Bristol Myers Squibb Co v. Impax Laboratories LLC

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Bristol-Myers Squibb Company (Delaware); Pfizer Inc. (Delaware)
  • Defendant: Impax Laboratories, Inc. (Delaware)
  • Plaintiff’s Counsel: Farnan, LLP; Wilmer Cutler Pickering Hale and Dorr LLP
• Case Identification: 1:17-cv-00403, D. Del., 04/10/2017
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant is a Delaware corporation, transacts business in the district, and has committed the alleged acts of infringement in the district.
• Core Dispute: Plaintiffs allege that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to market a generic version of the anticoagulant drug Eliquis® infringes a patent covering a specific formulation of apixaban designed to ensure consistent patient absorption.
• Technical Context: The case concerns pharmaceutical formulations for apixaban, a Factor Xa inhibitor used to treat and prevent thromboembolic disorders such as deep vein thrombosis and stroke in patients with atrial fibrillation.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant Impax’s notification to Plaintiffs of its ANDA filing for generic apixaban. The complaint states that Impax’s notice letter included a Paragraph IV certification, asserting that the patent-in-suit is invalid, unenforceable, or will not be infringed by Impax’s proposed generic product. This certification constitutes the act of infringement under 35 U.S.C. § 271(e)(2) that gives rise to this lawsuit.

Case Timeline

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 9,326,945 - “Apixaban Formulations,” issued May 3, 2016

The Invention Explained

• Problem Addressed: The patent addresses the problem of inconsistent patient exposure to the active pharmaceutical ingredient apixaban, despite its adequate aqueous solubility. The background notes that formulations made with a wet granulation process or with large apixaban particles resulted in "less than optimal exposures," which could compromise therapeutic consistency (’945 Patent, col. 1:56-62). This was unexpected because apixaban's solubility characteristics suggested that particle size should not be critical for achieving consistent plasma profiles (’945 Patent, col. 1:45-56).
• The Patented Solution: The invention is a solid pharmaceutical composition of apixaban where the crystalline drug particles are controlled to a specific, relatively small size. The patent discloses that by ensuring 90% of the particle volume has a diameter (D90) of 89 microns or less, the formulation achieves consistent in-vivo dissolution and, consequently, more predictable and reliable therapeutic effects in patients (’945 Patent, Abstract; col. 2:6-17). The patent further links this particle size to a specific in-vitro dissolution rate, creating a quality control standard (’945 Patent, col. 11:1-6).
• Technical Importance: The invention provides a method to overcome inconsistent bioavailability for a poorly soluble drug, enabling the development of a reliable oral dosage form with predictable therapeutic outcomes.

Key Claims at a Glance

• The complaint asserts infringement of claims 1, 9-12, 20-23, 25, 27, 29, 31, 33, 35, and 37 (Compl. ¶23). Independent claim 1 is representative.
• Independent Claim 1: A solid pharmaceutical composition comprising:
  • a therapeutically effective amount of crystalline apixaban particles and a pharmaceutically acceptable diluent or carrier,
  • wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm, and
  • wherein at least 77 wt % of apixaban dissolves within 30 minutes in a pH 6.8 phosphate buffer containing 0.05% sodium lauryl sulfate.
• The complaint reserves the right to assert other claims, which would include various dependent claims reciting specific dosages (e.g., 2.5 mg or 5 mg), excipients (e.g., sodium lauryl sulfate), and dosage forms (e.g., a tablet) (’945 Patent, claims 9-11, 25, 27, 29).

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is the "Impax ANDA product," which are proposed 2.5 mg and 5 mg tablets of apixaban for which Impax seeks FDA approval via ANDA No. 209810 (Compl. ¶2).

Functionality and Market Context

• The complaint alleges that Impax’s product is a generic version of Plaintiffs' Eliquis® drug (Compl. ¶2). By filing an ANDA, Impax represents to the FDA that its product has the same active ingredient, dosage form, strength, and is bioequivalent to Eliquis® (Compl. ¶17). The infringement theory is therefore premised on the allegation that to be bioequivalent to Eliquis®, the Impax ANDA product must necessarily possess the formulation characteristics, including the particle size and dissolution profile, claimed in the ’945 patent.

IV. Analysis of Infringement Allegations

The complaint does not contain a formal claim chart. The infringement theory is based on Impax’s filing of an ANDA for a generic version of Eliquis®, which Plaintiffs allege is covered by the claims of the ’945 patent.

’945 Patent Infringement Allegations

• Identified Points of Contention:
  • Factual Question: The central dispute will likely be factual: does the specific formulation described in Impax's confidential ANDA actually meet the particle size (D90 ≤ 89 µm) and dissolution rate limitations of the asserted claims? Discovery into the characteristics of the Impax ANDA product will be critical.
  • Scope Question: A key legal dispute may concern the scope of the term "about 89 µm." The court will need to determine the range of particle sizes encompassed by this term, and whether Impax’s product, even if not exactly at or below 89 µm, falls within that range.

V. Key Claim Terms for Construction

• The Term: "D90 equal to or less than about 89 µm"
• Context and Importance: This term is the central technical limitation that distinguishes the patented invention from prior formulations. The patent repeatedly emphasizes the discovery of this specific particle size threshold as the key to achieving consistent bioavailability (’945 Patent, col. 2:50-58). The definition of "about 89 µm" will be determinative of infringement, as a slight deviation in the D90 of Impax's product could place it inside or outside the claim scope.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The use of the word "about" itself suggests the patentee did not intend to be limited to the precise numerical value of 89 µm. Practitioners may argue this term was intended to cover minor, insignificant variations from the stated value that would be understood by a person of ordinary skill in the art.
  • Evidence for a Narrower Interpretation: The patent specification describes the 89 µm value as a specific discovery, stating "it has surprisingly been found, however, that the particle size that impacts apixaban absorption rate is about a D90 of 89 µm" (’945 Patent, col. 2:52-55). Figures 3 and 4 graphically depict this threshold. A party could argue that this specificity limits the scope of "about" to a very narrow range, such as that accounted for by measurement variability.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that Impax’s commercial manufacture, use, sale, or importation of its ANDA product would constitute inducement of and/or contribution to infringement by others, such as patients and physicians (Compl. ¶24). The factual basis for this is Impax's intent to market a bioequivalent product for the same indications as Eliquis® (Compl. ¶18).
• Willful Infringement: The complaint does not contain specific allegations of pre-suit willfulness. The prayer for relief seeks damages for infringement that will occur post-filing if Impax launches its product, which could form the basis for a later claim of post-filing willfulness, but the complaint does not explicitly plead it as a separate count or with detailed factual support.

VII. Analyst’s Conclusion: Key Questions for the Case

1. A central issue will be one of factual proof: Does the proposed Impax generic product, as defined in its confidential ANDA submission, contain crystalline apixaban with a D90 particle size of 89 µm or less and exhibit the dissolution rate of at least 77% in 30 minutes, as required by the patent’s independent claims?
2. The case will likely involve a critical question of claim construction: What is the legally permissible range of the term "about 89 µm"? The outcome of this construction could determine whether Impax's product, which may have a particle size distribution near the claimed boundary, is ultimately found to infringe.
3. A third question relates to the link between bioequivalence and infringement: To what extent can Plaintiffs rely on Impax’s regulatory representation of bioequivalence to prove that the generic product meets the specific formulation parameters of the patent claims, versus needing to prove those parameters directly through testing and analysis of the Impax product itself?