DCT

1:24-cv-00551

AstraZeneca Ab v. Apotex Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00551, D. Del., 05/06/2024
  • Venue Allegations: Plaintiff alleges venue is proper for Apotex Corp. as a Delaware corporation and for Apotex Inc. as a foreign corporation that may be sued in any judicial district.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) for generic versions of Plaintiff's XIGDUO XR® drug product constitutes an act of infringement of four patents related to dapagliflozin crystal structures, pharmaceutical compositions, formulations, and methods of use.
  • Technical Context: The technology concerns pharmaceutical treatments for type 2 diabetes, a major global health issue, focusing on the SGLT2 inhibitor dapagliflozin, both as a specific crystalline compound and in combination formulations with metformin.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 219266 and a formal Notice Letter with a Paragraph IV certification, dated March 22, 2024, challenging the asserted patents before their expiration. The asserted patents are listed in the FDA's Orange Book for XIGDUO XR® and have received patent term extensions.

Case Timeline

Date Event
2006-06-28 Earliest Priority Date for ’598 and ’698 Patents
2009-05-27 Earliest Priority Date for ’934 Patent
2009-11-13 Earliest Priority Date for ’028 Patent
2011-04-05 ’598 Patent Issued
2013-08-06 ’698 Patent Issued
2014-04-01 ’934 Patent Issued
2014-10-29 FDA Approved NDA for XIGDUO XR®
2017-04-11 ’028 Patent Issued
2024-03-22 Apotex sent Notice Letter to AstraZeneca
2024-05-06 Complaint Filed

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

U.S. Patent No. 7,919,598 - Crystal Structures of SGLT2 Inhibitors and Processes for Preparing Same

The Invention Explained

  • Problem Addressed: The patent's background describes the prevalence of type II diabetes, which is characterized by hyperglycemia resulting from excessive glucose production and insulin resistance (Compl. ¶ 1; ’598 Patent, col. 1:21-28). A key mechanism in the kidney, SGLT2, is responsible for reabsorbing glucose back into the bloodstream, contributing to this hyperglycemia (’598 Patent, col. 1:31-45).
  • The Patented Solution: The invention provides specific, stable crystalline forms of an SGLT2 inhibitor compound (dapagliflozin) to solve this problem (’598 Patent, Abstract). Specifically, it discloses a crystalline solvate of the compound with (S)-propylene glycol, designated as "form SC-3," which is described as having advantageous properties for pharmaceutical formulation (’598 Patent, col. 2:3-6). The patent provides detailed characterization data, including powder X-ray diffraction (PXRD) patterns, to define this specific physical form (’598 Patent, FIG. 1).
  • Technical Importance: Identifying a stable and consistent crystalline form of an active pharmaceutical ingredient is a critical step in drug development, as it directly impacts the drug's stability, dissolution rate, and manufacturability (’598 Patent, col. 1:11-18).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶ 46).
  • Claim 1 requires:
    • A crystalline (S)-propylene glycol solvate of a compound of formula I.
    • The solvate is characterized by a powder x-ray diffraction pattern comprising 2θ values at several specific angles (3.8±0.1, 7.6±0.1, 8.1±0.1, 8.7±0.1, 15.2±0.1, 15.7±0.1, 17.1±0.1, 18.9±0.1 and 20.1±0.1).
  • The complaint reserves the right to assert other claims, including claims 8, 10, and 13 (Compl. ¶ 47).

U.S. Patent No. 8,501,698 - Crystal Structures of SGLT2 Inhibitors and Processes for Preparing Same

The Invention Explained

  • Problem Addressed: As with its parent, the ’598 patent, this patent addresses the need for effective treatments for type II diabetes by inhibiting SGLT2-mediated renal glucose reabsorption (’698 Patent, col. 1:24-60).
  • The Patented Solution: The invention moves from the crystal structure itself to its application, claiming pharmaceutical compositions that contain the specific crystalline (S)-propylene glycol solvate of dapagliflozin (’698 Patent, Abstract). By claiming the composition, the patent protects the formulated drug product that incorporates the specific crystalline form of the active ingredient along with pharmaceutically acceptable carriers (’698 Patent, col. 2:65-col. 3:3).
  • Technical Importance: This patent protects the final drug product, a crucial commercial asset, by claiming the combination of the specific, stable crystalline active ingredient with the excipients necessary for administration to a patient.

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶ 58).
  • Claim 1 requires:
    • A pharmaceutical composition comprising a crystalline (S)-propylene glycol solvate of a compound of formula I.
    • The composition further comprises a pharmaceutically acceptable carrier.
  • The complaint reserves the right to assert other claims, including claim 22 (Compl. ¶ 59).

Multi-Patent Capsule: U.S. Patent No. 8,685,934

  • Patent Identification: U.S. Patent No. 8,685,934, Methods for Treating Extreme Insulin Resistance in Patients Resistant to Previous Treatment with Other Anti-diabetic Drugs Employing an SGLT2 Inhibitor and Compositions Thereof, issued April 1, 2014 (Compl. ¶ 65).
  • Technology Synopsis: The patent addresses the technical problem of treating type 2 diabetes in patients who have "extreme insulin resistance" and have not responded adequately to prior treatments (Compl. ¶ 65; ’934 Patent, Abstract). The patented solution is a method of administering an SGLT2 inhibitor, such as dapagliflozin, to this specific patient population (’934 Patent, Abstract).
  • Asserted Claims: Independent claim 8 is asserted (Compl. ¶ 72).
  • Accused Features: The complaint alleges that Apotex's ANDA product, intended for treating type 2 diabetes, will be prescribed and used in a manner that directly infringes the claimed method, and that Apotex will induce and contribute to this infringement through its product labeling (Compl. ¶¶ 73-75).

Multi-Patent Capsule: U.S. Patent No. 9,616,028

  • Patent Identification: U.S. Patent No. 9,616,028, Bilayer Tablet Formulations, issued April 11, 2017 (Compl. ¶ 78).
  • Technology Synopsis: The patent addresses the technical challenge of combining two different drugs with distinct release profiles into a single dosage form (’028 Patent, col. 2:15-24). The patented solution is a bilayer tablet that includes an extended-release layer of metformin and a second layer containing an SGLT2 inhibitor (dapagliflozin) (’028 Patent, Abstract).
  • Asserted Claims: Independent claim 1 is asserted (Compl. ¶ 85).
  • Accused Features: The complaint alleges that Apotex's generic dapagliflozin/metformin hydrochloride extended-release tablets are bilayer tablet formulations that will infringe the claims of the ’028 patent (Compl. ¶¶ 1, 86).

III. The Accused Instrumentality

Product Identification

  • The accused products are Apotex's generic dapagliflozin/metformin hydrochloride extended-release tablets in 2.5 mg/1000 mg, 5 mg/500 mg, 5 mg/1000 mg, 10 mg/500 mg, and 10 mg/1000 mg dosages (the "ANDA Products") (Compl. ¶ 1). Apotex seeks approval to market these products through its Abbreviated New Drug Application (ANDA) No. 219266 (Compl. ¶ 1).

Functionality and Market Context

  • The ANDA Products are identified as generic versions of AstraZeneca’s XIGDUO XR® drug product (Compl. ¶ 1). XIGDUO XR® is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (Compl. ¶ 42). The functionality of the accused products is therefore to provide a combination therapy of dapagliflozin, an SGLT2 inhibitor, and metformin hydrochloride, an oral anti-diabetic agent, in a single extended-release tablet for the treatment of type 2 diabetes (Compl. ¶ 1). The complaint alleges infringement based on the product specifications contained within Apotex's confidential ANDA submission to the FDA (Compl. ¶ 46).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide specific evidence, such as a claim chart exhibit, detailing how the accused ANDA products meet each claim limitation. The infringement allegations are based on the statutory act of filing an ANDA under 35 U.S.C. § 271(e)(2)(A), which seeks approval for a drug claimed in a patent prior to its expiration. The core allegation is that the products described in ANDA No. 219266, if manufactured and sold, would infringe the asserted patents.

  • ’598 Patent Infringement Allegations
    The complaint does not provide sufficient detail for analysis of how the accused products meet each limitation of claim 1. The narrative theory alleges, upon information and belief, that the ANDA Products described in ANDA No. 219266 will contain the specific crystalline (S)-propylene glycol solvate of dapagliflozin claimed in the ’598 Patent (Compl. ¶¶ 46-47).

  • ’698 Patent Infringement Allegations
    The complaint does not provide sufficient detail for analysis of how the accused products meet each limitation of claim 1. The infringement theory is that the ANDA Products are pharmaceutical compositions that will contain the crystalline form of dapagliflozin claimed in the ’598 Patent, combined with one or more pharmaceutically acceptable carriers, thereby infringing claim 1 of the ’698 Patent (Compl. ¶¶ 58-59).

  • Identified Points of Contention:

    • Technical Questions: A primary factual dispute may be whether the drug product detailed in Apotex's ANDA contains the specific crystalline (S)-propylene glycol solvate of dapagliflozin (form SC-3), as required by the claims of the ’598 and ’698 patents. The case could turn on evidence related to polymorphism—whether Apotex's product utilizes a different, non-infringing crystalline form or an amorphous form of the active ingredient.
    • Scope Questions: What is the scope of the term "crystalline (S)-propylene glycol solvate"? The resolution may depend on whether the claim is construed to cover any such solvate exhibiting the listed PXRD peaks or is limited to the specific "form SC-3" extensively characterized in the patent's specification.

V. Key Claim Terms for Construction

  • The Term: "crystalline (S)-propylene glycol solvate" (’598 Patent, Claim 1)
  • Context and Importance: This term defines the specific physical form of the active pharmaceutical ingredient. Its construction is central because pharmaceutical patent disputes frequently turn on whether a generic product's active ingredient has the exact polymorphic form as the patented drug. Practitioners may focus on this term because a finding that Apotex's product contains a different form could lead to a judgment of non-infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language itself defines the solvate by reference to a set of characteristic peaks from a powder X-ray diffraction pattern (’598 Patent, col. 32:9-15). A party might argue that any crystalline form meeting these specific PXRD criteria infringes, regardless of other physical properties.
    • Evidence for a Narrower Interpretation: The specification repeatedly refers to the invention as a specific polymorph, "form SC-3" (’598 Patent, col. 2:6, col. 5:48-49). A party could argue that the claim term should be limited to form SC-3, which the specification further characterizes with additional data beyond the claimed PXRD peaks, such as NMR, DSC, and TGA data (’598 Patent, FIGs. 3, 5, 7).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced and contributory infringement of the ’698 and ’934 patents (Compl. ¶¶ 61-62, 74-75). The allegations are based on the premise that Apotex's product instructions and labeling, which are required to copy the FDA-approved labeling for XIGDUO XR®, will encourage and instruct physicians and patients to use the generic product in an infringing manner (Compl. ¶ 61). Knowledge and intent are alleged to be established by Apotex’s Notice Letter (Compl. ¶¶ 57, 71).
  • Willful Infringement: The complaint does not explicitly plead "willful infringement." It does, however, allege that Apotex has "actual knowledge" of the Patents-in-Suit as of its receipt of the Notice Letter (Compl. ¶¶ 45, 57, 71, 84). Furthermore, the prayer for relief requests a declaration that the case is "exceptional" under 35 U.S.C. § 285, a remedy often associated with findings of willful infringement or other litigation misconduct (Compl. Prayer for Relief ¶ 24).

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

  • A core issue will be one of polymorphic identity: Does the product described in Apotex's confidential ANDA filing contain the specific crystalline (S)-propylene glycol solvate of dapagliflozin ("form SC-3") as defined by the asserted claims, or does it contain an alternative, non-infringing physical form of the active ingredient?
  • A key evidentiary question will be one of infringing use: Can AstraZeneca establish that the future marketing and sale of Apotex’s generic product will inevitably lead to infringement of the asserted method (’934 Patent) and formulation (’028 Patent) claims, particularly given that infringement will depend on the actions of third-party physicians and patients?