PTAB

IPR2017-01512

CSL Behring GmbH v. Shire ViroPharma Incorporated

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1. Case Identification

  • Patent #: 9,616,111
  • Filed: May 31, 2017
  • Petitioner(s): CSL Behring GmbH and CSL Behring LLC
  • Patent Owner(s): Shire Viropharma Inc.
  • Challenged Claims: 1-18

2. Patent Overview

  • Title: Method of Treating Hereditary Angioedema
  • Brief Description: The ’111 patent is directed to methods for treating hereditary angioedema (HAE) by subcutaneously administering a C1 esterase inhibitor (C1-INH) composition. The claims require a C1-INH concentration of at least about 400U/mL in a citrate or phosphate buffer at a pH of 6.5-8.0, with the C1-INH having at least 95% identity to a specific amino acid sequence, administered at a dose of at least 1000U to increase blood levels of C1-INH to at least 0.4U/mL.

3. Grounds for Unpatentability

Ground 1: Claims 1-18 are obvious over Schranz in view of Gatlin, Pharming, and Levi.

  • Prior Art Relied Upon: Schranz (a 2012 poster presentation on Cinryze® clinical studies), Gatlin (a 1999 book chapter on parenteral drug formulation), Pharming (WO 2007/073186), Levi (a 2006 journal article), Bock (a 1986 journal article), and the Cinryze® Label (2012).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner asserted that Schranz, which was submitted to the USPTO late in prosecution and not substantively considered, is the closest prior art. Schranz disclosed results from a study (the "Prior 200 Study") involving the successful subcutaneous (sc) administration of a 2000U dose of Cinryze® at a concentration of 333U/mL. This administration achieved the claimed therapeutic C1-INH plasma level of ≥0.4U/mL in HAE patients. Petitioner argued that other limitations of independent claim 1 were inherently disclosed because Schranz used the commercially available Cinryze® product, which the product label and Bock established contains a citrate buffer, has a pH of 6.6-7.4, and comprises a C1-INH protein with an amino acid sequence 100% identical to the claimed sequence. Accordingly, the only limitation not explicitly taught by Schranz was the concentration of "at least about 400U/mL."
    • Motivation to Combine: A person of ordinary skill in the art (POSA) would have been motivated to modify Schranz's formulation by increasing its concentration based on the teachings of Gatlin. Gatlin explained that a principal goal in developing sc formulations is to reduce total injection volume to enhance patient convenience, minimize pain, and ensure compliance. To administer the 2000U dose at 333U/mL, Schranz required a total volume of 6mL (administered as four 1.5mL injections). Petitioner contended that a POSA would have found it obvious to increase the concentration by a modest 17% to 400U/mL, thereby reducing the total injection volume to a more desirable 5mL.
    • Expectation of Success: A POSA would have possessed a reasonable expectation of success in making this modification. The feasibility of higher-concentration C1-INH formulations was established by Pharming, which taught intramuscular formulations with a median concentration of ~455U/mL. Petitioner argued that the known physical and chemical properties of the C1-INH protein presented no significant technical barriers to this concentration increase. Furthermore, because Schranz demonstrated that the therapeutic dose (2000U), not the concentration, was the key driver of plasma levels, a POSA would reasonably expect the slightly more concentrated formulation to remain effective. Dependent claims were argued to be obvious for similar reasons, as the specific features were either taught by the primary references or were well-known and predictable variations (e.g., using a phosphate buffer instead of citrate, as taught by Gatlin).

Ground 2: Claims 1-18 are obvious over Jiang in view of Gatlin, Pharming, Zuraw, and Levi.

  • Prior Art Relied Upon: Jiang (a 2010 journal article), Gatlin (a 1999 book chapter), Pharming (WO 2007/073186), Zuraw (a 2010 journal article), Levi (a 2006 journal article), Bock (a 1986 journal article), and the Cinryze® Label (2012).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground presented an obviousness challenge based on the prior art the Examiner primarily relied upon during prosecution. Jiang taught sc administration of Cinryze® at a 100U/mL concentration in a pig model, which was established as having skin physiology similar to humans. This administration achieved C1-INH plasma levels comparable to those from intravenous (IV) infusion. Levi was cited to confirm that IV administration routinely achieves plasma levels above the 0.4U/mL therapeutic threshold claimed in the patent. As in Ground 1, the Cinryze® label and Bock were used to establish the inherent properties of the formulation (buffer, pH, sequence). The primary missing element was again the high concentration.
    • Motivation to Combine: Petitioner argued the motivation to increase the concentration of Jiang's formulation was compelling. The 100U/mL concentration required large and inconvenient injection volumes of 8-11.5mL. A POSA, following the explicit guidance of Gatlin to target smaller injection volumes (e.g., 1-2mL) for sc administration, would have been strongly motivated to increase the concentration from 100U/mL to at least 400U/mL. This modification would allow the same therapeutic dose to be delivered in a significantly smaller, more practical, and less painful volume.
    • Expectation of Success: The expectation of success was based on the same reasoning as in Ground 1, citing Pharming's disclosure of higher-concentration formulations and the absence of known technical hurdles. Petitioner further argued that the Patent Owner overcame the Examiner's initial rejection based on Jiang only by presenting misleading arguments about secondary considerations. Petitioner contended that any alleged "long-felt need" for an sc therapy was not long-standing and, in any event, had been satisfied by the work disclosed in Schranz prior to the patent's filing. Similarly, arguments of "unexpected results" were flawed because they compared different C1-INH products (Cinryze® vs. Berinert®) rather than comparing the claimed invention to the closest prior art.

4. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 1-18 of Patent 9,616,111 as unpatentable under 35 U.S.C. §103.