DCT
1:23-cv-21098
Bristol Myers Squibb Co v. Zydus Pharma USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Bristol-Myers Squibb Company (Delaware)
- Defendant: Zydus Pharmaceuticals (USA) Inc. (New Jersey) and Zydus Lifesciences Limited (India)
- Plaintiff’s Counsel: Walsh Pizzi O'Reilly Falanga LLP
- Case Identification: 1:23-cv-21098, D.N.J., 10/12/2023
- Venue Allegations: Venue is alleged to be proper as to Zydus Pharmaceuticals (USA) Inc. because it is incorporated in and has its principal place of business in New Jersey. Venue is alleged as to Zydus Lifesciences Limited on the basis that it is a foreign corporation and has previously been sued in the district without contesting venue.
- Core Dispute: Plaintiff alleges that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to the FDA for approval of generic dasatinib tablets constitutes an act of infringement of two U.S. patents listed in the Orange Book for Plaintiff's cancer drug, SPRYCEL®.
- Technical Context: The technology relates to pharmaceutical compositions and processes for preparing 2-aminothiazole-5-aromatic carboxamides, a class of compounds that function as kinase inhibitors useful in oncology treatments.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Paragraph IV certification notice letter from Defendants on or about September 7, 2023, which stated that claims of the patents-in-suit are invalid or will not be infringed by the proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 2004-02-06 | Earliest Priority Date ('725 & '103 Patents) |
| 2009-02-17 | U.S. Patent No. 7,491,725 Issued |
| 2014-03-25 | U.S. Patent No. 8,680,103 Issued |
| 2023-09-07 | BMS receives Zydus's Paragraph IV ANDA Notice Letter |
| 2023-10-12 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,491,725, “Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors,” issued February 17, 2009
The Invention Explained
- Problem Addressed: The patent’s background section notes that prior art methods for synthesizing 2-aminothiazole-5-carboxamide compounds suffered from drawbacks including the production of side-products, the use of expensive reagents, undesirable yields, and the need for multiple reaction steps (ʼ725 Patent, col. 3:6-10).
- The Patented Solution: The invention provides a new and efficient process for creating these compounds, which are useful as kinase inhibitors (ʼ725 Patent, col. 2:36-44). The process involves halogenating a β-(P*)oxy-a,β-unsaturated carboxyl aromatic amide and reacting it with a thiourea compound, a method which the inventors state can be efficiently prepared in high yield (ʼ725 Patent, Abstract; col. 3:49-54). The patent also claims specific crystalline forms of the resulting drug product, dasatinib.
- Technical Importance: The invention provides an improved manufacturing process and specific stable crystalline forms for an active pharmaceutical ingredient used in the treatment of oncological disorders such as chronic myelogenous leukemia (ʼ725 Patent, col. 27:45-46).
Key Claims at a Glance
- The complaint asserts infringement of at least one claim (Compl. ¶35). A representative asserted claim for a final drug product is independent claim 12.
- Independent Claim 12 elements:
- Crystalline monohydrate
- of the compound of formula (IV) [N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, also known as dasatinib]
- The complaint does not explicitly reserve the right to assert other claims, but this is standard practice in patent litigation.
U.S. Patent No. 8,680,103, “Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors,” issued March 25, 2014
The Invention Explained
- Problem Addressed: The patent, which shares a specification with the ʼ725 patent, addresses the same drawbacks in prior art synthesis methods, such as low yields and the need for expensive or multi-step processes (ʼ103 Patent, col. 3:9-13).
- The Patented Solution: The patent claims pharmaceutical compositions containing a specific crystalline monohydrate form of dasatinib (ʼ103 Patent, col. 26:1-6). This stable form is produced via the improved synthesis methods described in the specification.
- Technical Importance: The invention provides specific, stable pharmaceutical formulations of a kinase inhibitor, which is critical for consistent delivery and efficacy in treating cancer (ʼ103 Patent, col. 27:45-47).
Key Claims at a Glance
- The complaint asserts infringement of at least one claim (Compl. ¶47). A representative asserted claim is independent claim 1.
- Independent Claim 1 elements:
- A pharmaceutical composition comprising,
- a therapeutically acceptable amount of crystalline monohydrate of the compound of formula (IV)
- and pharmaceutically acceptable carriers, including two or more of, a binder, a diluent, a disintegrant, and/or a lubricant.
- The complaint does not explicitly reserve the right to assert other claims.
III. The Accused Instrumentality
- Product Identification: The accused instrumentalities are Defendants’ proposed 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg dasatinib oral tablets ("Zydus ANDA Products"), for which Defendants seek FDA approval via ANDA No. 218719 (Compl. ¶9-10).
- Functionality and Market Context: The Zydus ANDA Products are intended to be generic versions of Plaintiff's SPRYCEL® (dasatinib) tablets, a treatment for certain types of cancer (Compl. ¶1). The Zydus ANDA relies upon the safety and efficacy data of SPRYCEL® and purports to demonstrate the bioequivalence of its generic product to the branded drug (Compl. ¶33). The infringing act alleged is the submission of the ANDA to the FDA seeking approval to market this generic product prior to the expiration of the patents-in-suit (Compl. ¶35, ¶47).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint does not provide specific claim charts. The following analysis is based on the allegations in the complaint and the nature of an ANDA filing for a generic equivalent of a branded drug product.
’725 Patent Infringement Allegations
| Claim Element (from Independent Claim 12) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| Crystalline monohydrate of the compound of formula (IV) | The Zydus ANDA Products are dasatinib (formula IV) oral tablets. The filing of an ANDA for a generic version of SPRYCEL®, for which the '725 patent is listed in the Orange Book, alleges that the product will contain this specific crystalline monohydrate form. | ¶10, ¶35 | col. 26:47-50 |
’103 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition | The Zydus ANDA Products are oral tablets, which are pharmaceutical compositions. | ¶10 | col. 26:1-6 |
| comprising, a therapeutically acceptable amount of crystalline monohydrate of the compound of formula (IV) | The Zydus ANDA Products contain dasatinib (formula IV) in therapeutically effective dosages (e.g., 20 mg, 50 mg, etc.). The complaint alleges these products will contain the claimed crystalline monohydrate form upon approval and commercialization. | ¶10, ¶50 | col. 26:1-6 |
| and pharmaceutically acceptable carriers, including two or more of, a binder, a diluent, a disintegrant, and/or a lubricant. | As oral tablet formulations, the Zydus ANDA Products necessarily contain pharmaceutically acceptable carriers (excipients). A standard tablet formulation would require at least two of the listed carrier types to achieve proper compression, dissolution, and stability. | ¶10, ¶50 | col. 26:1-6 |
- Identified Points of Contention:
- Scope Questions: A primary point of contention may be whether the term "crystalline monohydrate" reads on the specific solid-state form of dasatinib used in the Zydus ANDA Products. The dispute will likely focus on whether Zydus's product uses the exact polymorph claimed or an alternative, non-infringing form (e.g., an amorphous form or a different crystalline solvate or anhydrate).
- Technical Questions: A key evidentiary question will be what the analytical data (e.g., XRPD, DSC) for Zydus's proposed product reveals about its solid-state structure. The court will need to compare this data against the characterization data disclosed in the patents for the claimed monohydrate.
V. Key Claim Terms for Construction
- The Term: "crystalline monohydrate"
- Context and Importance: This term is dispositive for infringement of both asserted patents. In pharmaceutical patent law, different solid-state forms (polymorphs) of the same active ingredient are treated as distinct inventions. If Zydus's product contains a form of dasatinib that is not the specific "crystalline monohydrate" claimed, it will not infringe. Practitioners may focus on this term because the patents disclose multiple other crystalline forms (e.g., butanol solvate, ethanol solvate), establishing that the inventors considered the specific monohydrate form to be a distinct entity.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: A party seeking a broader interpretation might argue that minor variations in analytical data should not preclude a finding that a substance is the claimed monohydrate, so long as it generally conforms to the properties of a hydrated crystal of the compound. However, the specificity of the patent makes this a difficult position.
- Evidence for a Narrower Interpretation: The specifications of both the ’725 and ’103 patents provide highly specific analytical data to define the "crystalline monohydrate" form. This includes characteristic X-ray powder diffraction (XRPD) peaks listed in Table 1 and depicted in Figure 1, and a specific Differential Scanning Calorimetry (DSC) thermogram in Figure 2 (’725 Patent, col. 44, Table 1; Fig. 1-2). A party will argue that to be the "crystalline monohydrate," an accused product must exhibit these precise physical and chemical characteristics, distinguishing it from other potential forms.
VI. Other Allegations
- Indirect Infringement: The complaint includes allegations of induced and contributory infringement, asserting that Defendants know their product is especially adapted for infringement and that their promotional activities and package inserts will instruct medical professionals and patients to use the drug in an infringing manner (Compl. ¶41-42, ¶53-54).
- Willful Infringement: The complaint seeks a finding of an "exceptional case" warranting attorneys' fees but does not plead specific facts to support willfulness beyond Defendants' knowledge of the patents, evidenced by the Paragraph IV certification letter sent on or about September 7, 2023 (Compl. ¶34, ¶44, ¶56).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of technical identity: does the active pharmaceutical ingredient in Zydus’s proposed generic product meet the specific structural and analytical definition of the "crystalline monohydrate" of dasatinib as claimed in the patents, or does it utilize a non-infringing solid-state form?
- A central legal and factual question will be one of validity: as asserted in their Paragraph IV letter, can Defendants prove by clear and convincing evidence that the asserted claims covering the specific crystalline form of dasatinib and compositions containing it are invalid over the prior art?