Erythropoietin – USA

On Dec 16, 2019, Federal Circuit affirmed district court’s decision which awarded $70 million to Amgen as certain batches of Hospira’s biosimilar found to infringe method of preparation claim.

The patents-in-suit are US 5,856,298 and US 5,756,349. The claims of the ’298 patent claim related to 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. The ’349 patent is directed to recombinant cells that are capable of producing EPO at certain rates when grown in culture.

In 2014, Hospira submitted BLA 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 sub-stance 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 then 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.

Hospira appealed on various issues.

With respect to infringement of claim 27, Hospira contended that it is entitled to a judgment of noninfringement.

Claim 27 of US’298 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 erythropoi-etin 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.

During appeal Hospira argued that, Amgen’s evidence is insufficient to establish that Hospira’s EPO has a “predetermined in vivo specific activity,” as required by claim 27. Amgen contended that Hospira’s statements in its BLA show that its EPO falls within a specified range of in vivo specific activity, a range that was, in Amgen’s view, “predetermined based on the reference product”. Court said that substantial evidence supports the jury’s infringement verdict. As to whether Hospira’s process results in EPO that has a predetermined in vivo specific activity, Hospira’s BLA states that 100% of its EPO batches have a specified range of in vivo activity, i.e., 93–147 U/μg. Amgen’s expert, Dr. Cummings, testified that all of Hos-pira’s EPO batches have an in vivo specific activity within a specified range, a range predetermined based on Epogen, the reference product.

With respect to safe harbor provision, Hospira contended that no reasonable jury could have found that some, but not all, of Hospira’s drug substance batches were protected by the Safe Harbor defense. Hospira argued that all twenty-one batches were used for the development and submission of information included in the original BLA filing or in a subsequent filing necessitated by a Complete Response Letter (CRL) from the FDA. In Hospira’s view, “the jury instructions and verdict form improperly focused the jury on the reasons why each batch of EPO was manufactured, not how each batch was used or whether that use was reasonably related to the development and submission of in-formation to support Hospira’s BLA.” According to Amgen, the jury instructions “properly focused the jury on Hospira’s use of the patented invention, that is, the manufacture of [Hospira’s EPO] drug substance, and then asked whether each act of manufacture was for uses reasonably related to seeking FDA approval.”

Court said that here, the patented inventions are Amgen’s claimed methods of manufacture. The accused activity is Hospira’s use of Amgen’s claimed methods of manufacture. The 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 as required by safe harbor. At issue are twenty-one batches of EPO Hospira manufactured in 2013, 2014, and 2015. The jury found seven batches were protected under the Safe Harbor, whereas fourteen were not. The protected batches include two batches used for qualifying Hospira’s process to make the drug and for qualifying alternate equipment (manufactured in 2013) and five batches used for a mandatory pre-approval inspection by the FDA (manufactured in 2015). For all other batches, the jury found no Safe Harbor protection.

Hospira used the EPO batches at issue for various types of testing, including biosimilarity, revisions to re-lease specifications, stability testing, and continued process verification (CPV). According to Hospira, each type of testing was conducted as part of its BLA submission or its response to the FDA’s CRL.

Court further said that substantial evidence supports the jury’s finding that the batches at issue were not manufactured “solely for uses reasonably related to the development and submission of information” to the FDA. For example, Amgen’s expert, Dr. Martin-Moe, testified that Hospira was not required to manufacture additional batches after it made its 2012 batches. She also explained that stability testing of Hospira’s 2013 batches was not required but would be part of a “continuing program for stability that is a post-approval commitment.” She further explained that CPV is an ongoing process that applies to batches made for commercial use. Hospira’s regulatory witness, Ms. Dianis, admitted that CPV is not required before FDA approval. Further, Hospira’s Senior Director of Analytical R&D, Dr. Srebalus-Barnes, admitted that Hospira did not manufacture any drug substance batches in response to the FDA’s CRL and the CRL did not require manufacture of additional batches. Accordingly, the jury reasonably found that certain batches at issue were not protected under the Safe Harbor.