Factor VIII / Adynovate® – USA

Factor VIII / Adynovate® – USA

On Mar. 01, 2021, Federal Circuit affirmed District Court which found Hemophilia patent valid & infringed.


Bayer sued Baxalta/Nektar for infringement of US 9,364,520 patent alleging that Baxalta’s biologic product Adynovate® infringes certain claims of the patent. US’520 patent is directed to recombinant forms of human factor VIII (responsible for blood coagulation). FVIII is a protein having different structural domains among which “B-domain” is of relevance here. The patent explains that by doing “PEGylation” (attaching PEG molecule), the in vivo half-life of a protein has been increased. This has been done by “specific pre-defined” site pegylation & not at “random” site of Factor VIII. “Random” modification of FVIII by PEGylation was known in the art which was having certain disadvantages.


Claim 1 is the only asserted independent claim and recites: (Bold highlighted portions were relevant to claim construction inquiry)


1. An isolated polypeptide conjugate comprising a functional factor VIII polypeptide and one or more biocompatible polymers, wherein the functional factor VIII polypeptide comprises the amino acid sequence of SEQ ID NO: 4 or an allelic variant thereof and has a B-domain, and further wherein the biocompatible polymer comprises polyalkylene oxide and is covalently attached to the functional factor VIII polypeptide at the B-domain.


Claim construction:

The district court construed the claim term “an isolated polypeptide conjugate” in claim 1 to mean “a polypeptide
conjugate where conjugation was not random.” The district court determined that, during prosecution of the ’520 patent, Bayer had “clearly and unmistakably disclaimed any ‘polypeptide conjugate where conjugation was random.” In addition, the district court construed the claim term “at the B-domain” in claim 1 to mean “attachment at the B-domain such that the resulting conjugate retains functional factor VIII activity.” Baxalta contended that the district court erred in failing to construe the term to exclude amine/lysine conjugation. Baxalta argued that the specification disparages amine/lysine conjugation. But, Federal Circuit said that the plain language of claim 1 does not require PEGylation at any particular amino acid sites in the B-domain, let alone exclude from its scope any specific amino acids as attachment sites in the B-domain. Rather, claim 1 more broadly requires PEGylation at the B-domain as a region. Specification & Prosecution History also support this construction.  During prosecution, Bayer argued that Bossard (prior art) did not teach the claimed conjugates because Bossard’s “alleged showing of B-domain attachment is random PEGylation and does not ensure that attachment occurs at the B-domain.” Federal Circuit, thus rejected Baxalta’s argument & agreed with District Court’s construction.



Bayer presented documentary evidence and expert witness testimony demonstrating that Adynovate® meets the
limitations of claim 1 of the ’520 patent as construed by the district court. In its submission, Baxalta represented to the FDA that “Adynovate is a modified recombinant FVIII protein created by the pre-translational inclusion of the B-domain, and controlled, targeted chemical addition of 20 [kilodalton] PEG conjugates to this FVIII B-domain.” Baxalta’s submission also stated that “evidence suggests that the B-domain is more surface-exposed than the other domains, and becomes accessible to the PEG-reagent under the specific reaction conditions. Baxalta made specific reaction condition choices to “allow [it] to target the PEGylation reaction to the B-domain” of FVIII. Moreover, Baxalta’s BLA for Adynovate mentioned test results which showed that PEG was attached at the B-domain. These are sufficient evidences, Federal Circuit said.


Lack of Enablement:

Baxalta argued that US’520 patent does not enable “non-random lysine PEGylation.” Court said that the specification of the ’520 patent includes detailed instructions as to the reaction conditions required to practice the claimed invention using cysteine PEGylation, and includes a working example for non-random cysteine PEGylation at the B-domain. Bayer presented evidence to the jury bridging the gap between the patent’s disclosures about cysteine PEGylation on the one hand and non-random PEGylation, including non-random lysine PEGylation, on the other. In addition, multiple witnesses testified that random lysine PEGylation was known at the time of the invention.  Court said that Bayer presented substantial evidence from which a reasonable juror could find that the specification’s disclosure of instructions as to the reaction conditions required to practice the claimed invention using cysteine PEGylation were sufficient to enable not only non-random cysteine PEGylation at the B-domain, but also non-random lysine PEGylation at the B-domain. Therefore, the district court did not err in its legal analysis.


Damages: Federal Circuit sided with jury regarding royalty rate of 17.78% chosen for damages.


Thus, Federal Circuit affirmed the district court’s judgments of infringement, enablement, damages, pre-verdict supplemental damages, and no willfulness.


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