Pfizer Inc v. Zydus Pharma USA Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Pfizer Inc. (Delaware), C.P. Pharmaceuticals International C.V. (Netherlands), PF Prism CV. (Netherlands), PBG Puerto Rico LLC (Puerto Rico), and PF Prism Imb BV. (Netherlands)
  • 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-00300, D. Del., 02/28/2020
• Venue Allegations: Venue is alleged based on Defendants having previously litigated the same patents and Abbreviated New Drug Application (ANDA) in the same court without contesting venue, and alternatively, on the grounds that the ANDA filing constitutes a tortious act of patent infringement causing foreseeable harm to Plaintiffs in Delaware.
• Core Dispute: Plaintiff alleges that Defendant’s filing of an ANDA to market a generic version of Pfizer’s drug Xeljanz® constitutes an act of infringement of three U.S. patents covering the drug's active ingredient and a specific crystalline form.
• Technical Context: The technology concerns tofacitinib citrate, a small molecule inhibitor of Janus kinases (JAKs) used to treat autoimmune diseases such as rheumatoid arthritis, a significant pharmaceutical market.
• Key Procedural History: The complaint notes that this action follows a previously filed, pending litigation between the same parties concerning the same patents and ANDA. The RE’783 patent is a reissue of an earlier patent, and its expiration date was extended by the USPTO. The ’023 patent is subject to a terminal disclaimer based on the RE’783 patent.

Case Timeline

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

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: The patent discloses that the underlying compound, an inhibitor of Janus Kinase 3 (JAK3), is useful for treating various autoimmune diseases (e.g., rheumatoid arthritis) ('027 Patent, col. 1:33-47). For a chemical compound to be developed into a tablet-based drug, it must have stable and consistent physical properties. The patent implies a need for a solid form of the compound suitable for pharmaceutical development, stating the claimed crystalline form has "solid state properties which are acceptable to support tablet development" ('027 Patent, col. 1:52-58).
• The Patented Solution: The patent discloses a specific, novel crystalline form of the tofacitinib monocitrate salt ('027 Patent, Abstract; col. 1:62-65). This crystalline structure, or polymorph, is uniquely identified and defined by its characteristic X-ray powder diffraction (XRPD) pattern and its melting point as measured by differential scanning calorimetry (DSC) ('027 Patent, col. 2:7-24; FIGs. 1-2).
• Technical Importance: Identifying a stable, reproducible crystalline polymorph is a critical step in drug development, as it ensures consistency in manufacturing, dosage, shelf life, and bioavailability of the active pharmaceutical ingredient ('027 Patent, col. 1:52-58).

Key Claims at a Glance

• The complaint asserts infringement of at least independent claim 1 (Compl. ¶48).
• Claim 1 elements:
  • 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.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 7,301,023, "Chiral Salt Resolution," Issued November 27, 2007

The Invention Explained

• Problem Addressed: The patent’s background explains that while pyrrolo[2,3-d]pyrimidine compounds are useful as JAK3 inhibitors, they are often first synthesized as a racemic mixture, which contains multiple, non-superimposable mirror-image versions (enantiomers) of the molecule ('023 Patent, col. 1:39-43). For therapeutic use, it is often necessary to isolate a single, specific enantiomer, as different enantiomers can have different biological activities or toxicities ('023 Patent, col. 1:41-43).
• The Patented Solution: The patent describes a method for separating, or resolving, the desired (3R,4R) enantiomer from a racemic mixture ('023 Patent, col. 5:2-6). The method involves using a chiral resolving agent, such as di-p-toluoyl-L-tartaric acid, which selectively binds to one enantiomer and causes it to precipitate from a solution, allowing the desired, pure enantiomer to be isolated ('023 Patent, col. 5:43-50, col. 6:53-65).
• Technical Importance: Developing an efficient method for chiral resolution is essential for the large-scale, cost-effective manufacturing of a single-enantiomer drug, ensuring patient safety and therapeutic efficacy.

Key Claims at a Glance

• The complaint asserts infringement of claim 1 (Compl. ¶54).
• Claim 1 elements (as corrected by a Certificate of Correction, Feb. 17, 2009):
  • The compound 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile
  • or a pharmaceutically acceptable salt thereof.
• The complaint does not explicitly reserve the right to assert dependent claims.

Multi-Patent Capsule

• Patent Identification: U.S. Reissue Patent No. RE41,783, "Pyrrolo[2,3-d]pyrimidine Compounds," Issued September 28, 2010 (Compl. ¶32).
• Technology Synopsis: The patent addresses the need for compounds that can inhibit protein kinases like JAK3 for use as immunosuppressive agents in treating conditions like organ transplant rejection and autoimmune diseases (RE’783 Patent, Abstract). The invention provides a family (genus) of chemical compounds, defined by a general formula, that possess this inhibitory activity (RE’783 Patent, Abstract; col. 21:1-65).
• Asserted Claims: The complaint asserts infringement of at least claims 3 and 4 (Compl. ¶62).
• Accused Features: The accused Zydus generic tablets contain tofacitinib citrate as the active ingredient (Compl. ¶40). Claim 4 of the RE’783 patent is a species claim that specifically recites the compound tofacitinib (3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile) (RE’783 Patent, col. 23:31-39, col. 24:28-39). The complaint alleges infringement based on the presence of this compound in the accused product (Compl. ¶62).

III. The Accused Instrumentality

• Product Identification: The accused instrumentalities are Zydus's 10 mg generic tablets containing tofacitinib citrate, for which Zydus filed ANDA No. 209829 with the FDA (Compl. ¶¶2, 13).
• Functionality and Market Context: The Zydus product is a generic version of Pfizer’s Xeljanz®, a JAK inhibitor indicated for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (Compl. ¶15). The active ingredient is tofacitinib citrate (Compl. ¶¶16, 40). The filing of the ANDA is a statutory act of infringement under 35 U.S.C. § 271(e)(2), which allows patent holders to sue before the generic drug is actually marketed (Compl. ¶48). Zydus seeks approval to sell its generic tablets prior to the expiration of the patents-in-suit (Compl. ¶38).

IV. Analysis of Infringement Allegations

The complaint alleges infringement under 35 U.S.C. § 271(e)(2)(A), where the filing of an ANDA for a drug claimed in a patent is a statutory act of infringement (Compl. ¶¶48, 54, 60). The core of the infringement allegation is that Zydus's proposed generic product, if manufactured and sold, would contain the patented inventions. The complaint does not provide sufficient detail for analysis of the specific infringing functionality against each claim limitation in a claim chart format.

No probative visual evidence provided in complaint.

• Identified Points of Contention:
  • Factual Question (’027 Patent): The central question regarding the ’027 patent will be factual: does the tofacitinib citrate in Zydus’s ANDA product possess the specific crystalline structure claimed in the patent? The dispute will likely focus on analytical evidence (e.g., XRPD, DSC) comparing Zydus's product to the polymorph defined in the ’027 patent specification. Zydus may contend that its product uses a different, non-infringing polymorph or an amorphous form of the salt.
  • Scope & Validity Questions (’023 and RE’783 Patents): For the ’023 patent and the RE’783 patent, which claim the tofacitinib molecule itself, infringement appears to be a lower hurdle if Zydus's product contains tofacitinib citrate as alleged (Compl. ¶40). Consequently, the primary dispute for these patents will likely concern the validity of the claims, which Zydus has challenged in its Paragraph IV certification letter (Compl. ¶¶39, 44).

V. Key Claim Terms for Construction

• ’027 Patent: "crystalline form" (from Claim 1)

  • Context and Importance: This term is the crux of the ’027 patent’s invention. Its construction will determine whether the claim is limited to the single, specific polymorph detailed in the patent or if it can encompass other crystalline structures of tofacitinib citrate. Practitioners may focus on this term because the existence of different, non-infringing polymorphs is a common defense strategy in pharmaceutical patent litigation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language itself is simple: "A crystalline form..." One could argue that without further limiting language in the claim itself, it is not textually restricted to a single polymorph.
    • Evidence for a Narrower Interpretation: The specification strongly suggests a narrow definition. It repeatedly refers to "The novel crystalline form" and proceeds to define it with highly specific data, 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, as depicted in FIG. 1" (’027 Patent, col. 2:7-14). A party arguing for a narrow scope would assert that the term "crystalline form" is effectively defined by these specific, disclosed properties.

• ’023 Patent: "3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile" (from Claim 1)

  • Context and Importance: This term is the chemical name for the tofacitinib molecule, with specific stereochemistry (3R,4R). While the chemical identity is not likely to be disputed, the precise stereochemistry is a critical limitation of the claim. Infringement requires the accused product to contain this specific stereoisomer.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent itself does not appear to offer evidence for an interpretation broader than the plain meaning of the chemical name and its designated stereochemistry.
    • Evidence for a Narrower Interpretation: The specification is dedicated to methods for resolving and isolating this specific (3R,4R) enantiomer from other isomers, reinforcing the importance of the recited stereochemistry as a fundamental aspect of the invention (’023 Patent, col. 5:61-65).

VI. Other Allegations

• Indirect Infringement: The prayer for relief requests an injunction against inducing or contributing to infringement (Prayer for Relief ¶C). However, the body of the complaint does not contain specific factual allegations, such as references to instructions in a product label, to support a claim for indirect infringement.
• Willful Infringement: The complaint does not use the term "willful" or request enhanced damages. It does allege that Zydus had knowledge of the patents-in-suit when it submitted its ANDA (Compl. ¶¶49, 55, 61). It also requests a finding that the case is "exceptional" under 35 U.S.C. § 285, which would entitle Pfizer to an award of attorneys' fees (Prayer for Relief ¶D).

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

• A key factual issue will be one of polymorphic identity: Does the generic product described in Zydus's ANDA contain the specific crystalline form of tofacitinib citrate defined by the data in the ’027 patent, or does it utilize a different, non-infringing polymorph or an amorphous form?
• A central legal and factual question will be one of patent validity: Can Zydus prove by clear and convincing evidence that the asserted claims of the ’027, ’023, and RE’783 patents are invalid for reasons such as anticipation or obviousness, as it asserted in its Paragraph IV certification?
• A subsidiary legal question for the ’027 patent will be the scope of "crystalline form": Will the court construe the term as being strictly limited to the polymorph exhibiting the exact physical characteristics disclosed in the specification, or could it be interpreted to cover forms with substantially similar properties?