Mylan Pharmaceuticals Inc v. Pfizer Inc

1. Case Identification

• Case #: IPR2018-00892
• Patent #: 9,326,945
• Filed: April 5, 2018
• Petitioner(s): Mylan Pharmaceuticals Inc.
• Patent Owner(s): Bristol-Myers Squibb Company and Pfizer Inc.
• Challenged Claims: 1-38

2. Patent Overview

• Title: Apixaban Formulations
• Brief Description: The ’945 patent discloses solid pharmaceutical compositions of the anticoagulant apixaban. The invention is directed to formulations where the crystalline apixaban particles have a specific particle size distribution (D90 equal to or less than about 89 µm) and a corresponding dissolution profile.

3. Grounds for Unpatentability

Ground 1: Claims 1-38 are obvious over Carreiro, in view of Wei and the FDA Dissolution Guidance.

• Prior Art Relied Upon: Carreiro (a 2008 clinical trial report), Wei (Application # 2006/0160841), and the FDA Dissolution Guidance (a 1997 guidance document).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that apixaban was a well-known anticoagulant (disclosed in Carreiro) but was also known to be "practically insoluble" or "sparingly soluble," presenting a formulation challenge. Carreiro taught the clinical use of 2.5 mg and 5 mg apixaban tablets. Wei taught that the bioavailability of sparingly soluble compounds like apixaban is enhanced by reducing particle size and disclosed a process for making crystalline Form N-1 apixaban with a D90 of less than 20 µm, which satisfies the ’945 patent’s particle size limitation (≤ 89 µm). Petitioner contended the claimed dissolution profile—at least 77 wt% dissolution in 30 minutes—is an inherent result of applying Wei's particle size reduction to apixaban and testing it under the standard conditions taught by the FDA Dissolution Guidance, which recommends a pH 6.8 buffer and the use of a surfactant (like sodium lauryl sulfate) for poorly soluble drugs.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA), aware of apixaban's clinical utility from Carreiro but also its poor solubility, would be motivated to improve its dissolution rate to ensure fast-acting efficacy. The POSA would turn to Wei's established technique of particle size reduction to achieve this goal and would consult the FDA Dissolution Guidance for standard methods to test the resulting formulation.
  • Expectation of Success: Petitioner asserted a high expectation of success, as particle size reduction is a fundamental and predictable technique in pharmaceutical science for increasing the dissolution rate of poorly soluble drugs. The relationship between smaller particle size, increased surface area, and faster dissolution was described as well-known and routine.

Ground 2: Claims 1-38 are obvious over the ’208 Patent and Wei, in view of the FDA Dissolution Guidance.

• Prior Art Relied Upon: Patent 6,967,208 (’208 patent), Wei (Application # 2006/0160841), and the FDA Dissolution Guidance.

• Core Argument for this Ground:

  • Prior Art Mapping: This ground substitutes the foundational ’208 patent for Carreiro. The ’208 patent, which is prior art to and cited by the ’945 patent, disclosed the apixaban compound itself, its utility as a Factor Xa inhibitor, and its formulation into oral dosage forms like tablets and capsules. As in Ground 1, Wei provided the method for creating small apixaban particles (D90 < 20 µm) to improve the bioavailability of the sparingly soluble compound, and the FDA Guidance provided the standard dissolution testing parameters.
  • Motivation to Combine: A POSA starting with the apixaban compound disclosed in the ’208 patent would recognize its poor solubility and be motivated to improve it for effective oral administration. The POSA would combine the compound from the ’208 patent with the particle size reduction process from Wei to create a formulation with improved dissolution, and then use the FDA Guidance to verify its properties.
  • Expectation of Success: The expectation of success was based on the same principles as Ground 1: applying a routine formulation strategy (particle size reduction) to a known compound to predictably improve a known problem (poor dissolution).

• Additional Grounds: Petitioner asserted two additional obviousness challenges that built upon the core combinations above. Ground 2 added Rudnic (a 2002 pharmaceutical textbook chapter) to the combination of Carreiro, Wei, and the FDA Guidance. Ground 4 added Rudnic to the combination of the ’208 patent, Wei, and the FDA Guidance. In both grounds, Rudnic was cited to provide further motivation for using sodium lauryl sulfate as a common surfactant and lubricant to enhance the dissolution rate of very poorly soluble drugs, reinforcing the teachings of the other references.

4. Key Technical Contentions (Beyond Claim Construction)

• Apixaban Solubility Classification: A central technical contention was the correct classification of apixaban's solubility. The Petitioner argued that during prosecution, the Patent Owner incorrectly characterized apixaban as a "highly soluble" drug under the Biopharmaceutical Classification System (BCS). Petitioner asserted that under established United States Pharmacopeia (USP) standards, apixaban's known solubility of ~40 µg/mL renders it "practically insoluble." This poor solubility, known in the prior art, is the very reason a POSA would have been motivated to reduce its particle size, making the claimed invention an obvious solution to a known problem, not a surprising result.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) would be inappropriate because the grounds presented are not the same or substantially the same as those considered during prosecution. Specifically, Petitioner noted that key references, including Carreiro, Rudnic, and the FDA Dissolution Guidance, were never cited or considered by the Examiner. Furthermore, Petitioner contended that while the Examiner cited Wei, its full teachings regarding particle size reduction for improving bioavailability were not fully appreciated, particularly in light of the new prior art combinations presented in the petition.

6. Relief Requested

• Petitioner requested the institution of an inter partes review and the cancellation of claims 1-38 of the ’945 patent as unpatentable under 35 U.S.C. §103.