PTAB

IPR2017-01912

Fresenius Kabi USA LLC v. AstraZeneca Ab

Key Events

Petition

petition

Title: Method of Treating Breast Cancer with Fulvestrant
Brief Description: The ’139 patent relates to a method for treating hormone-dependent breast cancer using a specific sustained-release, injectable formulation of fulvestrant. The patent does not claim the fulvestrant compound itself, which was an established antiestrogen therapy prior to the patent.

Prior Art Relied Upon: Howell (a 1996 clinical study on the effects of fulvestrant in women with advanced breast cancer).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued that Howell taught the core limitations of the challenged claims. Howell disclosed a method of treating advanced breast cancer via monthly intramuscular (IM) injection of a 50 mg/mL fulvestrant formulation in a castor oil vehicle. It also reported achieving and maintaining the claimed blood plasma concentration (at least 2.5 ng/mL) for prolonged periods.
- Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would have been motivated by the "high response rate" and "promising" results reported in Howell to develop a formulation that could replicate them. To achieve the 50 mg/mL concentration, a POSA would have performed routine solubility screening and been motivated to add known co-solvents—ethanol, benzyl alcohol, and benzyl benzoate—to the castor oil base, as all were well-known for enhancing steroid solubility in oils.
- Expectation of Success: Petitioner asserted that a POSA would have a high expectation of success because the required excipients were conventional for steroidal formulations. The specific amounts recited in the claims fall within known safe ranges disclosed in the FDA's Inactive Ingredient Guide (IIG) for IM injection, making their combination presumptively safe and obvious.

Prior Art Relied Upon: Howell (a 1996 clinical study) and McLeskey (a 1998 research paper on tamoxifen-resistant cancer cells).
Core Argument for this Ground:
- Prior Art Mapping: This ground uses Howell as the primary motivation. A POSA, seeking to replicate Howell's successful clinical outcomes, would need a stable, injectable 50 mg/mL fulvestrant formulation. McLeskey provides the missing piece by disclosing the exact claimed formulation: fulvestrant at 50 mg/mL in a vehicle of 10% ethanol, 10% benzyl alcohol, 15% benzyl benzoate, and castor oil.
- Motivation to Combine: Petitioner argued that a routine literature search for known fulvestrant formulations would have led a POSA directly to McLeskey. Among the few known castor oil-based formulations, McLeskey's was the only one that both met the 50 mg/mL target concentration from Howell and used excipients at pharmaceutically acceptable levels. Other formulations, like Dukes, would have been rejected for having an excessively high benzyl alcohol content.
- Expectation of Success: A POSA would expect the McLeskey formulation, when administered via the IM route taught in Howell, to achieve the same sustained-release profile. This is because both formulations use castor oil as the rate-limiting excipient for drug release from the injection depot. The other, more water-soluble excipients in McLeskey would be expected to dissipate quickly and not affect the long-term release profile.

Prior Art Relied Upon: Howell (a 1996 clinical study), McLeskey (a 1998 research paper), and O’Regan (a 1998 research paper on antiestrogens).
Core Argument for this Ground:
- Prior Art Mapping: This ground adds O'Regan to the combination of Howell and McLeskey to explicitly confirm the appropriateness of the IM administration route in humans. While McLeskey used subcutaneous (SC) injections in mice, O'Regan expressly teaches that clinically, fulvestrant "must be given by depot intramuscular injection because of low oral potency."
- Motivation to Combine: O'Regan, which itself cites Howell's promising clinical results, provides a clear rationale for selecting the IM route for human administration. This reinforces the motivation to administer the formulation from McLeskey via the IM route taught in Howell, bridging any perceived gap between the animal model (McLeskey) and the human application (Howell).
- Expectation of Success: O'Regan's explicit teaching would have eliminated any uncertainty a POSA might have had about extrapolating from the SC route used in mice to the IM route in humans. This strengthens the reasonable expectation that the combination would be successful.

Petitioner adopted the Board's constructions from a related IPR, proposing that the terms "achieves" (claim 1) and "attained" (claim 10) should 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."
Petitioner also argued that the pharmacokinetic clauses (e.g., "achieves a blood plasma fulvestrant concentration of at least 2.5 ngml-1 for at least 2 weeks") should be interpreted as limitations of the claims.

McLeskey Was Not a "Treatment Failure": Petitioner argued that Patent Owner mischaracterized the McLeskey study. The study's purpose was to investigate hormone-independent cancer growth pathways. To do so, researchers used fulvestrant to successfully block estrogen receptors, thereby isolating the effect of the FGF growth factor. In this context, fulvestrant performed its intended function successfully, and the study was not a failure of the drug.
Predictability of Excipients and Administration: Petitioner contended that the claimed excipients were conventional for parenteral steroid formulations and their effects were predictable. A POSA would understand that castor oil provides sustained release and that co-solvents like ethanol and benzyl benzoate were known to enhance solubility. The choice of IM administration for a large-volume (5 mL) injection was also predictable and known to be necessary for human use.

Petitioner argued that institution was proper and not duplicative of a prior IPR filed by Mylan (the Mylan IPRs). The petition asserted it was substantially different under 35 U.S.C. §325(d) because it cured specific gaps the Board had identified in denying institution of the Mylan IPRs.
Key distinctions included: (1) using Howell as the lead reference and primary motivation, not McLeskey; (2) providing new evidence, including a declaration from one of McLeskey's authors to correct the record; and (3) systematically refuting the specific expert arguments that the Patent Owner had relied upon in the prior proceeding.

Petitioner requested the institution of an inter partes review and the cancellation of claims 1, 3, 10, 11, 13, and 20 of Patent 8,466,139 as unpatentable under 35 U.S.C. §103.