Bristol Myers Squibb Co v. Prinston Pharmaceutical Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Bristol-Myers Squibb Company (Delaware); Pfizer Inc. (Delaware)
  • Defendant: Prinston Pharmaceutical Inc. (Delaware)
  • Plaintiff’s Counsel: Farnan, LLP; Wilmer Cutler Pickering Hale and Dorr LLP
• Case Identification: 1:17-cv-00426, D. Del., 04/13/2017
• Venue Allegations: Venue is based on Defendant's incorporation in Delaware and its agreement not to contest venue in the District of Delaware for this matter.
• Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market generic versions of the anticoagulant drug Eliquis® constitutes an act of infringement of a patent covering specific formulations of the active ingredient, apixaban.
• Technical Context: The technology concerns pharmaceutical formulations for apixaban, a poorly water-soluble drug, where controlling the particle size of the active ingredient is asserted to be critical for achieving consistent bioavailability and therapeutic effect.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act, triggered by a notification letter from Prinston concerning its ANDA No. 210133. In that ANDA, Prinston made a "Paragraph IV" certification, asserting that U.S. Patent No. 9,326,945 is invalid, unenforceable, and/or will not be infringed by its proposed generic product. The complaint was filed within the 45-day statutory window following receipt of the notice letter.

Case Timeline

Date	Event
2010-02-25	’945 Patent Priority Date
2016-05-03	’945 Patent Issue Date
2017-04-05	Prinston sends ANDA notification letter to Plaintiffs
2017-04-07	Plaintiffs receive Prinston's ANDA notification letter (no earlier than)
2017-04-13	Complaint Filing Date

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

U.S. Patent No. 9,326,945 - "Apixaban Formulations"

• Patent Identification: U.S. Patent No. 9,326,945, "Apixaban Formulations", issued May 3, 2016.

The Invention Explained

• Problem Addressed: The patent addresses the challenge of formulating apixaban, an active pharmaceutical ingredient with low aqueous solubility. The background section notes that initial formulations, including those made by wet granulation or using larger drug particles, led to "less than optimal exposures" in patients, which could create "quality control challenges" (’945 Patent, col. 1:56-62). This was unexpected, as standard biopharmaceutical principles suggested particle size should not be critical for the dose levels in question (’945 Patent, col. 1:47-56).
• The Patented Solution: The invention is a solid pharmaceutical composition comprising crystalline apixaban particles with a specifically controlled, fine particle size—namely, a D90 (meaning 90% of the particles by volume have a diameter less than this value) equal to or less than approximately 89 micrometers (µm) (’945 Patent, Abstract; col. 2:8-17). This specific particle size, in combination with a specified dissolution rate, is asserted to produce "consistent in-vivo dissolution in humans," leading to a more reliable and consistent therapeutic effect (’945 Patent, col. 2:1-5).
• Technical Importance: For an anticoagulant like apixaban, consistent drug absorption and predictable blood concentration are critical for both safety and efficacy. The patent asserts the "surprising and unexpected" discovery of a specific particle size threshold that is crucial for achieving this consistency (’945 Patent, col. 1:63-col. 2:1).

Key Claims at a Glance

• The complaint asserts infringement of claims including independent claims 1 and 12, as well as several dependent claims (Compl. ¶ 19).
• 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.
• Independent Claim 12:
  • A solid pharmaceutical composition comprising a therapeutically effective amount of apixaban and a pharmaceutically acceptable diluent or carrier,
  • wherein apixaban comprises crystalline apixaban particles,
  • wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm, and
  • wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL, of a dissolution medium at 37° C., at least 77 wt % of apixaban in the pharmaceutical composition dissolves within 30 minutes...and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.

III. The Accused Instrumentality

Product Identification

• The "Prinston ANDA product," which are 2.5 mg and 5 mg tablets of apixaban intended to be marketed as generic versions of Plaintiffs' Eliquis® drug product (Compl. ¶ 2).

Functionality and Market Context

• The accused product is a factor Xa inhibitor anticoagulant. Prinston is seeking FDA approval to market its product for the same indications as Eliquis®, which include treating and preventing thromboembolic disorders like deep vein thrombosis (DVT) and reducing the risk of stroke in patients with nonvalvular atrial fibrillation (Compl. ¶¶ 10, 14). By filing an ANDA, Prinston has represented to the FDA that its product contains the same active ingredient, has the same dosage form and strength as Eliquis®, and is bioequivalent to Eliquis® (Compl. ¶ 13).

IV. Analysis of Infringement Allegations

The complaint does not provide a claim chart or specific factual allegations mapping elements of the Prinston ANDA product to the claim limitations. Instead, it presents a theory of infringement common in ANDA litigation, which is based on the regulatory requirements for generic drug approval. The central allegation is that Prinston's submission of its ANDA is a technical act of infringement under 35 U.S.C. § 271(e)(2)(A) because the product that will be marketed upon approval will infringe the ’945 patent (Compl. ¶ 19). The infringement theory appears to rest on the assertion that for Prinston’s product to be bioequivalent to Eliquis®, as required for FDA approval, it must necessarily possess the particle size and dissolution characteristics claimed in the ’945 patent (Compl. ¶ 13).
No probative visual evidence provided in complaint.

• Identified Points of Contention:
  • Technical Question: What are the actual physical characteristics of the apixaban particles in Prinston's proposed generic product, specifically the D90 particle size and the in-vitro dissolution profile under the conditions specified in the claims? This information, contained within Prinston's confidential ANDA, will be central to the infringement analysis.
  • Legal Question: Could Prinston's formulation achieve bioequivalence with Eliquis® through a different technical approach that does not meet all limitations of the asserted claims (e.g., using different excipients or a manufacturing process that yields a product with a D90 greater than 89 µm but still achieves a bioequivalent profile)?

V. Key Claim Terms for Construction

• The Term: "a D90 equal to or less than about 89 µm" (from Claim 1)

  • Context and Importance: This limitation defines the core of the asserted invention. The interpretation of the word "about" will be critical, as it determines the permissible deviation from the 89 µm value. Practitioners may focus on this term because numerical boundaries in claims are frequent subjects of dispute, and the outcome could determine whether a product with a D90 slightly above 89 µm infringes.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent discloses that the 77% dissolution rate at 30 minutes is the "threshold for achieving consistent exposure" (’945 Patent, col. 9:26-28). Figure 4 of the patent shows a data point for a formulation with a 119 µm particle size that achieves a dissolution rate "marginally greater than 77%" (’945 Patent, col. 9:40-43). This could be used to argue that 89 µm is not a rigid, "knife-edge" cutoff, supporting a broader reading of "about."
    • Evidence for a Narrower Interpretation: The specification repeatedly highlights 89 µm as the key discovery. It states, "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. 2:52-54). This phrasing suggests the identification of a specific threshold, which could support an argument that "about" allows for only minor variance, such as that attributable to measurement error.

• The Term: "crystalline apixaban particles" (from Claim 1)

  • Context and Importance: This term specifies the physical form of the active ingredient. Its construction is important because infringement may depend on whether Prinston's ANDA product uses a form of apixaban that falls within the scope of this term.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The plain language is not limited to a specific crystal form (polymorph). The specification states that "apixaban in any form which will crystallize can be used in this invention" (’945 Patent, col. 4:37-38). Furthermore, dependent claim 2 explicitly recites "Form N-1 of apixaban," which suggests by the doctrine of claim differentiation that parent claim 1 is broader and not limited to that specific form (’945 Patent, col. 9:58-60).
    • Evidence for a Narrower Interpretation: The patent’s examples and detailed characterization data focus on specific crystalline forms, primarily Form N-1 and Form H2-2 (’945 Patent, Table 1, col. 4:43-65). A party might argue that the invention’s properties are tied to these disclosed forms and that the term’s scope should be interpreted in light of these specific embodiments.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that Prinston’s future commercial activities would constitute inducement of infringement and contributory infringement (Compl. ¶ 20). The factual basis for this allegation is that Prinston intends to sell its generic product for the same approved indications as Eliquis®, and the product's labeling would instruct medical professionals and patients to administer the drug in a manner that infringes the patent claims (Compl. ¶¶ 14, 21).
• Willful Infringement: The complaint does not contain an explicit allegation of willful infringement. However, it pleads facts that could support such a claim, noting that Prinston provided Plaintiffs with a notice letter dated April 5, 2017, which demonstrates Prinston's pre-suit knowledge of the ’945 patent and its relevance to the accused product (Compl. ¶ 11).

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

• A central evidentiary question will be one of product characterization: What are the actual physical properties—specifically the D90 particle size and the dissolution rate under the claimed test conditions—of the apixaban formulation detailed in Prinston’s confidential ANDA filing? The resolution of the infringement dispute will depend almost entirely on this factual data.
• A core issue for claim construction will be one of definitional scope: How will the court construe the term "about 89 µm"? The interpretation will be dispositive if Prinston’s product has a particle size that is close to, but not strictly less than, the 89 µm value.
• As Prinston has certified that the patent is invalid, a key question for the court will be one of non-obviousness: Was it obvious to a person of ordinary skill in pharmaceutical formulation to control the particle size of apixaban to the specific D90 ≤ 89 µm range to ensure consistent bioavailability, or does this represent the "surprising and unexpected" discovery that the patentee alleges?