (1) the district court's claim construction was erroneous, and no reasonable jury could find infringement under the proper construction; and (2) even under the district court's construction, Amgen did not establish Hospira's infringement of every limitation. Hospira also argues that under the district court's construction, no reasonable jury could find claim 27 not invalid over U.S. Patent No. 4, 667, 016 (Lai). As discussed below, we find Hospira's arguments unavailing.

         i. Claim Construction

         Claim construction is a question of law we review de novo, with subsidiary factual findings based on extrinsic evidence reviewed for clear error. Teva Pharm. USA, Inc. v. Sandoz, Inc., 574 U.S. 318 (2015).

         Claim 27 recites:

A method for obtaining an erythropoietin composition having a predetermined in vivo specific activity comprising preparing a mixture of two or more erythropoietin isoforms of claim 1.

         Claim 1 recites:

An isolated biologically active erythropoietin isoform having a single isoelectric point and having a specific number of sialic acids per molecule, said number selected from the group consisting of 1-14, and said isoform being the product of the expression of an exogenous DNA sequence in a non-human eucaryotic host cell.

         On appeal, the parties do not dispute the district court's finding that, although claim 27 refers to claim 1, it is an independent claim. Defendant-Appellant's Resp. Br. 14-15; Plaintiffs-Cross-Appellants' Br. 28. The district court construed the term "[a]n isolated biologically active erythropoietin isoform" in claim 1 to mean "a group of molecules that has a single isoelectric focusing point and a specific number of sialic acids per molecule, and appears as a single band on an isoelectric focusing gel (an example of which is shown in Figure 1 of the '298 patent)." J.A. 192-93. The district court construed the limitation in claim 27, "a mixture of two or more erythropoietin isoforms of claim 1," to mean "a mixture of two or more of the isolated erythropoietin isoforms of Claim 1." J.A. 174. In denying Hospira's motion for summary judgment of noninfringement, the district court explained that "[n]othing in [the claim] language suggests that the individual isoforms of claim 1 have to be separately prepared prior to making the mixture." J.A.169. Accordingly, the final claim construction provided to the jury included the following sentence: "Claim 27 does not require the individual isoforms of Claim 1 to be separately prepared prior to making the mixture." J.A. 160.

         Hospira challenges this last portion of the construction. According to Hospira, the proper construction of claim 27 requires a mixture of "isolated" isoforms of claim 1, but the district court's construction reads out the phrase "isolated" by stating that the isoforms do not need to be separately prepared prior to making the mixture. Hospira argues that this construction contradicts the intrinsic evidence and the testimony of the inventor Dr. Strickland, who stated that the purpose of his invention "was to separate isoforms and then 'recombine' them or 'mix those fractions back together' to make EPO compositions with specific in vivo activity." Defendant-Appellant's Br. 37 (quoting J.A. 720 at 375:12- 377:18). Hospira contends that under the proper ...


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