Fresenius Kabi USA LLC v. AstraZeneca Ab

1. Case Identification

• Case #: IPR2017-01910
• Patent #: 6,774,122
• Filed: August 4, 2017
• Petitioner(s): Fresenius-Kabi USA LLC
• Patent Owner(s): AstraZeneca AB
• Challenged Claims: 1, 2, 5, and 9

2. Patent Overview

• Title: Method of Treating Breast Cancer
• Brief Description: The ’122 patent relates to a method for treating hormone-dependent breast cancer by intramuscularly injecting a specific sustained-release formulation of the antiestrogen drug fulvestrant.

3. Grounds for Unpatentability

Ground 1: Claims 1, 2, 5, and 9 are obvious over Howell

• Prior Art Relied Upon: Howell (a 1996 journal article describing a clinical study of fulvestrant).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Howell taught nearly every limitation of the challenged claims. Specifically, Howell disclosed a method of treating advanced breast cancer with a 50 mg/ml concentration of fulvestrant in a castor oil-based vehicle, administered via a 5 ml monthly intramuscular (IM) injection. Petitioner asserted Howell also disclosed achieving and maintaining the claimed blood plasma concentration (at least 2.5 ng/ml) for at least four weeks. The only elements not explicitly disclosed were the specific co-solvents (10% ethanol, 10% benzyl alcohol, and 15% benzyl benzoate).
  • Motivation to Combine (with POSA knowledge): A person of ordinary skill in the art (POSA) would have been motivated to replicate the promising clinical results reported in Howell (e.g., a 69% response rate). To do so, a POSA would have sought to develop a stable, injectable formulation at the 50 mg/ml concentration used in the study.
  • Expectation of Success: Petitioner contended that developing the final formulation required only routine optimization. A POSA would have known that co-solvents like ethanol, benzyl alcohol, and benzyl benzoate were conventional and effective for solubilizing steroids in oil vehicles like castor oil. A POSA would have had a reasonable expectation of success in using these well-known excipients to create the necessary formulation to practice Howell's method.

Ground 2: Claims 1, 2, 5, and 9 are obvious over Howell in view of McLeskey

• Prior Art Relied Upon: Howell (a 1996 journal article), McLeskey (a 1998 journal article studying tamoxifen-resistant cells).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground strengthened the argument from Ground 1 by introducing McLeskey, which Petitioner asserted disclosed the exact claimed formulation. Howell provided the clinical method and motivation (successful human trials, target plasma levels, IM administration). McLeskey provided the missing piece: a fulvestrant formulation containing 10% ethanol, 10% benzyl alcohol, 15% benzyl benzoate, and castor oil, at the same 50 mg/ml concentration used in Howell.
  • Motivation to Combine: A POSA, motivated by Howell’s clinical success, would conduct a literature search for known castor oil-based fulvestrant formulations capable of achieving a 50 mg/ml concentration. This search would have identified a finite number of options, with McLeskey disclosing the only formulation that both met the concentration target and used excipients at pharmaceutically acceptable levels. The common elements of fulvestrant, castor oil, and the 50 mg/ml concentration provided a strong bridge between the references.
  • Expectation of Success: A POSA would have had a high expectation of success in applying McLeskey's pre-made, stable formulation to Howell's proven clinical method. Since McLeskey provided the exact formulation needed to replicate Howell's study parameters, its use was a predictable solution with a high likelihood of achieving the same therapeutic effect.

Ground 3: Claims 1, 2, 5, and 9 are obvious over Howell, McLeskey, and O'Regan

• Prior Art Relied Upon: Howell (a 1996 journal article), McLeskey (a 1998 journal article), and O'Regan (a 1998 journal article on antiestrogens).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground added O'Regan to further confirm the rationale for selecting the IM route of administration. Petitioner argued that O'Regan explicitly stated that "[c]linically, [fulvestrant] must be given by depot intramuscular injection because of low oral potency." This teaching reinforced the method disclosed in Howell and the suitability of the injectable formulation disclosed in McLeskey.
  • Motivation to Combine: O'Regan confirmed the established clinical understanding that IM injection was the necessary and proper route for administering fulvestrant. This would have further motivated a POSA following Howell to seek out an IM-injectable formulation, leading directly to McLeskey.
  • Expectation of Success: By confirming that IM administration was the standard and expected route for fulvestrant, O'Regan removed any uncertainty and strengthened the POSA's expectation of success in using the McLeskey formulation as part of the IM treatment method taught by Howell.

4. Key Claim Construction Positions

• "attained": Petitioner proposed that for claims 1 and 2, this term should be construed to mean that "the concentration of fulvestrant in a patient's blood plasma is at or above the specified minimum concentration for the specified time period." This construction was argued to be critical for defining the scope of the pharmacokinetic limitation.

5. Key Technical Contentions (Beyond Claim Construction)

• McLeskey Was a Scientific Success, Not a "Treatment Failure": Petitioner argued that Patent Owner mischaracterized the McLeskey reference as a "treatment failure." Petitioner contended a POSA would understand McLeskey was a successful preclinical study where fulvestrant performed its expected function (blocking estrogen receptors) in a specially engineered, hormone-independent cancer cell line to investigate mechanisms of resistance.
• Excipient Formulation Was Predictable: Petitioner asserted that the selection of ethanol, benzyl alcohol, and benzyl benzoate as co-solvents was not an unexpected or surprising discovery. These were well-known, conventional excipients for enhancing the solubility of steroids in oil, and their use at the claimed concentrations was within ranges already approved by the FDA for IM injections, making the formulation work predictable.

6. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under 35 U.S.C. §325(d) would be inappropriate because its petition was substantially different from a previously filed Mylan IPR. The petition asserted it presented new grounds (using Howell as the primary reference instead of McLeskey), new evidence (including a declaration from one of McLeskey's authors), and new arguments that cured specific deficiencies the Board had identified in the Mylan proceeding.

7. Relief Requested

• Petitioner requested the institution of an inter partes review and the cancellation of claims 1, 2, 5, and 9 of the ’122 patent as unpatentable.