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Amgen Inc. v. Hospira, Inc.

United States District Court, D. Delaware

August 27, 2018

HOSPIRA, INC., Defendant.

          Robert W. Whetzel and Jason J. Rawnsley, RICHARDS, LAYTON & FINGER, P.A., Wilmington, DE; Kevin M. Flowers, Mark H. Izraelewicz, John R. Labbe, Julianne M. Hartzell, Benjamin T. Horton, Tiffany D. Gehrke, and Douglas G. Bolesch, MARSHALL, GERSTEIN & BORUN LLP, Chicago, IL; Nicholas Groombridge, Eric Alan Stone, Jennifer H. Wu, and Stephen A Maniscalco, PAUL, WEISS, RIFKIND, WHARTON & GARRISON LLP, New York, NY. Attorneys for Plaintiffs.

          Dominick T. Gattuso, HEYMAN ENERIO GATTUSO & HIRZEL LLP, Wilmington, DE; Thomas J. Meloro, Michael W. Johnson, Heather M. Schneider, Dan Constantinescu, M. Diana Danca, Tara L. Thieme, and Philip F. DiSanto, WILKIE FARR & GALLAGHER LLP, New York, NY. Attorneys for Defendant.



         On September 18, 2015, Amgen, Inc. and Amgen Manufacturing, Limited (collectively, "Amgen") sued Hospira, Inc. for infringement of U.S. Patent No. 5, 856, 298 under 35 U.S.C. §§ 271(a) and 271(e)(2)(C) and for infringement of U.S. Pat. No. 5, 756, 349 under § 271(a). (D.I. 1). The '298 patent and the '349 patent cover erythropoietin ("epoetin" or "EPO") isoforms and aspects of their production. Hospira submitted Biologic License Application ("BLA") No. 125-545 to the FDA in December 2014, seeking FDA approval for Hospira's epoetin biosimilar product. (D.I. 290-1 at 1). Amgen asserts that Hospira's manufacture of drug substance for its epoetin biosimilar drug product infringes claims 24 and 27 of the '298 patent and claims 1-7 of the '349 patent. (D.I. 290 at 1).

         I held a jury trial from September 18-22, 2017. (D.I. 328-332 ("Trial Tr.")).[1] The jury found each of the asserted claims not proved invalid, decided that the asserted claims of the '349 patent were not infringed, and returned a verdict of infringement of all asserted claims of the '298 patent. (D.I. 325 at 2). Of Hospira's twenty-one accused drug substance batches, the jury found seven batches entitled to the safe harbor defense. (Id. at 3). The jury awarded Amgen $70 million in damages for Hospira's infringement. (Id. at 4).

         Presently before the Court are Hospira's Rule 50(a) Motion for Judgment as a Matter of Law on the Issues of Safe Harbor, Noninfringement, Invalidity, and Damages and related briefing (D.I. 336, 337, 348, 351), Hospira's Motion for Judgment as a Matter of Law Under Rule 50(b) and, in the Alternative, For Remittitur or New Trial Under Rule 59 and related briefing (D.I. 355, 357, 374, 381), Hospira's Motion to Seal Confidential Exhibits Admitted at Trial and related briefing (D.I. 361, 369, 370), Amgen's Renewed Motion for Judgment as a Matter of Law of Infringement of the '349 Patent or, in the Alternative, for a New Trial and related briefing (D.I. 356, 358, 373, 380), and Amgen's Motion for Prejudgment and Post-judgment Interest and related briefing (D.I. 352, 376, 382).


         A. Judgment as a Matter of Law

         Judgment as a matter of law is appropriate if "the court finds that a reasonable jury would not have a legally sufficient evidentiary basis to find for [a] party" on an issue. Fed.R.Civ.P. 50(a)(1). "Entry of judgment as a matter of law is a 'sparingly' invoked remedy, 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 liability." Marra v. Phila. Hous. Auth, 497 F.3d 286, 300 (3d Cir. 2007) (citation omitted).

         In assessing the sufficiency of the evidence, the Court must give the nonmovant, "as [the] verdict winner, the benefit of all logical inferences that could be drawn from the evidence presented, resolve all conflicts in the evidence in his favor and, in general, view the record in the light most favorable to him." Williamson v. Consol. Rail Corp., 926 F.2d 1344, 1348 (3d Cir. 1991). The Court may "not determine the credibility of the witnesses [nor] substitute its choice for that of the jury between conflicting elements in the evidence." Perkin-Elmer Corp. v. Computervision Corp., 732 F.2d 888, 893 (Fed. Cir. 1984). Rather, the Court must determine whether the evidence reasonably supports the jury's verdict. See Gomez v. Allegheny Health Servs. Inc., 71 F.3d 1079, 1083 (3d Cir. 1995); 9B Charles Alan Wright & Arthur R. Miller, Federal Practice and Procedure § 2524 (3d ed. 2008) ("The question is not whether there is literally no evidence supporting the party against whom the motion is directed but whether there is evidence upon which the jury might reasonably find a verdict for that party.").

         Where the movant bears the burden of proof, the Third Circuit applies a stricter standard. Fireman's Fund Ins. Co. v. Videfreeze Corp., 540 F.2d 1171, 1177 (3d Cir. 1976). To grant judgment as a matter of law in favor of a party that bears the burden of proof on an issue, the Court "must be able to say not only that there is sufficient evidence to support the [movant's proposed] finding, even though other evidence could support as well a contrary finding, but additionally that there is insufficient evidence for permitting any different finding." Id.

         B. New Trial

         Federal Rule of Civil Procedure 59(a)(1)(A) provides, in pertinent part: "The court may, on motion, grant a new trial on all or some of the issues-and to any party- . . . after a jury trial, for any reason for which a new trial has heretofore been granted in an action at law in federal court. . . ." Among the most common reasons for granting a new trial are: "(1) when the jury's verdict is against the clear weight of the evidence, and a new trial must be granted to prevent a miscarriage of justice; (2) when newly discovered evidence exists that would likely alter the outcome of the trial; (3) when improper conduct by an attorney or the court unfairly influenced the verdict; or (4) when the jury's verdict was facially inconsistent." See Zarow-Smith v. N.J. Transit Rail Operations, Inc., 953 F.Supp. 581, 584-85 (D.N.J. 1997) (citations omitted).

         The decision to grant or deny a new trial is committed to the sound discretion of the district court. Allied Chem. Corp. v. Daiflon, Inc., 449 U.S. 33, 36 (1980); Olefins Trading, Inc. v. Han Yang Chem Corp., 9 F.3d 282, 289 (3d Cir. 1993). Although the standard for granting a new trial is less rigorous than the standard for granting judgment as a matter of law-in that the Court need not view the evidence in the light most favorable to the verdict winner-a new trial should only be granted where "a miscarriage of justice would result if the verdict were to stand" or where the verdict "cries out to be overturned" or "shocks [the] conscience." Williamson, 926 F.2d at 1352-53.

         II. HOSPIRA'S 50(a) AND 50(b) MOTIONS

         Hospira's Rule 50(a) motion raises the same issues as its Rule 50(b) motion.[2] Having considered and decided the issues in ruling on Hospira's Rule 50(b) motion, I will dismiss Hospira's Rule 50(a) motion as moot.

         Hospira seeks judgment as a matter of law on the issues of the applicability of its safe harbor defense, noninfringement and invalidity of the '298 patent, and damages. (D.I. 357, pp. 1-22). Alternatively, Hospira seeks a new trial based on what it characterizes as improper jury instructions on the safe harbor defense and third party liability, improper claim construction, and contradictory infringement and validity verdicts. (Id. pp. 22-30). Finally, Hospira argues that it is entitled to a remittitur of the damages award. (Id. p. 28).

         A. JMOL

         I. Safe Harbor

         The parties dispute whether any reasonable jury could have found some, but not all, of Hospira's drug substance batches protected by the "safe harbor" defense. (Id. p. 1; D.I. 374, p. 2).

         The Biologies Price Competition and Innovation Act of 2009 ("BPCIA") "create[s] an artificial 'act of infringement,' similar to that of 35 U.S.C. § 271(e)(2)(A), and [allows] infringement suits to begin based on the filing of a biosimilar application prior to FDA approval and prior to marketing of the biological product." Amgen Inc. v. Sandoz Inc., 877 F.3d 1315, 1321 (Fed. Cir. 2017) (citing 35 U.S.C. § 271(e)(2)(C), (e)(4), (e)(6)). Section 271(e)(1) carves out an exception to this rule, creating a "safe harbor" defense for defendants when their otherwise-infringing activities are "solely for uses reasonably related" to obtaining FDA approval. 35 U.S.C. § 271(e)(1) ("It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . .. solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products."); Abtox, Inc. v. Exitron Corp., 122 F.3d 1019, 1027 (Fed. Cir. 1997) ("By its terms, this shield from infringement permits use of 'patented invention[s]' to acquire information for regulatory approval of 'drugs or veterinary biological products.'") (brackets in original). "As long as the activity is reasonably related to FDA approval, [a party's] intent or alternative uses are irrelevant to its qualification to invoke the section 271(e)(1) shield." Abtox, 122 F.3d at 1030.

         Hospira asserts that no reasonable jury could find that the safe harbor defense did not protect each of its twenty-one drug substance batches. (D.I. 357, p. 1). Additionally, Hospira contends that Amgen's arguments improperly limited the applicability of the safe harbor defense to batches required for FDA approval. (Id. p. 5). Since each batch was used for one or more of biosimilarity[3] testing, updating product specifications, process validation, stability testing, or continued process verification, Hospira insists that no reasonable jury could have found that each of the batches was not reasonably related to obtaining FDA approval. (Id. pp. 4-8). According to Hospira, the jury improperly second-guessed the number of batches that Hospira manufactured, when "the subjective reason why any batch was made is not relevant" to whether the safe harbor applies. (D.I. 381, pp. 3-4). Essentially, Hospira argues that since Hospira generated test data for each batch prior to FDA approval, each batch could conceivably have been used to respond to inquiries from the FDA, and each batch was reasonably related to FDA approval.

         Amgen disagrees and maintains that substantial evidence supports the jury's reasonable conclusion that Hospira failed to prove that the safe harbor defense applies to each of Hospira's drug substance batches. (D.I. 374, p. 2). According to Amgen, the evidence presented at trial gave the jury ample reason to reject Hospira's arguments about biosimilarity, product specifications, process validation, stability, and continued process verification; credit Amgen's witnesses; and conclude that the safe harbor applied to only seven of Hospira's twenty-one drug substance batches. (Id. pp. 2-4).

         Regarding biosimilarity, even accepting as true that ten reference product lots are required to establish biosimilarity, Amgen points out that Hospira performed biosimilarity testing on drug product batches, not drug substance batches, and that Hospira had previously manufactured twenty-six drug product batches from four drug substance batches. (Id. p. 12 (citing Trial Tr. 811:24-812:8; DTX-266 at 3-4)). Therefore, Amgen argues, though Hospira performed biosimilarity testing on nine drug substance batches, "the jury reasonably concluded that the final two of those batches were not made for uses reasonably related to seeking FDA approval where Hospira had made 26 drug product batches from just 4 of those drug substance batches for biosimilarity testing." (Id. pp. 12-13).

         Amgen also argues, "Hospira's witnesses admitted, and its submissions to the FDA confirmed, that the FDA never required Hospira to manufacture any additional batches of its drug substance to support its narrowed release specifications." (Id. p. 10 (citing Trial Tr. 823:4-824:1)). Regardless, Hospira would be required to perform release testing on all batches manufactured before or after FDA approval to ensure that the batches complied with the release specifications in place at the time of manufacture. (Trial Tr. 819:11-22). Each of the batches at issue in this case "were released against specifications that were in place at the time of manufacture, not against revised specifications," and they remain available to Hospira for future use, since they comply with the release specifications at the time of their manufacture (D.I. 374, p. 10 (citing Trial Tr. 820:24-822:1)). Therefore, Amgen asserts, Hospira's revised product specifications do not justify the conclusion that product specification testing on each of the batches at issue was reasonably related to obtaining FDA approval.

         Regarding process validation, Amgen submits that the "Process Validation and/or Evaluation" section of Hospira's BLA does not refer to batches other than those admitted by Amgen or found by the jury to fall within the safe harbor. (Id. p. 11 (citing DTX-250)). Amgen points out that even Hospira's updated BLA does not list any of the fourteen batches that the jury found to fall outside the safe harbor defense. (Id.). Additionally, Amgen notes, cleaning validation is "the only specific process validation that Hospira raises in its motion," and "Hospira's FDA expert, Dr. Levine, admitted that cleaning validation need not be completed before FDA approval."[4] (Id. (citing Trial Tr. 1102:14-24, 1153:16-18); see also Trial Tr. 878:5-18 (Dr. Billingham acknowledging same)).

         Stability testing would not have required a reasonable jury to conclude that each of Hospira's batches was protected by the safe harbor, Amgen argues, because FDA guidance requires only three batches to demonstrate stability before obtaining FDA approval. (D.I. 374, p. 9 (citing PTX-492, p. 3)). Amgen argues that the jury was therefore free to credit Dr. Martin-Moe's testimony that Hospira's five batches from 2009 to 2012 would have provided sufficient stability data. (Id. (citing Trial Tr. 1329:6-1331:9)). Additionally, stability testing was required each time a new drug substance batch was made, regardless of the future uses for the batch. (Trial Tr. 1338:2-1339:5). As further support, Amgen cites an internal Hospira Risk Authorization document confirming Hospira's belief that material from drug substance batches manufactured in 2009 and 2012 was sufficient to "support [the drug substance] 'shelf life and commercial saleability of material produced in subsequent campaigns.'" (D.I. 374, pp. 9-10 (quoting PTX-342 at 1)). The Risk Authorization further states, "The balance of the material from the 2013 campaign (approximately 50%) and most of the material from the 2014 and 2015 campaigns will serve as commercial inventory to support single dose vial launch stock."[5] (PTX-342 at 1).

         Like stability testing, Amgen's witnesses testified that continued process verification is "an ongoing program . .. during routine commercial production" that sometimes "can take many years to complete." (D.I. 374, p. 8 (citing Trial Tr. 1336:21-1337:9)). Though the FDA requires that applicants have committed to a continued process verification program before approval, completing continued process verification is not required to obtain FDA approval. (Trial Tr. 1337:10-13; see also PTX-435, p. 14). Hospira's witnesses confirmed that continued process verification need not be completed before FDA approval, and Hospira made no commitment to manufacture the thirty batches tested for continued process verification prior to FDA approval. (Trial Tr. 752:7-11 (Ms. Dianis), 747:17-748:3 (Ms. Dianis), 883:3-6 (Dr. Billingham), 1095:8-24 (Dr. Levine)).

         Amgen further argues that the jury was free to credit Amgen's witnesses over Hospira's witnesses given the evidence presented. (D.I. 374, pp. 4-5). First, though Hospira argues that it manufactured each of the 2013, 2014, and 2015 drug substance batches for use in obtaining FDA approval, Amgen notes that Ms. Dianis, the regulatory lead for Hospira's EPO product, "admitted that she did not know why Hospira made its 2015 batches, or why Hospira made as many batches as it did, and that she assumed Hospira's supply team (not the regulatory team) made those decisions." (Id. (citing Trial Tr. 738:22-740:2)). Second, though Hospira informed the FDA in 2014 that its 2013 and 2014 batches were for "commercial inventory," Hospira's 2015 resubmission (after litigation began) designated these batches for use for continued process verification. (Id. at 5 (citing PTX-250 at 4-6; DTX-255 at 5-8); see also Trial Tr. 748:9-751:23). Third, Dr. Levine admitted that he did not consider whether Hospira made any batches for commercial inventory, and that "simply submitting data [to the FDA] isn't a justification" for manufacturing a batch of drug substance. (Trial Tr. 1075:18-1076:1, 1098:1-10).

         I agree with Amgen and conclude that substantial evidence supports the jury's verdict that not all of Hospira's drug substance batches are protected by the safe harbor. To demonstrate entitlement to judgment as a matter of law on its safe harbor defense, Hospira must demonstrate that "there is insufficient evidence for permitting any other finding." Fireman's Fund Ins. Co., 54OF.2d at 1177. Hospira has not met that burden.

         A reasonable jury could have concluded that fewer than all of the batches were protected by the safe harbor defense. Testimony by Ms. Dianis and Dr. Levine either called into question or contradicted Hospira's argument that each of the batches at issue fell within the safe harbor defense. Amgen's presentation of FDA guidance documents, admissions in Hospira's internal documents, and post-litigation changes to Hospira's representations to the FDA also challenged Hospira's assertion that each batch at issue was covered by the safe harbor. Finally, Hospira's argument that the jury impermissibly focused on Hospira's intent in manufacturing the batches does not stand up to further scrutiny. Though all of the 2015 batches were designated for use as "commercial inventory" in Hospira's Risk Authorization, the jury nonetheless found that some of those batches were protected by the safe harbor. (D.I. 325 at 3). This suggests that the jury did not improperly base its verdict on Hospira's intent. I therefore conclude that substantial evidence supports the jury's verdict that only some batches at issue are covered by the safe harbor defense. I will deny Hospira's motion for JMOL on this ground.

         2. Noninfringement of the '298 Patent

         Hospira submits that I should grant its motion for JMOL that it does not infringe claims 24 or 27 of the '298 patent.

         Hospira contends that it is entitled to JMOL of noninfringement of claim 24 of the 298 patent because "Amgen failed to prove that Hospira's process 'selectively elutes' isoforms as required by claim 24 and as construed by the Court." (D.I. 357, p. 12). According to Hospira, elution of all biologically active isoforms does not qualify as selective elution. (Id.). Specifically, "Hospira's process does not achieve a precise set of isoforms;" instead, it "results in a variable number of different isoforms [i.e., five to eight], and a variable amount of each isoform in the drug substance." (Id. (citing Trial Tr. 984:5-989:17 (Dr. Levine))). Dr. Levine opined that such variability is not consistent with selective elution, because one would expect consistent levels of each isoform across batches in a selective elution process. (Trial Tr. 989:3-9, 1580:4-23). Finally, Hospira argues that Amgen failed to prove infringement of the '298 patent because it did not provide any analysis of the starting material that Hospira puts into the chromatography column. (D.I. 381, p. 9).

         Amgen maintains that substantial evidence supports the jury's conclusion that Hospira's process "selectively elutes" isoforms as required by claim 24 of the '298 patent. Dr. Cummings testified that Hospira's process "selectively elutes" isoforms because it "first elute[s] more basic isoforms from the chromatography column, then elute[s] the remaining desired isoforms." (D.I. 374, p. 13 (citing Trial Tr. 468:11-469:4)). During trial, Amgen argued that Dr. Levine ignored the first step in the elution process, and that Dr. Levine admitted that he "was intentionally not showing those [more basic isoform elution] steps because [he] had already discussed this" the day before. (Trial Tr. 1156:22-1157:13). Amgen also notes that contrary to Hospira's argument, the Court's claim construction for claim 24 does not "require a 'precise set of predetermined isoforms.'" (D.I. 374, p. 14; see also D.I. 180 at 2). Further, Dr. Strickland, the inventor on the '298 patent, testified that the process he invented "select[s] isoforms by-well, specific mixtures of isoforms[, ] by selective elution of an ion exchange chromatography column." (Trial Tr. 373:14-20). As further evidence that Hospira's process met the "selectively elute" limitation, Amgen offered Hospira's lot release specifications, which specified five isoforms that must be present, and three additional isoforms that may be present, with specific ranges for each isoform. (DTX-141, p. 7; Trial Tr. 470:13-472:19). Finally, Amgen asserts that Hospira's "starting material" argument is frivolous because "Hospira admitted in its BLA that its ion-exchange chromatography process first removed the 'more basic' isoforms .. . from the column (DTX-116 at 58), a step that would not be necessary if the starting material did not contain isoforms that were 'more basic' than the isoforms required by Hospira's release specification." (D.I. 374, p. 15). Similarly, Hospira's BLA test results reveal that the only isoforms present in the material leaving the column in Hospira's process are the same isoforms present in Hospira's drug substance. (Id. (citing DTX-139, p. 102; DTX-141, p. 7; Trial Tr. 474:19-476:11)).

         I agree with Amgen that substantial evidence supports the jury's verdict that Hospira infringes claim 24 of the '298 patent. Dr. Strickland's testimony, Hospira's release specifications, and Dr. Cummings' testimony provided the jury substantial evidence to conclude that Hospira's process met the "selectively elute" limitation and infringed claim 24 of the '298 patent. Additionally, I think Dr. Levine's admission that he did not include all steps of the process in his demonstratives for the jury provided a basis for the jury to question the reliability of his conclusions and discount his testimony.

         Claim 27 of the '298 patent requires "preparing a mixture of two or more erythropoietin isoforms of claim 1." Though I construed claim 27 as an independent claim, Hospira argues that it is entitled to JMOL because Amgen did not mention claim 1 during trial, nor did it present evidence that "isoforms are isolated during Hospira's manufacturing process." (D.I. 357, p. 13). Amgen responds that since claim 27 is an independent claim, Amgen was not required to present evidence that each of the limitations of claim 1 was met in order to prove infringement of claim 27. (Id. p. 15). As to the isolation of isoforms, Amgen notes that the Court's construction of claim 27 "does not require the isoforms of Claim 1 to be separately prepared prior to making the mixture." (D.I. 374, p. 15 (citing D.I. 308 at 2)). Regardless, Amgen urges, "the evidence at trial showed that the limitations of claim 1 were satisfied, that is, that Hospira's product contains 'biologically active' EPO." (Id. (citing DTX-270, p. 17; Trial Tr. 394:1-4 (admission by Dr. Strickland that "all EPO isoforms have biological activity."))).

         I agree with Amgen. Though Hospira may be correct that Amgen never explicitly mentioned claim 1 at trial, Hospira does not discuss substantively how Amgen failed to prove that the limitations of claim 1 were met. Amgen has also offered citations to Hospira's BLA and to the trial transcript to support the conclusion that the limitations of claim 1 were satisfied.

         Claim 27 also has a limitation requiring the creation of an EPO composition with a "predetermined in vivo specific activity." Hospira argues that Amgen failed to prove that Hospira infringed this limitation because "Dr. Cummings did not provide any evidence of the actual in vivo specific activity of Hospira's product," and Hospira's product targets a range of in vivo specific activities, rather than targeting a specific activity. (D.I. 357, p. 14). Hospira also contends, "Dr. Strickland testified that in order to achieve a predetermined specific in vivo activity, one selects individual isoforms and prepares them in such a way to know what biological activity they are going to get."[6] (D.I. 381, pp. 9-10 (citing Trial Tr. 375:12-376:2)). Since there is no evidence that Hospira separates and selects individual isoforms, Hospira argues, there was insufficient evidence for the jury to conclude that Hospira infringed claim 27. (Id. p. 10). Amgen responds that Dr. Cummings relied on Hospira's BLA, which stated that 100% of lots fell within an in vivo specific activity of 93-147 U/µg.[7] (D.I. 374, p. 16 (citing DTX-270, p. 17)).

         I agree with Amgen. I do not find Dr. Strickland's testimony, cited by Hospira, inconsistent with Hospira's BLA, which identifies a predetermined in vivo specific activity-93-147 U/µg. (DTX-270, p. 17; see Trial Tr. 375:12-376:2). Hospira's BLA provided the jury with substantial evidence to conclude that Hospira's process achieved an EPO composition having a predetermined in vivo specific activity.

         I therefore conclude that substantial evidence supports the jury's verdict that Hospira infringes claims 24 and 27 of the '298 patent. I will deny Hospira's JMOL on this ground.

         3. Invalidity of the '298 Patent

         Hospira argues that it is entitled to JMOL that the '298 patent is invalid because no reasonable jury could have found that claims 24 and 27 were not anticipated or obvious over U.S. Pat. No. 4, 667, 016 ("Lai"). (D.I. 357, p. 14). Since it was Hospira's burden to prove invalidity, to prevail on its JMOL, Hospira must demonstrate that "there is insufficient evidence for permitting any different finding" than that the disclosures in Lai render invalid claims 24 and 27 of the '298 patent. See Fireman's Fund Ins. Co., 54OF.2d at 1177.

         The parties dispute whether Hospira adequately proved that the Lai process inherently anticipates claim 24 of the '298 patent. Specifically, they dispute whether Hospira proved that Lai meets the "selectively eluting" and "predetermined number of sialic acids" limitations of claim 24.

         Hospira asserts that Dr. Levine's testimony, Dr. Strickland's testimony, and Dr. Cummings' testimony conclusively established that Lai includes a "selective elution" step. (Id. pp. 15-16). Dr. Levine did not dispute that Lai does not refer to the removal of biologically active EPO in ion exchange chromatography. (Trial Tr. 1010:10-16). Based on "the fundamental principles on which ion exchange chromatography works, and the difference in pKa[8] between high sialic and low sialic acid containing isoforms," however, Dr. Levine opined that Lai's step 2 example 2 "low pH, low salt wash will remove proteins that have a pKa greater than the biologically active EPO . . . [which] will include the isoforms of EPO that have a small number of sialic acid[s] and are therefore not biologically active, or less biologically active." (Id. 1010:1-16). As further support, Hospira points to Dr. Levine's and Dr. Strickland's discussions of the '298 patent's disclosure that the starting material for the fourth isoform of EPO is the material removed from the column in Example 2 of Lai, which contains EPO isoforms with less than or equal to nine sialic acids. (Id. 1034:5-14, 393:14-21). Dr. Cummings confirmed that when Dr. Strickland replicated the experiment reported in Example 2 of Lai, the result was that EPO isoforms containing nine to fourteen sialic acids were retained on the chromatography column after the first acid wash step. (Id. 1508:15-1509:9). Therefore, Hospira argues, Lai inherently discloses selective elution of EPO with less than nine sialic acids. (D.I. 357, p. 16).

         Amgen responds that the jury declined to credit Hospira's argument that "practicing Example 2 of Lai 'necessarily and inevitably' resulted in 'selectively eluting' EPO molecules with a 'predetermined' number of sialic acids." (D.I. 374, pp. 16-17). Amgen points to Dr. Cummings, who testified that, contrary to Dr. Levine's assertion, "all EPO is biologically active," and the purpose of Lai was to purify EPO, not to separate EPO isoforms. (Trial Tr. 1494:12-1495:4). Amgen maintains that despite testimony that "some isoforms may be removed in Example 2 of Lai, none of the witnesses "testified that Example 2 in Lai 'necessarily and inevitably' results in" selectively eluting EPO isoforms with a predetermined number of sialic acids, as would be required to prove inherent anticipation. (D.I. 374, p. 18). Amgen argues that Dr. Levine's admission that several factors could affect which isoforms are present in the starting material (including cell culture conditions and the components of the cell culture medium) further supports that the Lai process does not "necessarily and inevitably" meet the limitations ...

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