PTAB

IPR2018-01313

CSL Behring LLC, CSL Behring GmbH, and CSL Behring Recombinant Facility AG v. Bioverativ Therapeutics, Inc.

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1. Case Identification

2. Patent Overview

  • Title: Methods of Dosing Chimeric Factor IX Polypeptides
  • Brief Description: The ’091 patent claims methods for treating hemophilia B by administering a chimeric Factor IX (FIX) polypeptide. The claimed method requires intravenous administration of multiple doses of about 50-100 IU/kg at a dosing interval of about 10-14 days to maintain plasma FIX activity above 1 IU/dL and reduce the frequency of spontaneous bleeding.

3. Grounds for Unpatentability

Ground I: Obviousness over Peters and Shapiro - Claims 1-17, 20, 22, 24, and 28 are obvious over Peters 2010 in view of Shapiro and the knowledge of a POSA.

  • Prior Art Relied Upon: Peters et al., Prolonged Activity of Factor IX as a Monomeric Fc Fusion Protein, 115 Blood 2057 (2010) (“Peters 2010”); and Shapiro et al., The Safety and Efficacy of Recombinant Human Blood Coagulation Factor IX in Previously Untreated Patients..., 105 Blood 518 (2005) (“Shapiro”).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Peters 2010 disclosed a chimeric FIX-Fc fusion protein (rFIXFc) with an extended in vivo half-life that was 3- to 4-fold longer than standard recombinant FIX (rFIX). Shapiro taught successful weekly prophylactic treatment of hemophilia B using rFIX at doses (50-100 IU/kg) that overlap with the claimed dose range. Petitioner asserted that Peters 2010 also taught the goal of maintaining FIX levels above 1% (1 IU/dL) and recognized that a longer half-life product would require fewer injections. The combination of Peters 2010's extended half-life molecule and Shapiro's established effective dosing for rFIX allegedly rendered the claimed dosing regimen obvious.
    • Motivation to Combine: A person of ordinary skill in the art (POSA) would have been motivated to combine the teachings to address the well-known need for less frequent FIX dosing regimens to improve patient convenience and compliance. A POSA would look to an established, effective dosing regimen like Shapiro's as a starting point and modify the interval based on the extended half-life (3-4 fold longer) of the rFIXFc molecule disclosed in Peters 2010. The natural modification would be to extend the 7-day interval of Shapiro to a 10-14 day interval.
    • Expectation of Success: A POSA would have had a reasonable expectation of success. Peters 2010 showed that rFIXFc was comparably effective to rFIX in animal models, which were understood to be predictive of human results for efficacy and half-life extension. Knowing from Shapiro that weekly rFIX doses of 50-100 IU/kg were safe and effective, a POSA would reasonably expect that administering a similar dose of the longer-lasting rFIXFc at a proportionally longer interval (e.g., 10-14 days) would successfully maintain therapeutic FIX levels and reduce bleeding.

Ground II: Obviousness over Metzner/’755, Shapiro, and Carlsson - Claims 1-16, 18, 19, 21, and 23-27 are obvious over Metzner and/or the ’755 publication in view of Shapiro, Carlsson, and the knowledge of a POSA.

  • Prior Art Relied Upon: Metzner et al., Genetic Fusion to Albumin Improves the Pharmacokinetic Properties of Factor IX, 102 J. Thrombosis & Haemostasis 634 (2009) (“Metzner”); U.S. Application # 2008/0260755 (“’755 publication”); Shapiro (2005); and Carlsson et al., Multidose Pharmacokinetics of Factor IX..., 4 Haemophilia 83 (1998) (“Carlsson”).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner contended that Metzner and the ’755 publication disclosed a different extended half-life molecule: a recombinant FIX-albumin fusion protein (rIX-FP) with a 2- to 5-fold longer half-life than rFIX in animals. As in Ground I, Shapiro provided an established, overlapping dose range (50-100 IU/kg) for weekly rFIX prophylaxis. Carlsson further taught that the goal of prophylactic treatment is to maintain plasma FIX activity levels at or above 1 IU/dL to prevent bleeding. Together, these references taught a method of treating hemophilia B with a long-acting FIX-albumin fusion protein.
    • Motivation to Combine: The motivation was identical to Ground I: to use a novel extended half-life molecule (here, rIX-FP from Metzner/’755 publication) to achieve a less frequent dosing schedule, a recognized goal in the art explicitly stated in the primary references. A POSA would be motivated to apply the known effective dosing parameters for rFIX (from Shapiro) to the new rIX-FP molecule, modifying the dosing interval to leverage its extended half-life.
    • Expectation of Success: A POSA would have had a reasonable expectation of success because Metzner and the ’755 publication demonstrated that rIX-FP was effective and had a significantly extended half-life (up to 4-5 times longer) in predictive animal models. Combining this with the known effective dose range from Shapiro and the therapeutic target from Carlsson would lead a POSA to reasonably expect that administering rIX-FP at a similar dose but at a longer interval of 10-14 days would be safe and effective.

4. Key Technical Contentions (Beyond Claim Construction)

  • Validity of Peters 2010 as Prior Art: A central argument was that the Examiner erred during prosecution by disqualifying the Peters 2010 reference. The disqualification was based on a declaration from a co-inventor of the ’091 patent, which Petitioner argued was conclusory and insufficient under pre-AIA 35 U.S.C. §102(a) to establish that the reference was not "by another." Petitioner contended that the declaration failed to overcome evidence in the article itself showing inventive contributions from other, non-inventor co-authors.
  • Entitlement to Priority Date: Petitioner argued that the ’091 patent was not entitled to its claimed priority dates from its provisional applications. The argument was based on a lack of written description and enablement under 35 U.S.C. §112. Petitioner asserted the provisional applications disclosed data for only one specific molecule (rFIXFc), which was insufficient to support the broad genus of chimeric FIX polypeptides claimed. Without the benefit of the earlier priority dates, both Peters 2010 and Metzner would qualify as prior art under §102(b).

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of all challenged claims, 1-28, of the ’091 patent as unpatentable under 35 U.S.C. §103.