Bristol Myers Squibb Co v. Torrent Pharma Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
  • Defendant: Torrent Pharmaceuticals Ltd. (India)
  • Plaintiff’s Counsel: Farnan LLP
• Case Identification: 1:17-cv-00381, D. Del., 04/05/2017
• Venue Allegations: Defendant Torrent, through counsel, agreed by e-mail not to contest jurisdiction or venue in the District of Delaware.
• Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market generic versions of the anticoagulant drug Eliquis® (apixaban) constitutes an act of infringement of two patents covering the apixaban compound and specific formulations thereof.
• Technical Context: The case concerns Factor Xa inhibitors, a class of anticoagulant medications used to treat and prevent blood clots in various clinical settings, representing a significant market for therapies addressing thromboembolic disorders.
• Key Procedural History: This lawsuit was filed under the Hatch-Waxman Act, triggered by a notice letter from Torrent informing Plaintiffs of its ANDA filing seeking FDA approval to market a generic apixaban product prior to the expiration of the patents-in-suit. The complaint notes that Torrent's offer of confidential access to its ANDA contained "unreasonable restrictions," prompting the filing of the complaint before the expiration of the standard forty-five-day window.

Case Timeline

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

U.S. Patent No. 6,967,208 - “Lactam-Containing Compounds and Derivatives thereof as Factor Xa Inhibitors”

• Issued: November 22, 2005

The Invention Explained

• Problem Addressed: The patent identifies a need for new, effective, and orally available inhibitors of Factor Xa, a key enzyme in the blood coagulation cascade, for the treatment of thromboembolic disorders (’208 Patent, col. 5:23-28). The background notes a desire for compounds with improved pharmacological characteristics, such as better selectivity and bioavailability, compared to existing agents (’208 Patent, col. 5:29-51).
• The Patented Solution: The invention provides a class of novel lactam-containing compounds that are asserted to be potent and selective inhibitors of Factor Xa (’208 Patent, col. 5:52-56). The patent discloses a broad chemical genus defined by a core structure (Formula I) and claims specific compounds within that genus, including the compound that would later be known as apixaban (’208 Patent, col. 5:4-21, Claim 8).
• Technical Importance: Developing specific, oral Factor Xa inhibitors represented a significant advance over older anticoagulants like warfarin, offering the potential for more predictable dosing and fewer side effects.

Key Claims at a Glance

• The complaint asserts independent claim 1 and dependent claims 8, 13, 26-27, and 55-61 (Compl. ¶20). Claim 8 is a compound claim specifically reciting apixaban.
• Essential elements of Independent Claim 1:
  • A compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof
  • Wherein the various substituent groups (P, M, M1, M4, Z, A, B, etc.) are selected from extensive lists of chemical moieties, defining a large genus of related compounds.
• The complaint reserves the right to assert other claims (’208 Patent, col. 269:1-276:31).

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

• Issued: May 3, 2016

The Invention Explained

• Problem Addressed: The patent addresses the unexpected discovery that apixaban formulations exhibited suboptimal and inconsistent drug exposure in humans, despite apixaban having adequate aqueous solubility that would suggest particle size should not be a critical factor (’945 Patent, col. 1:46-62). This variability presented potential "quality control challenges" for creating a reliable drug product (’945 Patent, col. 1:61-62).
• The Patented Solution: The invention is a pharmaceutical composition containing crystalline apixaban particles with a specific, controlled particle size distribution. The patent teaches that by ensuring 90% of the particles have a diameter (D90) of 89 micrometers (µm) or less, one can achieve consistent in-vivo dissolution and predictable therapeutic effect (’945 Patent, col. 2:7-18). This formulation is designed to be manufactured using a dry granulation process (’945 Patent, col. 2:5-7).
• Technical Importance: Controlling particle size to ensure consistent bioavailability is a critical aspect of pharmaceutical formulation, and this patent claims a specific solution for apixaban that was found to be necessary contrary to initial expectations based on the drug's solubility.

Key Claims at a Glance

• The complaint asserts independent claims 1 and dependent claims 9-12, 20-23, 25, 27, 29, 31, 33, 35, and 37 (Compl. ¶26).
• Essential elements of 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
  • Wherein at least 77 wt % of apixaban dissolves within 30 minutes in a specified buffer.
• The complaint reserves the right to assert other claims (’945 Patent, col. 10:49-11:65).

III. The Accused Instrumentality

Product Identification

The "Torrent ANDA product," identified as 2.5 mg and 5 mg tablets of apixaban, for which Torrent seeks FDA approval under ANDA No. 210156 (Compl. ¶2).

Functionality and Market Context

• The complaint alleges that by filing its ANDA, Torrent has represented to the FDA that its proposed generic product contains the same active ingredient (apixaban) as Plaintiffs' Eliquis® product (Compl. ¶14).
• The complaint further alleges that Torrent's product has the same dosage form and strength as Eliquis®, is bioequivalent to Eliquis®, and is intended for the same approved medical indications, such as reducing the risk of stroke and treating deep vein thrombosis (Compl. ¶¶ 11, 14, 15).
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint alleges that the very act of submitting ANDA No. 210156 constitutes a technical act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶¶ 20, 26). The infringement theory is based on the allegation that Torrent’s proposed product is a generic version of Eliquis® and therefore contains the claimed compound and embodies the claimed formulation.

’208 Patent Infringement Allegations

’945 Patent Infringement Allegations

• Identified Points of Contention:
  • Factual Question (’208 Patent): The primary question is factual: is the active pharmaceutical ingredient in Torrent's ANDA product the specific compound claimed in claim 8 of the ’208 Patent? Given the nature of an ANDA filing, this is typically conceded unless the defendant argues the patent is invalid.
  • Scope & Technical Questions (’945 Patent): A central dispute may concern whether Torrent's specific formulation falls within the scope of the ’945 Patent's claims. This raises questions such as: Does Torrent's product actually have a D90 particle size of "about 89 µm" or less? Does it meet the dissolution rate of "at least 77 wt %"? The defendant may argue its formulation achieves bioequivalence through a different, non-infringing technical approach.

V. Key Claim Terms for Construction

• The Term: "about 89 µm" (from claim 1 of the ’945 Patent)
• Context and Importance: The precise scope of "about" will be critical to determining infringement of the ’945 Patent. The patent ties this specific particle size threshold to achieving consistent bioavailability, a key element of the invention. Practitioners may focus on this term because Torrent could argue its product's particle size is, for example, 95 µm, and that this value is not "about 89 µm," thereby avoiding literal infringement. The patent holder will argue for a scope that covers particle sizes that achieve the same novel result.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification repeatedly frames the invention around achieving a functional outcome: "consistent in-vivo dissolution" and "consistent exposure" (’945 Patent, col. 2:1-5). A party could argue that "about 89 µm" should be interpreted functionally to include any particle size that solves the problem of inconsistent exposure that the patent purports to solve.
  • Evidence for a Narrower Interpretation: The patent explicitly 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. 2:51-54). A party could argue this language defines 89 µm as a specific, experimentally determined critical threshold, suggesting "about" should be construed very narrowly to cover only minor variations attributable to measurement error. The patent also provides dissolution data for a formulation with a particle size of 119 µm, noting it is "marginally greater than 77%" dissolved, which could be used to argue that the 89 µm boundary is a firm cliff (’945 Patent, col. 10:39-42).

VI. Other Allegations

• Indirect Infringement: The complaint alleges that upon FDA approval, Torrent's commercial manufacture, use, sale, and importation of its ANDA product would induce and/or contribute to infringement by others (e.g., patients and doctors) (Compl. ¶¶ 21, 23, 27-28). The basis for this allegation is the presumed product labeling that will instruct users on the patented methods of use.
• Willful Infringement: The complaint does not contain an explicit allegation of willful infringement or a request for enhanced damages under 35 U.S.C. § 284.

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

1. Validity of the Compound Patent: A threshold question will be the validity of claim 8 of the ’208 Patent, which covers the apixaban compound itself. As this is an ANDA case, the defendant will almost certainly challenge the patent's validity on grounds such as obviousness or lack of written description, turning on the state of the art in Factor Xa inhibitor chemistry prior to 2001.

2. Scope of the Formulation Patent: The core infringement dispute for the ’945 Patent will likely be one of functional boundaries: does the term "about 89 µm," when read in light of the specification's focus on achieving "consistent exposure," cover any formulation that is bioequivalent to Eliquis®, as Plaintiffs will likely argue? Or, is it limited to a narrow numerical range close to 89 µm, potentially allowing Defendant to design a non-infringing formulation with a different particle size that still achieves bioequivalence?

3. Obviousness of the Formulation: A key validity question for the ’954 Patent will be whether it was obvious to a person of ordinary skill in the art of pharmaceutical formulation to control apixaban's particle size to the claimed D90 of less than 89 µm to achieve consistent dissolution, particularly in light of the patent's own assertion that this discovery was "surprising" and contrary to what the drug's aqueous solubility would suggest.