Pfizer Inc v. Zydus Pharma USA Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Pfizer Inc. and related entities (Delaware, Netherlands, Puerto Rico)
  • Defendant: Zydus Pharmaceuticals (USA) Inc. (New Jersey) and Cadila Healthcare Ltd. (India)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:20-cv-00301, D. Del., 02/28/2020
• Venue Allegations: Plaintiff alleges venue is proper because Defendants did not contest it in a prior, pending case involving the same parties and patents, and alternatively, because Defendants’ filing of an Abbreviated New Drug Application (ANDA) constitutes a tortious act causing foreseeable harm in Delaware.
• Core Dispute: Plaintiff alleges that Defendants’ filing of an ANDA to seek FDA approval for a generic version of the drug Xeljanz XR® constitutes an act of infringement of three U.S. patents covering the drug's active ingredient and its specific crystalline salt form.
• Technical Context: The technology relates to small molecule inhibitors of Janus kinase 3 (JAK3), a protein implicated in immune response, used for the treatment of autoimmune diseases such as rheumatoid arthritis and ulcerative colitis.
• Key Procedural History: This action is filed under the Hatch-Waxman Act, triggered by Defendants' ANDA filing containing a "Paragraph IV" certification alleging non-infringement or invalidity of the patents-in-suit. The complaint notes a prior pending litigation between the same parties concerning the same patents (C.A. No. 17-158-GJP, D. Del.). U.S. Patent No. RE41,783 is a reissue of a prior patent, and its expiration date was extended by the USPTO. U.S. Patent No. 7,301,023 is subject to a terminal disclaimer over the RE'783 patent.

Case Timeline

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

U.S. Reissue Patent No. RE41,783 - "Pyrrolo[2,3-d]pyrimidine Compounds"

Issued September 28, 2010.

The Invention Explained

• Problem Addressed: The patent describes a need for effective immunosuppressive agents for treating organ transplant rejection and a variety of autoimmune diseases (RE'783 Patent, col. 1:12-23). It identifies the protein enzyme Janus Kinase 3 (JAK3) as a promising therapeutic target because its expression is largely limited to hematopoietic cells, suggesting that its inhibition could modulate the immune system with potentially fewer side effects than less targeted agents (RE'783 Patent, col. 1:24-30).
• The Patented Solution: The patent discloses a class of pyrrolo[2,3-d]pyrimidine compounds that function as inhibitors of JAK3 (RE'783 Patent, Abstract). The core of the invention is a specific chemical scaffold with various substituents, designed to bind to and inhibit the enzyme, thereby preventing the signaling cascade that leads to T-cell proliferation and immune response (RE'783 Patent, col. 1:44-50; col. 2:50-65).
• Technical Importance: This approach represented a targeted mechanism for immunosuppression, distinct from broader-acting agents, offering the potential for a more refined treatment of T-cell proliferative disorders (RE'783 Patent, col. 1:36-41).

Key Claims at a Glance

• The complaint asserts dependent claims 3 and 4 (Compl. ¶49).
• The asserted claims depend from independent claim 1, which claims a broad genus of pyrrolo[2,3-d]pyrimidine compounds.
  • Claim 3 specifically claims the compound 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile, known as tofacitinib.
  • Claim 4 claims a pharmaceutically acceptable salt of the compound of claim 3.

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 November 15, 2005.

The Invention Explained

• Problem Addressed: While the tofacitinib compound was known, the patent notes that for effective pharmaceutical development, particularly for solid dosage forms like tablets, the active ingredient must possess consistent and acceptable solid-state properties ('027 Patent, col. 1:53-57). Amorphous or less stable crystalline forms can lead to issues with manufacturing, stability, and bioavailability.
• The Patented Solution: The patent discloses a novel and specific crystalline form of the mono-citrate salt of tofacitinib ('027 Patent, col. 1:15-25). This specific crystal structure, or polymorph, is defined by a characteristic X-ray powder diffraction (XRPD) pattern and a differential scanning calorimetry (DSC) thermogram, which provide a fingerprint for this physical form (RE'783 Patent, Fig. 1; col. 2:7-14).
• Technical Importance: The discovery of a stable, manufacturable crystalline polymorph is a critical step in drug development, as it ensures batch-to-batch consistency, predictable dissolution rates, and adequate shelf life for a solid oral drug product ('027 Patent, col. 1:53-57).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶55).
• 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

U.S. Patent No. 7,301,023 - "Chiral Salt Resolution"

Issued November 27, 2007.

Technology Synopsis

The patent background explains that compounds like tofacitinib are chiral and are often initially synthesized as a racemic mixture of two non-superimposable mirror-image molecules (enantiomers) ('023 Patent, col. 3:39-44). For therapeutic use, it is often necessary to isolate a single, specific enantiomer. The patent originally described a method for achieving this separation ("chiral resolution"), but the granted claim after a Certificate of Correction is directed to the specific compound itself.

Asserted Claims

The complaint asserts claim 1, which, as corrected, is an independent product claim ('023 Patent, Certificate of Correction; Compl. ¶61).

Accused Features

The complaint alleges that the Zydus Generic XR Tablets, which contain tofacitinib citrate, will infringe claim 1 of the '023 patent (Compl. ¶¶39, 61).

III. The Accused Instrumentality

Product Identification

Zydus Generic XR Tablets, which are proposed generic copies of Xeljanz XR® (tofacitinib citrate EQ 11 mg base extended-release tablets) (Compl. ¶37).

Functionality and Market Context

The accused product is an extended-release tablet containing tofacitinib citrate as the active pharmaceutical ingredient (Compl. ¶¶15, 39). Tofacitinib is an inhibitor of Janus kinases (JAKs) indicated for the treatment of several autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (Compl. ¶16). Zydus has filed an ANDA seeking FDA approval to market this product as a generic equivalent to Pfizer's branded Xeljanz XR® prior to the expiration of the patents-in-suit (Compl. ¶2). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

RE41,783 Infringement Allegations

Identified Points of Contention

• Technical Questions: In an ANDA case involving a small molecule compound patent, infringement is often not the primary dispute. The core technical question is whether the active ingredient in Zydus's proposed generic product is, in fact, the compound claimed in the RE’783 patent. Given that a generic must be bioequivalent to the branded drug, this is typically conceded, shifting the focus to the patent's validity. The complaint notes Zydus's notification letter asserts invalidity for all claims of the patent (Compl. ¶43).

'027 Patent Infringement Allegations

Identified Points of Contention

• Scope Questions: A central question for the court will be how to define the scope of "A crystalline form." Does the claim cover only the specific polymorph characterized by the XRPD and DSC data in the specification, or could it be interpreted more broadly?
• Technical Questions: The primary technical dispute will be evidentiary: does the crystalline material in Zydus's proposed product exhibit the same physical characteristics (e.g., XRPD pattern) as the polymorph claimed in the '027 patent? A defendant in such a case may argue that its product uses a different, non-infringing polymorph or an amorphous version of the drug substance.

V. Key Claim Terms for Construction

The Term: "A crystalline form" ('027 Patent, Claim 1)

Context and Importance

The determination of infringement for the '027 patent hinges entirely on the meaning of this term. Pharmaceutical compounds can often exist in multiple different crystalline forms (polymorphs) or in a non-crystalline (amorphous) state, each with different physical properties and potentially different patentability. Practitioners may focus on this term because the scope of the patent will be defined by whether it is limited to the single, specific polymorph disclosed in the patent or could cover other crystalline forms.

Intrinsic Evidence for Interpretation

• Evidence for a Broader Interpretation: The plain language of claim 1 itself does not recite any specific characterization data (e.g., diffraction peaks), which a plaintiff could argue supports a reading that is not strictly limited to the examples.
• Evidence for a Narrower Interpretation: The specification repeatedly refers to "a novel crystalline form" and explicitly defines it with reference to its characteristic XRPD pattern in Figure 1 and DSC thermogram in Figure 2 ('027 Patent, col. 2:7-25). A defendant will almost certainly argue that the term "A crystalline form" is implicitly limited by the specification to the specific polymorph disclosed and characterized therein, a common outcome in pharmaceutical patent litigation.

VI. Other Allegations

Indirect Infringement

While the prayer for relief seeks an injunction against inducing or contributing to infringement, the substantive counts are based on the artificial act of infringement under 35 U.S.C. § 271(e)(2)(A) stemming from the ANDA submission (Compl. ¶¶47, 53, 59; p. 11, ¶C). The complaint does not plead specific facts supporting a standalone theory of inducement, such as active instruction to physicians or patients.

Willful Infringement

The complaint does not contain a formal count for willful infringement. However, it alleges that Zydus had knowledge of each of the patents-in-suit at the time it submitted its ANDA (Compl. ¶¶48, 54, 60). Furthermore, the prayer for relief requests that the court find the case to be "exceptional" under 35 U.S.C. § 285, which could entitle Plaintiff to an award of attorneys' fees (Compl. p. 12, ¶D).

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

• A central issue, characteristic of Hatch-Waxman litigation, will be one of patent validity. The complaint indicates that Zydus's defense strategy focuses on the alleged invalidity of all asserted claims, suggesting the case will likely turn on prior art challenges (obviousness) or other invalidity theories rather than on a dispute over whether the generic product contains the claimed invention (Compl. ¶43).
• For the '027 patent, a key evidentiary question will be one of polymorphic identity: does the active ingredient in Zydus's proposed generic product exist in the specific crystalline form defined by the characterization data in the patent, or does it utilize a different, non-infringing crystalline or amorphous form?
• A potential legal issue involves the overlapping subject matter of the RE'783 patent and the '023 patent, both of which claim the same tofacitinib compound. While the terminal disclaimer filed for the '023 patent is intended to address statutory double patenting, the assertion of both patents could lead to complex arguments regarding claim differentiation and validity.