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Hospira Requests En Banc Review as to its Entitlement to Safe Harbor Protections for Manufacturing its Epogen® Biosimilar


On January 15, 2020, Hospira, Inc. filed a petition for rehearing en banc of the Federal Circuit’s December 16, 2019 panel decision in Amgen, Inc. v. Hospira, Inc., Nos. 2019-1067, 2019-1102 (Fed.Cir. 2019) in which Hospira lost on the issue of whether its EPO biosimilar manufacturing activities are entitled to Safe Harbor protections. The petition requested review on the question of “[w]hether 35 U.S.C. § 271(e)(1) provides a safe harbor against infringement of patents claiming a method of manufacture, when the product manufactured is used to generate information for submission to the Food and Drug Administration (‘FDA’) in order to seek approval of a biosimilar drug.” Petition, page 1.  Hospira also alleges that the panel decision is contrary to the Safe Harbor precedent of the US Supreme Court and the Federal Circuit, as well as erring in its claim construction by improperly “reading out a claim limitation” relating to the meaning of “mixture…of isoforms.” The Federal Circuit has yet to decide on the petition.

The Asserted Claims

Amgen asserted two manufacturing patents (US 5,856,298 and US 5,756,349) covering manufacture of Epogen® (erythropoietin or EPO), a glycoprotein hormone that regulates the manufacture and production of red blood cells. Amgen’s suit was filed in response to Hospira’s 2014 Biologics License Application (BLA) seeking approval of its Epogen® biosimilar. Amgen asserted that “Hospira’s manufacture of twenty-one batches [in 2013, 2014, and 2015] 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.” Panel Decision, p. 4. A jury at district court found the ‘349 patent to be not infringed, and  claims 24 and 27 of the ‘298 patent to be valid and infringed. However, of the twenty-one allegedly infringing biosimilar batches, the jury found that seven of those batches were entitled to the Safe Harbor defense. Hospira appealed the district court’s decision on a range of issues, including the jury’s findings regarding the lack of the Safe Harbor defense for most of the product batches and the claim construction of claim 27 on the meaning of “mixture of…isoforms” in claim 27. The Federal Circuit concluded that substantial evidence supported the jury’s findings that claim 27 was not invalid and infringed, and that the district court did not err in its determination that the Safe Harbor did not apply to fourteen biosimilar product batches. The Federal Circuit did not rule on claim 24 and, as such, is not further addressed here. Claims 27 and 1 of the ‘298 patent are as follows (with the language subject to claim construction  in bold):

  • 27. 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.
  • 1. An isolatedbiologically 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.

The Claim Construction Issue

Following a district court trial, a jury found claim 27 of the ‘298 patent valid and infringed. The district court upheld this finding by denying Hospira’s renewed motion for judgment as a matter of law, which Hospira then appealed. The panel decision of the Federal Circuit affirmed the district court’s ruling and the underlying jury finding on claim construction of claim 27.

The jury instruction included a construction of the recitation in claim 27 of “preparing a mixture of two or more erythropoietin isoforms of claim 1.” Hospira argued that in view of the subject matter of claim 1 being directed to “[a]n isolated” erythropoietin isoform, the recitation of “a mixture of two or more erythropoietin isoforms” should mean “a mixture of two or more of the isolated erythropoietin isoforms of Claim 1.” Panel Decision, page 6. According to Hospira, the court’s construction “read out” the term “isolated” from claim 1 and that under the proper construction, Hospira’s manufacturing would not infringe the ‘298 patent because it “does not mix isolated isoforms.” Panel Decision, page 7.   

The district court disagreed with Hospira’s construction because, according to the court, the claim language does not suggest or require “that the individual isoforms of claim 1 have to be separately prepared prior to making the mixture [of claim 27].” Consistent with this view, the district court’s jury instruction stated that claim 27 does not require separate preparation of individual isolated isoforms of claim 1 prior to making the mixture of claim 27. 

Hospira pointed to testimony from the inventor of the ‘298 patent (also an Amgen employee) who stated that his invention aimed to “separate isoforms and then ‘recombine’ them or ‘mix those fractions back together’ to make EPO compositions with specific in vivo activity.” Panel Decision, page 7. Amgen countered with the view that the phrase “preparing a mixture” of isoforms in claim 27 does not mean “mixing” isoforms since such a construction would give no meaning to the term “preparing.” Amgen contended during trial that “preparing a mixture” of isoforms contemplates obtaining a mixture of isoforms in more than one way—including simultaneous preparation of a mixture of different isoforms—thereby allegedly covering Hospira’s manufacturing process. The jury and district court found for Amgen, the judgment of which was affirmed by the Federal Circuit.

In its petition, Hospira argued that the Federal Circuit erred when it “read out” the term “isolated” by ignoring three claim construction principles, namely, (1) that each limitation of a claim must be meaningful, (2) express limitations cannot be ignored and (3) the courts cannot redraft claims. 

The Safe Harbor Issue

The Federal Circuit affirmed the district court’s ruling that only seven of 21 batches of Hospira’s manufactured biosimilar EPO were entitled to Safe Harbor protections of 35 U.S.C. 271(e)(1) against infringement of the asserted patents. Hospira asserts in its petition that en banc review is appropriate because “the panel misapplied the statutory Safe Harbor provided by 35 U.S.C. 271(e)(1) as well as Supreme Court and binding precedent of this Court, in a case involving one of the first Biologics License Application (“BLA”) submitted under the Biologics Price Competition and Innovation At (“BPCIA”).” Petition, page 3. Hospira supported its argument on two grounds. 

First, Hospira argued that the panel “erred by ignoring the broad, objective nature of the Safe Harbor” set out by the Supreme Court in Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005), which held that “[Congress] exempted from infringement all use of patented compounds ‘reasonably related’ to the process of developing information for submission under any federal law regulating the manufacture, use, or distribution of drugs.” Petition, page 10. Hospira argued that the use of patent compounds in any amount was protected under the Safe Harbor so long as there is a “reasonable basis” for believing that such uses will result in the kinds of information that are relevant to an “IND or NDA,” even if the information is not ultimately submitted. Citing to Intermedics, Inc. v. Ventritex, Inc., 775 F.Supp. 1269, 1280 (N.D. Cal. 1991), aff’d I991 F.2d 808 (Fed. Cir. 1993)

According to Hospira, the Federal Circuit and district court erred by focusing on the “underlying purpose” of Hospira’s use, i.e., its intention for manufacturing each of its batches, rather than the “objective nature” that each of Hospira’s product batches were, in fact, used to generate information submitted to the FDA during the approval process. In contending that this treatment was contrary to long-standing precedent, Hospira submitted that “[t]he relevant inquiry, therefore, is not how Hospira used each batch it manufactured, but whether each act of manufacture was for uses reasonably related to submitting information to the FDA.” Petition, page 11. 

Amgen had accused Hospira that much of its manufacturing batches from 2013, 2014, and 2015 (the twenty-one batches in question) were not intended solely to generate information relevant to the approval process, but rather were used to stockpile commercial amounts of the biologic. Amgen pointed to a range of evidence on specific uses, such as stability testing of various batches, Continued Process Verification testing (testing associated with commercial batches but which is not required for FDA approval) of batches, and documentary evidence showing that Hospira “planned for ‘the balance of the material from the 2013 campaign (approximately 50%) and most of the material from the 2014 and 2015 campaigns [to] serve as commercial inventory to support single dose vial launch stock.” Panel Decision, pages 17-18.

In a footnote, the Federal Circuit rejected “Hospira’s suggestion that simply submitting information about a drug substance lot to the FDA brings the manufacture of that lot within the Safe Harbor. We have explained that ‘routine record retention requirements associated with testing and other aspects of the commercial production process’ are not protected by the Safe Harbor,” citing to Momenta Pharms., Inc. v. Teva Pharms. USA, Inc., 809 F.3d 610, 620-21 (Fed. Cir. 2015).  Panel Decision, page. 17, footnote 3.

In its petition, Hospira maintained that the Safe Harbor was much broader in scope under Merck, pointing out that “[t]he accused batches actually were all used to generate data submitted to the FDA that was required for FDA approval” and that “no reasonable jury could have found that any of the accused batches fell outside the Safe Harbor.” Petition, page 19.

Second, Hospira contended that en banc review was warranted because “this appears to be the first litigation in which this Court specifically has considered the applicability of the Safe Harbor to patents claiming a method of manufacture.” Petition, page 20. Hospira draws a distinction between cases under Hatch-Waxman (which relate only to Orange Book patents covering drug product or uses thereof) and cases filed under the BPCIA, which “permits the inclusion of process [manufacturing] patents in biosimilar patent litigation brought under that act,” which according to Hospira, have been the main type of patents asserted in BPCIA litigations to date. Hospira argues that the panel’s acceptance of an “intended use” standard for process patents “has replaced the well-established test regarding uses of a patented product with an inquiry into the underlying purposes for why each batch was manufactured…” and that “[t]here is no justification for this departure.” Petition, pages 21-22.


Hospira’s petition highlights the continued uncertainty about the scope of protections (e.g., amounts, types of submitted information and for what purposes) under the Safe Harbor to which biologics manufacturing companies should be entitled with regard to biosimilar manufacturing activities in view of patents directed to manufacturing processes. Hospira also calls into question whether the Federal Circuit is treating process patents under the BPCIA using a different Safe Harbor standard as compared to how it has treated product patents under cases brought under the Hatch-Waxman Act.