PTAB

IPR2017-01913

Fresenius Kabi USA LLC v. AstraZeneca Ab

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Method for Treating Breast Cancer with Fulvestrant
  • Brief Description: The ’680 patent relates to a method for treating hormone-dependent breast cancer using a specific sustained-release, injectable formulation of fulvestrant. The claims require a formulation with specific excipients and achieving certain blood plasma concentrations of fulvestrant for at least four weeks.

3. Grounds for Unpatentability

Ground 1: Claims 1, 2, 3, and 6 are obvious over Howell.

  • Prior Art Relied Upon: Howell (a 1996 article in BRIT. J. CANCER).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Howell would be the logical starting point for a person of ordinary skill in the art (POSA) seeking to develop a fulvestrant treatment. Howell taught a method of treating advanced breast cancer using monthly intramuscular (IM) injections of a 50 mg/ml fulvestrant formulation in a castor oil-based vehicle, reporting a promising 69% response rate and a "long median duration of remission." While Howell did not disclose the full excipient list, Petitioner contended a POSA would have been motivated to develop a formulation that could replicate Howell's positive results. Howell also disclosed achieving and maintaining fulvestrant plasma concentrations that meet the limitations of claims 1, 2, 3, and 6.
    • Motivation to Combine (with POSA knowledge): A POSA would be motivated by Howell’s success to develop a stable, injectable 50 mg/ml fulvestrant formulation. Petitioner asserted that routine solubility screening, as described in the declaration of Patent Owner's own formulator Dr. Gellert, would lead a POSA to select castor oil as the vehicle and to add co-solvents like ethanol, benzyl alcohol, and benzyl benzoate to achieve the target concentration. These excipients were all known in the art for use in steroidal depot formulations.
    • Expectation of Success: A POSA would have a reasonable expectation of success because formulating with common, FDA-approved excipients to achieve a target solubility is routine. The FDA's Inactive Ingredient Guide (IIG) confirmed that the claimed excipient concentrations were within previously approved ranges for IM injections, creating a presumption of safety and effectiveness.

Ground 2: Claims 1, 2, 3, and 6 are obvious over Howell in view of McLeskey.

  • Prior Art Relied Upon: Howell (a 1996 article in BRIT. J. CANCER) and McLeskey (a 1998 article in CLIN. CANCER RESEARCH).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that a POSA, motivated by Howell's promising results with a castor oil vehicle, would conduct a literature review for known fulvestrant castor oil-based formulations. This search would identify McLeskey, which disclosed the exact formulation recited in the challenged claims: 50 mg/ml fulvestrant in a vehicle of 10% ethanol, 10% benzyl alcohol, 15% benzyl benzoate, and castor oil. This formulation was provided to the McLeskey authors directly by the Patent Owner.
    • Motivation to Combine: The motivation to combine was direct: Howell provided the successful clinical results and the problem to be solved (creating a stable formulation), while McLeskey provided the specific, known solution. Petitioner asserted that of the few known fulvestrant formulations, only McLeskey’s used pharmaceutically acceptable excipient levels to achieve the 50 mg/ml concentration taught by Howell, making it the leading and obvious candidate to select.
    • Expectation of Success: A POSA would have a high expectation of success because McLeskey used a pre-formulated, pharmaceutically acceptable solution from a major drug company. Further, because castor oil is the rate-limiting factor for drug release from the injection depot in both Howell and McLeskey, a POSA would expect the McLeskey formulation, when administered IM per Howell, to achieve the same successful pharmacokinetic profile reported in Howell.

Ground 3: Claims 1, 2, 3, and 6 are obvious over Howell and McLeskey in view of O'Regan.

  • Prior Art Relied Upon: Howell, McLeskey, and O'Regan (a 1998 article in J. NAT'L CANCER INST.).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground adds O'Regan to the combination of Howell and McLeskey. O'Regan provides further evidence reinforcing the appropriateness of the claimed method.
    • Motivation to Combine: Petitioner asserted O'Regan provided additional motivation and confirmation for the combination. O'Regan cited Howell for its promising clinical results and explicitly taught that, "[c]linically, [fulvestrant] must be given by depot intramuscular injection because of low oral potency." This teaching directly addressed any potential concern a POSA might have about administering the McLeskey formulation (which was used subcutaneously in mice) via the intramuscular route in humans, as taught by Howell.
    • Expectation of Success: O'Regan strengthened the expectation of success by confirming that IM injection is the necessary and required route for clinical use in humans, thereby bridging any perceived gap between the administration routes used in the primary references (IM in humans for Howell, SC in mice for McLeskey).

Ground 4: Claims 2 and 6 are obvious over Howell, McLeskey, and O'Regan in view of DeFriend.

  • Prior Art Relied Upon: Howell, McLeskey, O'Regan, and DeFriend (a 1994 article in CANCER RESEARCH).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground specifically addressed the higher plasma concentration limitation of claim 2 (at least 8.5 ngml⁻¹). DeFriend taught that the efficacy of fulvestrant is dose-dependent and that a higher dose (equivalent to 500 mg/month) was highly effective at inhibiting estrogen receptors (ERs) and was well-tolerated.
    • Motivation to Combine: A POSA would be motivated to improve upon Howell’s results, since a minority of patients in that study did not respond and companion data suggested incomplete ER inhibition. DeFriend provided the motivation to increase the dose from 250 mg/month (used in Howell) to 500 mg/month to achieve greater ER inhibition and superior efficacy. This dose increase would inherently result in higher plasma concentrations, such as the 8.5 ngml⁻¹ level of claim 2.
    • Expectation of Success: A POSA would reasonably predict that doubling the dose would increase plasma concentrations and improve outcomes, especially since DeFriend showed dose-dependent efficacy and Howell showed the treatment was well-tolerated.

4. Key Claim Construction Positions

  • "Achieves": Petitioner proposed this term be construed to mean "the concentration of fulvestrant in a patient's blood plasma is at or above the specified minimum concentration for the specified time period."
  • "Therapeutically Significant": Petitioner argued this term did not require express construction, consistent with the Board's prior analysis in a related IPR.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under §325(d) was inappropriate because its grounds were substantially different from those in a previously denied petition filed by Mylan (IPR2016-01325).
  • Key distinctions asserted included: (1) using Howell as the primary reference and motivation, whereas Mylan used McLeskey; (2) presenting new evidence, including a declaration from a co-author of the McLeskey reference (Dr. El-Ashry) to rebut Patent Owner's "treatment failure" arguments; and (3) systematically addressing the specific gaps in evidence and reasoning the Board identified in its Mylan denial decision.

6. Relief Requested

  • Petitioner requests institution of inter partes review and cancellation of claims 1-3 and 6 of Patent 8,329,680 as unpatentable.