Pfizer Inc v. Zydus Pharma USA Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Pfizer Inc. (Delaware) and its affiliated entities.
  • Defendant: Zydus Pharmaceuticals (USA) Inc. (New Jersey) and Cadila Healthcare Ltd. (India).
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP.
• Case Identification: 1:21-cv-00214, D. Del., 02/16/2021
• Venue Allegations: Venue is alleged to be proper in Delaware on the basis that Defendants, directly or through a subsidiary, manufacture, market, and sell generic drugs for distribution in the district.
• Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the rheumatoid arthritis drug Xeljanz® XR constitutes an act of infringement of two patents covering the active pharmaceutical ingredient, tofacitinib, and a specific crystalline salt form of that compound.
• Technical Context: The technology concerns small-molecule inhibitors of Janus kinases (JAKs) for treating autoimmune diseases, and the specific crystalline forms (polymorphs) of these molecules required for stable and effective pharmaceutical products.
• Key Procedural History: This is a Hatch-Waxman action triggered by Defendants' filing of an ANDA with a "Paragraph IV" certification, asserting that Plaintiff's patents are invalid or will not be infringed. The complaint notes that Defendants' notice letter and accompanying statement alleged invalidity for all asserted claims but did not include a non-infringement argument. U.S. Patent No. RE41,783 is a reissue of an earlier patent and its expiration date has been extended by the USPTO.

Case Timeline

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

U.S. Reissue Patent No. RE41,783 - “PYRROLO[2,3-D]PYRIMIDINE COMPOUNDS”, Issued Sep. 28, 2010

The Invention Explained

• Problem Addressed: The patent background describes a need for new immunosuppressive agents to treat a range of conditions, including organ transplant rejection and autoimmune diseases like rheumatoid arthritis, by inhibiting protein kinases (Compl. ¶18; RE’783 Patent, col. 5:11-24).
• The Patented Solution: The invention provides a class of chemical compounds, known as pyrrolo[2,3-d]pyrimidines, that are designed to inhibit the Janus Kinase 3 (JAK3) enzyme. By blocking JAK3, which plays a key role in the maturation and function of immune cells, these compounds can modulate the immune response (RE’783 Patent, Abstract; col. 5:26-48).
• Technical Importance: The selective inhibition of JAK3 was a significant approach because, unlike other Janus kinases, JAK3 expression is largely restricted to hematopoietic cells, suggesting that its inhibition could provide targeted immunosuppression with potentially fewer side effects than less specific agents (RE’783 Patent, col. 5:26-34).

Key Claims at a Glance

• The complaint asserts infringement of at least claim 4, which depends from independent claim 1 (Compl. ¶44).
• The essential elements of independent claim 1 are:
  • A compound of a specific chemical structure (Formula I) or a pharmaceutically acceptable salt thereof, where
  • R¹ is a group of a specified formula,
  • R⁵ is a piperidinyl ring substituted with one to five members of a specified list of chemical groups, and
  • R² and R³ are both hydrogen.
• Claim 4 specifies the compound as 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile (the compound known as tofacitinib), or a pharmaceutically acceptable salt thereof (RE’783 Patent, col. 24:26-31).

U.S. Patent No. 6,965,027 - “CRYSTALLINE 3-{4-METHYL-3-[METHYL-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)-AMINO]-PIPERIDIN-1-YL}-3-OXO-PROPIONITRILE CITRATE”, Issued Nov. 15, 2005

The Invention Explained

• Problem Addressed: The patent describes the need to identify a form of the tofacitinib compound with "solid state properties which are acceptable to support tablet development" ('027 Patent, col. 3:55-58). The physical form of a drug substance can impact its stability, manufacturability, and bioavailability.
• The Patented Solution: The invention is a specific, novel crystalline form of the mono-citrate salt of tofacitinib. This crystalline form is distinguished from other potential solid forms (such as amorphous material or other polymorphs) by unique physical characteristics, including a specific X-ray powder diffraction pattern and a distinct melting point ('027 Patent, Abstract; col. 3:15-21).
• Technical Importance: The discovery and characterization of a stable, reproducible crystalline polymorph is a critical step in drug development, as it allows for consistent manufacturing of a drug product with predictable stability and dissolution profiles, which are essential for regulatory approval and commercial use ('027 Patent, col. 3:55-58).

Key Claims at a Glance

• The complaint asserts infringement of at least independent claim 1 (Compl. ¶50).
• The essential elements of independent claim 1 are:
  • A crystalline form of
  • 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile
  • mono citrate salt.

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendants' proposed "Zydus 22 mg Generic XR Tablets," which are the subject of Abbreviated New Drug Application (ANDA) No. 214264 (Compl. ¶¶ 2, 34).

Functionality and Market Context

• The accused product is an extended-release tablet designed for once-daily administration that will contain tofacitinib citrate as its active ingredient (Compl. ¶¶ 34, 35). It is a generic version of Pfizer’s Xeljanz® XR product and is intended for the same indications, which include the treatment of moderately to severely active rheumatoid arthritis and ulcerative colitis (Compl. ¶¶ 2, 18).
• The filing of the ANDA seeking FDA approval to market this product prior to the expiration of Plaintiff's patents is the statutory act of infringement alleged in the complaint (Compl. ¶¶ 44, 50). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

RE'783 Patent Infringement Allegations

'027 Patent Infringement Allegations

• Identified Points of Contention:
  • Scope Questions: The complaint states that Zydus’s notice letter focused on invalidity and did not present a non-infringement argument (Compl. ¶40-41). This suggests the primary dispute for both patents may center on validity rather than claim scope or infringement.
  • Technical Questions: For the ’027 patent, a central technical question for the court will be one of physical identity. The analysis will require evidence (e.g., from X-ray diffraction or other analytical techniques) to determine if the crystalline structure of the tofacitinib citrate in Zydus’s proposed product is the same as the specific polymorph claimed in the patent.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for a full analysis of potential claim construction disputes. However, based on the technology, one term is central.

• The Term: "A crystalline form" ('027 Patent, Claim 1).
• Context and Importance: This term is the core of the ’027 patent, which does not claim the chemical compound itself but a specific solid-state form of its citrate salt. In pharmaceutical litigation, whether a generic product uses the same patented crystalline form (polymorph) as the branded drug is often a dispositive issue. Practitioners may focus on this term because the entire infringement case for the '027 patent depends on proving that Zydus's product contains this specific form.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: A party could argue the term "A crystalline form" should not be limited by the examples in the specification. However, this position may be difficult to maintain given the patent's focus on a "novel" form.
  • Evidence for a Narrower Interpretation: The specification explicitly defines the novel crystalline form by its physical properties, stating it "exhibits an X-ray diffraction pattern with characteristic peaks expressed in degrees 2-theta (2θ) at 5.7, 16.1, 20.2 and 20.5" and providing the corresponding diffraction pattern in Figure 1 ('027 Patent, col. 3:8-12). A party would argue that the claim term "A crystalline form" should be construed as being limited to a polymorph that exhibits these specific, defining characteristics.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that Defendant Cadila Healthcare Ltd. induced the infringement of its subsidiary, Zydus Pharmaceuticals (USA) Inc., by "actively and knowingly" causing, assisting with, participating in, and directing the submission of the ANDA to the FDA (Compl. ¶¶ 56-57).
• Willful Infringement: The complaint does not contain a separate count for willful infringement. However, it alleges that Zydus had "knowledge" of the RE'783 and '027 patents when it filed its ANDA (Compl. ¶¶ 45, 51). Furthermore, the prayer for relief requests a judgment that the case is "exceptional" under 35 U.S.C. § 285, a remedy available for findings of willful infringement or other litigation misconduct (Compl. p. 11, ¶E).

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

• A central issue for the court will be one of validity: as Defendants' pre-suit certification focused on invalidity, the case will likely turn on whether Defendants can prove by clear and convincing evidence that the asserted claims of the RE’783 patent (covering the tofacitinib compound) and the ’027 patent (covering its crystalline form) are invalid over the prior art.
• A key evidentiary question for the ’027 patent will be one of polymorphic identity: does the active ingredient in Defendants' proposed generic product, as specified in its ANDA, possess the specific crystalline structure defined by the characteristic peaks and thermal properties described in the ’027 patent specification?