DCT
1:17-cv-00412
Bristol Myers Squibb Co v. Zydus Pharma USA Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Bristol-Myers Squibb Company (Delaware) and Pfizer Inc. (Delaware)
- Defendant: Zydus Pharmaceuticals (USA) Inc. (New Jersey)
- Plaintiff’s Counsel: Farnan, LLP (with Wilmer Cutler Pickering Hale and Dorr LLP as Of Counsel)
- Case Identification: 1:17-cv-00412, D. Del., 04/10/2017
- Venue Allegations: The complaint states that Defendant Zydus, through its counsel, has agreed 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) for a generic version 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 technology relates to Factor Xa inhibitors, a class of oral anticoagulant drugs used to treat and prevent thromboembolic disorders such as deep vein thrombosis and stroke.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant’s submission of ANDA No. 210185. The complaint states that Defendant provided a notice letter with a Paragraph IV certification, asserting that Plaintiffs' patents are invalid, unenforceable, and/or will not be infringed by the proposed generic product. The complaint was filed within the 45-day statutory window, triggering an automatic 30-month stay on the FDA’s approval of the Zydus ANDA.
Case Timeline
| Date | Event |
|---|---|
| 2001-09-21 | Earliest Priority Date for '208 Patent |
| 2005-11-22 | U.S. Patent No. 6,967,208 Issued |
| 2010-02-25 | Priority Date for '945 Patent |
| 2016-05-03 | U.S. Patent No. 9,326,945 Issued |
| 2017-03-08 | Zydus Sends ANDA Notice Letter |
| 2017-03-09 | Plaintiffs Receive ANDA Notice Letter |
| 2017-04-10 | Complaint Filed |
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 (’208 Patent)
The Invention Explained
- Problem Addressed: The patent addresses the need for new and improved agents for treating thromboembolic disorders. It notes the desirability of finding potent and selective Factor Xa inhibitors that are orally bioavailable and possess favorable pharmacological profiles, which were limitations of existing therapies. (’208 Patent, col. 5:22-48).
- The Patented Solution: The invention provides a novel class of lactam-containing chemical compounds, defined by a general structural formula, that function as inhibitors of Factor Xa, a critical enzyme in the blood coagulation cascade. (’208 Patent, Abstract; col. 5:49-57). The patent specifically identifies the compound apixaban and details methods for its synthesis. (’208 Patent, col. 62:38-44).
- Technical Importance: The development of potent, selective, and orally active Factor Xa inhibitors represented a significant advance in antithrombotic therapy, offering an alternative to older anticoagulants that required frequent monitoring or had less favorable safety profiles. (’208 Patent, col. 5:6-10, 5:22-26).
Key Claims at a Glance
- The complaint asserts infringement of claims 8, 13, 26-27, and 55-61. (Compl. ¶¶20-23).
- The key asserted independent claim is Claim 8, a compound claim which recites:
- 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one [apixaban], or a stereoisomer or pharmaceutically acceptable salt thereof.
- The complaint also asserts method of treatment and composition claims that depend on the core compound claim.
U.S. Patent No. 9,326,945 - "Apixaban Formulations"
- Issued: May 3, 2016 (’945 Patent)
The Invention Explained
- Problem Addressed: The patent describes an unexpected challenge in formulating apixaban. Despite its adequate aqueous solubility, which would suggest particle size is not critical, early formulations demonstrated inconsistent drug exposure in humans, posing a "quality control challenge." (’945 Patent, col. 1:45-62).
- The Patented Solution: The inventors discovered that consistent in-vivo dissolution and bioavailability could be achieved by controlling the particle size of the crystalline apixaban active ingredient. The solution is a solid pharmaceutical composition comprising crystalline apixaban particles where 90% of the particles by volume have a diameter (D90) of 89 microns (µm) or less. This specific particle size distribution ensures a reliable dissolution rate and consistent therapeutic effect. (’945 Patent, Abstract; col. 2:6-18).
- Technical Importance: This finding enabled the development of a robust, mass-producible oral tablet formulation for apixaban that delivers consistent drug exposure, a critical factor for an anticoagulant where dosing precision is paramount. (’945 Patent, col. 2:1-5).
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. ¶¶26-28).
- The asserted independent claim is Claim 1, which requires:
- 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, including dependent claims. (Compl. ¶¶26-28).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is the "Zydus ANDA product," identified as 2.5 mg and 5 mg tablets of apixaban for which Defendant Zydus seeks FDA approval under ANDA No. 210185. (Compl. ¶2).
Functionality and Market Context
- The complaint alleges that by filing its ANDA, Zydus has represented to the FDA that its proposed product has the same active ingredient, dosage form, strength, and is bioequivalent to Plaintiffs' Eliquis® product. (Compl. ¶14). The Zydus product is intended for the same therapeutic indications as Eliquis®, namely the treatment and prevention of thromboembolic disorders. (Compl. ¶11, ¶15). The filing represents a commercial effort to market a generic version of Eliquis® upon receiving FDA approval. (Compl. ¶13).
IV. Analysis of Infringement Allegations
The complaint provides a generalized theory of infringement based on the ANDA filing, as is common in Hatch-Waxman litigation, rather than detailed, element-by-element evidence. The infringement allegations are premised on the representation that the Zydus ANDA product is a generic equivalent of Eliquis®.
'208 Patent Infringement Allegations
| Claim Element (from Independent Claim 8) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one, or a stereoisomer or pharmaceutically acceptable salt thereof. | The complaint alleges that the Zydus ANDA product contains apixaban as its active pharmaceutical ingredient. | ¶14, ¶20 | col. 62:38-44 |
'945 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A solid pharmaceutical composition comprising a therapeutically effective amount of crystalline apixaban particles and a pharmaceutically acceptable diluent or carrier | The Zydus ANDA product is alleged to be a solid tablet formulation containing apixaban. | ¶2, ¶14 | col. 10:50-53 |
| wherein the crystalline apixaban particles have a D90 equal to or less than about 89 µm | The complaint alleges that the Zydus product is bioequivalent to Eliquis®, which implies that it meets the particle size limitation the patent identifies as necessary for consistent bioavailability. | ¶14, ¶26 | col. 10:54-56 |
| 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 allegation of bioequivalence also implies that the Zydus product meets the claimed dissolution profile. Figure 3 of the '945 Patent, incorporated into the complaint as part of Exhibit B, depicts the claimed correlation between particle size and dissolution rate. | ¶10, ¶14, ¶26 | col. 10:57-61 |
Identified Points of Contention
- '208 Patent: For a compound patent in an ANDA case, the primary dispute is typically not over the chemical identity of the active ingredient but rather the patent's validity. The complaint states Zydus certified the patent as invalid, but does not specify the grounds (e.g., obviousness, lack of enablement). (Compl. ¶16).
- '945 Patent: The infringement analysis for the '945 Patent will likely raise key evidentiary questions. The complaint does not provide specific data from Zydus's ANDA. Therefore, a central question is whether Zydus’s product actually has crystalline apixaban particles with a D90 of "about 89 µm" or less and meets the claimed dissolution profile. Discovery into the contents of the Zydus ANDA will be required to resolve this.
V. Key Claim Terms for Construction
- The Term: "about 89 µm" (from '945 Patent, Claim 1)
- Context and Importance: The infringement analysis for the '945 Patent hinges on this numerical limitation. The construction of the word "about" will determine whether the claim covers only particle sizes strictly at or below 89 µm, or if it provides a margin of variability. Practitioners may focus on this term because Zydus could argue its product's particle size falls just outside a strict reading of "89 µm," while Plaintiffs may argue it falls within a reasonable interpretation of "about."
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification suggests the 89 µm threshold was chosen to ensure a dissolution rate that is consistently above a 77% minimum, and it explicitly mentions the need to allow for "typical variability (RSD=2 to 3%) in the dissolution results." (’945 Patent, col. 11:39-46). This language may support an argument that "about" was intended to accommodate minor process variations that do not affect the ultimate goal of consistent bioavailability.
- Evidence for a Narrower Interpretation: The patent repeatedly presents "89 µm" as a specific, surprising discovery that solves the bioavailability problem. (’945 Patent, Abstract; col. 2:10-14). A defendant may argue that this specific value represents a critical, hard-edged boundary that distinguishes the invention from the prior art and should not be broadened by the term "about."
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement of infringement and contributory infringement under 35 U.S.C. §§ 271(b) and (c). (Compl. ¶¶21, 23, 27). The factual basis alleged is that Zydus is seeking approval to market its generic product for the same indications as Eliquis® and that the product's label will instruct physicians and patients to use the drug in an infringing manner. (Compl. ¶15).
- Willful Infringement: The complaint does not explicitly allege willful infringement or request enhanced damages. However, it alleges that Zydus provided Plaintiffs with a notice letter on March 8, 2017, which establishes that Zydus had knowledge of the patents-in-suit prior to the filing of the complaint. (Compl. ¶12).
VII. Analyst’s Conclusion: Key Questions for the Case
- Patent Validity: As is typical in ANDA litigation, a central issue will be validity. The case will likely focus on whether the '208 and '945 patents are valid over the prior art, an issue raised by Zydus's Paragraph IV certification but not detailed in the complaint.
- Factual Infringement ('945 Patent): A key evidentiary question will be one of technical compliance: does the apixaban in Zydus’s ANDA product, as manufactured for commercial sale, actually meet the quantitative particle size (D90 ≤ ~89 µm) and dissolution rate (≥77% in 30 min) limitations of the '945 patent claims? The answer will depend on data revealed during discovery.
- Claim Scope ('945 Patent): The dispute may involve a question of definitional scope: how should the court construe the term "about 89 µm"? The resolution of whether this term imparts a degree of numerical flexibility or represents a hard ceiling will be critical to determining infringement of the '945 patent.