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: Arnold & Porter Kaye Scholer LLP
• Case Identification: 3:20-cv-02222, D.N.J., 02/28/2020
• Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Zydus Pharmaceuticals (USA) Inc. is a New Jersey corporation.
• Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the drug Xeljanz XR® constitutes an act of infringement of three U.S. patents covering the drug's active ingredient, its crystalline form, and its method of synthesis.
• Technical Context: The technology involves tofacitinib citrate, a small molecule inhibitor of Janus kinases (JAKs), which is used to treat autoimmune diseases such as rheumatoid arthritis and ulcerative colitis by modulating the body's immune response.
• Key Procedural History: This is a Hatch-Waxman action triggered by an ANDA filing. U.S. Patent No. RE41,783 is a reissue of U.S. Patent No. 6,627,754, and its expiration date was extended by the USPTO. U.S. Patent No. 7,301,023 is subject to a terminal disclaimer, linking its enforceability to the expiration of the RE'783 patent. The complaint notes that Defendants' Paragraph IV certification letter primarily asserts invalidity of the patents-in-suit rather than non-infringement.

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 background describes the role of the Janus Kinase 3 (JAK3) enzyme in the immune system and notes its expression is limited to hematopoietic cells, suggesting that inhibiting JAK3 could provide immunosuppression for treating T-cell proliferative disorders like transplant rejection and autoimmune diseases (RE’783 Patent, col. 1:24-43).
• The Patented Solution: The invention provides a class of chemical compounds, specifically pyrrolo[2,3-d]pyrimidines, that are designed to inhibit protein kinases, particularly JAK3. The detailed description provides methods for synthesizing these compounds, which include the active ingredient tofacitinib (RE’783 Patent, Abstract; col. 8:1-48).
• Technical Importance: The invention provides a targeted mechanism for immunosuppression, offering a potential therapeutic approach for a range of autoimmune diseases by selectively interfering with the JAK3 signaling pathway (RE’783 Patent, col. 1:13-23).

Key Claims at a Glance

• The complaint asserts infringement of at least claims 3 and 4 (Compl. ¶48). The independent claim from which these depend is Claim 1.
• Independent Claim 1 recites:
  • A compound of a specific chemical formula (Formula I) or its pharmaceutically acceptable salt.
  • Wherein substituent R¹ is a piperidinyl group with further specified chemical substitutions.
  • Wherein substituents R² and R³ are hydrogen.
• The complaint reserves the right to assert other claims.

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: For a chemical compound to be developed into a viable drug product, it must have stable physical properties. The patent notes the need for a form with "solid state properties which are acceptable to support tablet development" (’027 Patent, col. 3:55-57).
• The Patented Solution: The invention discloses and claims a specific, novel crystalline form of the citrate salt of tofacitinib. This crystalline form is defined by its characteristic X-ray powder diffraction (XRPD) pattern, which shows distinct peaks at specific 2-theta angles, and a specific melting temperature range ('027 Patent, Abstract; col. 3:8-16).
• Technical Importance: Identifying a stable crystalline form (polymorph) is a critical step in pharmaceutical development, as it ensures consistency in manufacturing, stability, and bioavailability of the final drug product.

Key Claims at a Glance

• The complaint asserts infringement of at least claim 1 (Compl. ¶52).
• Independent Claim 1 recites:
  • 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 reserves the right to assert other claims. Dependent claim 2 further defines the crystalline form by its characteristic XRPD peaks.

U.S. Patent No. 7,301,023, “Chiral Salt Resolution,” issued November 27, 2007

The Invention Explained

• The patent addresses the challenge of separating a racemic mixture of a chemical precursor into its distinct, mirror-image stereoisomers (enantiomers). It discloses a method for resolving the enantiomers of a key intermediate used to synthesize tofacitinib, allowing for the isolation of the therapeutically desired (3R,4R) form (’023 Patent, col. 3:11-21; col. 5:21-34).

Key Allegations

• Asserted Claims: The complaint asserts infringement of claim 1 ('023 Patent, Compl. ¶58).
• Accused Features: The complaint alleges that the filing of the ANDA to market a generic product containing the (3R,4R) enantiomer of tofacitinib is an act of infringement of the claimed resolution process, as making the final drug product would infringe the process claim (Compl. ¶58, ¶60-61).

III. The Accused Instrumentality

Product Identification

• "Zydus Generic XR Tablets," which are proposed generic copies of Pfizer's Xeljanz XR® (tofacitinib extended-release tablets, 11 mg) (Compl. ¶9, ¶36).

Functionality and Market Context

• The active ingredient in the accused product is alleged to be tofacitinib citrate (Compl. ¶38). Tofacitinib citrate functions as an inhibitor of Janus kinases (JAKs) and is indicated for the treatment of several autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (Compl. ¶15). The complaint alleges Zydus seeks to commercially manufacture, use, and sell its generic tablets in the United States upon receiving FDA approval (Compl. ¶40, ¶44).

IV. Analysis of Infringement Allegations

The complaint alleges infringement under 35 U.S.C. § 271(e)(2)(A), where the filing of the ANDA is the statutory act of infringement. The complaint states that Zydus's Paragraph IV notice letter did not contain a noninfringement argument for the asserted patents, aside from claim 5 of the '027 patent, but instead alleged that all claims are invalid (Compl. ¶42). This suggests the central dispute may concern validity rather than non-infringement.

No probative visual evidence provided in complaint.

RE41,783 Infringement Allegations

Identified Points of Contention

• Validity Question: The primary point of contention, as framed by the complaint, appears to be Zydus's allegation that the asserted claims are invalid (Compl. ¶42). The case may therefore focus on defenses such as obviousness or anticipation rather than disputes over the chemical structure.
• Scope Question: A potential question, though not detailed in the complaint, could arise regarding the definition of "pharmaceutically acceptable salt" if Zydus were to use a different salt form of tofacitinib, although the complaint alleges the use of tofacitinib citrate (Compl. ¶38).

6,965,027 Infringement Allegations

Identified Points of Contention

• Factual/Evidentiary Question: A central factual question for the court will be whether the specific crystalline form of tofacitinib citrate in Zydus's proposed product actually exhibits the XRPD peak pattern claimed in the '027 patent. This will depend on scientific evidence and expert testimony.
• Scope Question: The interpretation of the term "approximately" as it applies to the location of the XRPD peaks will be a key question of claim construction, defining the literal boundaries of infringement.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for analysis of key claim terms for the RE'783 or '023 patents. For the '027 patent, one term is prominent.

• The Term: "approximately" (from '027 Patent, Claim 2)
• Context and Importance: This term modifies the numerical values of the X-ray powder diffraction peaks that define the patented crystalline structure. Its construction is critical because it determines how much variability is permitted in an accused product's XRPD pattern before it falls outside the literal scope of the claim. Practitioners may focus on this term because the infringement analysis for polymorph patents often hinges on whether minor experimental variations place a product inside or outside the claimed range.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification uses the term "about" when describing the melting point and temperature ranges, suggesting an intent to claim with some degree of flexibility and not be limited to the exact numerical values disclosed ('027 Patent, col. 3:9-24).
  • Evidence for a Narrower Interpretation: The patent provides a detailed table (Table 1) listing numerous XRPD peaks with specific d-values and relative intensities ('027 Patent, col. 7:10-34). A party could argue that this high level of precision implies that "approximately" should be construed narrowly to encompass only minor instrumental and experimental error.

VI. Other Allegations

• Indirect Infringement: The complaint's formal counts are for direct infringement under 35 U.S.C. § 271(e)(2)(A), based on the filing of the ANDA (Compl. ¶46, ¶52, ¶58). The prayer for relief includes a request to enjoin inducing or contributing to infringement, but these theories are not developed as separate counts in the complaint (Compl., Prayer for Relief C).
• Willful Infringement: The complaint does not explicitly allege "willful infringement." However, it does allege that Zydus had knowledge of each of the patents-in-suit when it submitted its ANDA (Compl. ¶47, ¶53, ¶59). Furthermore, the complaint requests a judgment that the case is "exceptional" under 35 U.S.C. § 285, which would entitle Pfizer to an award of attorneys' fees (Compl., Prayer for Relief D).

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

1. A Threshold Question of Validity: Given the complaint's allegation that Zydus's defense is centered on invalidity rather than non-infringement (Compl. ¶42), a core issue will be whether Zydus can prove by clear and convincing evidence that Pfizer's patents are invalid, for instance, on grounds of obviousness over the prior art.
2. An Evidentiary Dispute over Physical Form: For the '027 patent, the case will likely turn on a key evidentiary question: does the tofacitinib citrate in Zydus’s proposed generic product, as a matter of scientific fact, possess the specific crystalline structure defined by the XRPD peaks in the asserted claims?
3. A Definitional Question of Scope: A dispositive legal issue for the '027 patent will be the court’s construction of the term "approximately." The scope afforded to this term will define the literal boundary of the claims and will be critical in determining whether Zydus’s product, which may have slight variations in its measured XRPD pattern, infringes.