DCT

1:17-cv-00714

AstraZeneca LP v. Apotex Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-00714, D. Del., 06/09/2017
  • Venue Allegations: Plaintiff alleges venue is proper based on Defendant Apotex Corp.'s incorporation in Delaware and Defendant Apotex Inc.'s systematic contacts with the state, including the direction of its Abbreviated New Drug Application (ANDA) notice letter to a Delaware-based AstraZeneca entity and its history of availing itself of the court's jurisdiction.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an ANDA to seek FDA approval for marketing a generic version of Plaintiff's BRILINTA® (ticagrelor) drug product constitutes an act of infringement of three U.S. patents.
  • Technical Context: The technology relates to pharmaceutical compounds and their specific crystalline forms used as anti-thrombotic agents to inhibit platelet aggregation in the treatment of cardiovascular conditions.
  • Key Procedural History: The complaint notes that this action follows a prior lawsuit (consolidated into Civ. Action No. 15-cv-01000-RGA) concerning Apotex's ANDA for a 90 mg dosage strength of ticagrelor. The current suit was triggered by Apotex's submission of a supplemented ANDA for a 60 mg dosage strength. The ’276 patent is a reissue of U.S. Patent No. 6,525,060, and the ’419 patent is subject to a terminal disclaimer.

Case Timeline

Date Event
1998-12-04 Earliest Priority Date for '276 and '419 Patents
2000-06-02 Priority Date for ’124 Patent
2007-07-31 '419 Patent Issued
2007-09-04 '124 Patent Issued
2015-01-01 Approximate filing of prior litigation regarding 90 mg dosage strength
2017-01-17 '276 Patent (Reissue) Issued
2017-05-02 Apotex sends Notice Letter for 60 mg dosage strength ANDA
2017-06-09 Complaint Filed

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

U.S. Reissue Patent No. RE 46,276 - “Triazolo(4,5-D)pyrimidine compounds,” Issued January 17, 2017

The Invention Explained

  • Problem Addressed: The patent family addresses arterial thrombosis, a condition initiated by platelet adhesion and aggregation, which can lead to severe cardiovascular events like myocardial infarction and unstable angina (’419 Patent, col. 1:20-29). The background notes the limitations of existing anti-thrombotic agents, such as aspirin, which only block one pathway of adenosine 5'-diphosphate (ADP) release and have limited efficacy (’419 Patent, col. 1:56-65).
  • The Patented Solution: The invention provides a class of triazolo[4,5-d]pyrimidine compounds that act as antagonists of the P2T receptor on the platelet membrane (’419 Patent, col. 2:1-5). By blocking this key receptor, the compounds inhibit ADP-induced platelet aggregation, thereby offering a more comprehensive anti-thrombotic effect than previous therapies (’419 Patent, col. 2:10-16).
  • Technical Importance: These compounds represent a targeted approach to anti-platelet therapy by directly antagonizing a primary receptor (P2T) involved in platelet aggregation, suggesting the potential for improved efficacy in preventing thrombotic events (’419 Patent, col. 2:10-16).

Key Claims at a Glance

  • The complaint asserts infringement of at least one claim (Compl. ¶44). Independent claim 18 is representative.
  • Claim 18 recites:
    • A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having a specific chemical structure with defined substituent groups R, R¹, R², R³, and R⁴.
  • The complaint reserves the right to assert other claims (Compl. ¶44).

U.S. Patent No. 7,250,419 - “Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition,” Issued July 31, 2007

The Invention Explained

  • Problem Addressed: The patent, which is a continuation of the application that led to the original '060 patent (reissued as '276), addresses the same problem of platelet-mediated arterial thrombosis and the need for more effective P2T receptor antagonists (’419 Patent, col. 1:20-31).
  • The Patented Solution: The invention discloses specific triazolo[4,5-d]pyrimidine compounds that are not only P2T antagonists but also possess a combination of high potency, high metabolic stability, and high bioavailability (’419 Patent, col. 2:17-26). This combination of properties is presented as advantageous for achieving prolonged inhibition of platelet aggregation in humans with a favorable therapeutic dose (’419 Patent, col. 2:23-26).
  • Technical Importance: The invention claims to have identified compounds within a known class that possess superior pharmacological properties, which is critical for developing a commercially viable and clinically effective drug (’419 Patent, col. 2:17-26).

Key Claims at a Glance

  • The complaint asserts infringement of at least one claim (Compl. ¶48). Independent claim 1 is representative.
  • Claim 1 recites:
    • A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where the compound has a specific chemical structure with defined R groups, subject to several provisos that narrow the scope from the broader genus.
  • The complaint reserves the right to assert other claims (Compl. ¶48).

U.S. Patent No. 7,265,124 - “Cristalline and amorphous form of a triazolo (4,5-D) pyridimine compound,” Issued September 4, 2007

Technology Synopsis

  • The patent addresses the challenge of producing a drug substance in a form that is stable, pure, and suitable for manufacturing (’124 Patent, col. 1:15-25). It discloses that the active compound, ticagrelor, can exist in four distinct crystalline forms (Polymorph I, II, III, and IV) as well as an amorphous form, and it claims these specific solid-state forms, which possess different physical properties relevant to pharmaceutical development (’124 Patent, col. 2:41-44).

Asserted Claims

  • The complaint asserts infringement of at least one claim (Compl. ¶52). Representative independent claim 1 covers a compound of formula (I) characterized as one of four specific polymorphs defined by their X-ray powder diffraction patterns.

Accused Features

  • The drug substance (ticagrelor) in Apotex’s proposed generic tablet is alleged to be one of the claimed crystalline forms (Compl. ¶51-52).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Apotex's generic ticagrelor oral tablets, in a 60 mg dosage strength, as described in its supplemented Abbreviated New Drug Application (ANDA) No. 208584 (Compl. ¶1, ¶37).
  • Functionality and Market Context: The proposed generic product contains ticagrelor, an active ingredient intended to inhibit platelet aggregation for the reduction of cardiovascular death, myocardial infarction, and stroke (Compl. ¶35). By filing an ANDA with a Paragraph IV certification, Apotex seeks to market its generic product prior to the expiration of AstraZeneca’s patents listed in the FDA's Orange Book for the brand-name drug BRILINTA® (Compl. ¶38-39).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint alleges that Apotex’s submission of its ANDA is an act of infringement under 35 U.S.C. § 271(e)(2)(A), and that commercialization of the product upon FDA approval will constitute further infringement (Compl. ¶43-44, 47-48, 51-52). The complaint does not provide detailed infringement contentions or claim charts. The allegations are summarized below based on the nature of the patents and the accused product.

RE 46,276 Infringement Allegations

Claim Element (from Independent Claim 18) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of formula (I)...or a pharmaceutically acceptable salt or solvate thereof... The active pharmaceutical ingredient (ticagrelor) in Apotex's proposed generic product is alleged to be a compound covered by formula (I) of the patent. ¶43-44 col. 8:14-41

7,250,419 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of formula (I)...or a pharmaceutically acceptable salt or solvate thereof...provided that... The active pharmaceutical ingredient (ticagrelor) in Apotex's proposed generic product is alleged to be a compound covered by the specific structure and provisos of formula (I). ¶47-48 col. 2:30-65

Identified Points of Contention

  • Scope Questions: Since Apotex filed a Paragraph IV certification, it asserts that its product will not infringe the Orange Book Patents (Compl. ¶39). For the '124 patent, a central question will be whether the crystalline form of ticagrelor in Apotex's ANDA product exhibits the specific physical characteristics (e.g., X-ray powder diffraction peaks) required by the asserted claims, or if Apotex has developed a different, non-infringing form.
  • Technical Questions: The primary technical dispute will likely involve detailed characterization of Apotex's drug substance. What evidence, such as comparative analytical data (XRPD, DSC), will be presented to determine if the solid-state structure of Apotex's ticagrelor is identical to one of the polymorphs claimed in the '124 patent?

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for analysis of most claim terms. However, based on the technology, certain terms in the '124 patent are likely to be central.

  • The Term: "substantially crystalline form" / "substantially pure"
  • Context and Importance: In patents claiming specific polymorphs, the degree of purity required to meet the claim is a frequent point of dispute. Apotex may argue its product contains a mixture of forms or sufficient amorphous content to fall outside a reasonable construction of "substantially pure." Practitioners may focus on this term because its definition could be dispositive of infringement for the '124 patent.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent does not provide an explicit numerical definition for "substantially crystalline," which could support a more flexible, qualitative interpretation based on the overall characteristics of the material.
    • Evidence for a Narrower Interpretation: The specification provides a quantitative definition for a related concept, defining an "anhydrous form" as having "less than 0.4 water molecules per compound molecule" (’124 Patent, col. 3:13-16). More directly, when discussing a polymorph being "substantially free" of another, the patent specifies this means "less than 10% of the other polymorph, preferably less than 5%" (’124 Patent, col. 5:56-58). A party could argue this language provides a specific numerical benchmark for what "substantially" means within the context of this patent.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Apotex will induce and contribute to infringement upon approval of its ANDA (Compl. ¶44, 48, 52). The alleged basis for inducement is that Apotex's product labeling and marketing materials will instruct physicians and patients to administer the generic drug for the patented indications, thereby encouraging direct infringement by end-users.
  • Willful Infringement: The complaint does not contain an explicit allegation of willful infringement or a prayer for enhanced damages under 35 U.S.C. § 284.

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

  • A central issue for the court will be one of patent validity: can Apotex prove by clear and convincing evidence that the asserted claims of the '276, '419, and '124 patents are invalid for reasons such as obviousness or anticipation, as asserted in its Paragraph IV certification?
  • A key evidentiary question will be one of polymorphic identity: does the specific solid-state form of the ticagrelor active ingredient in Apotex's ANDA product meet the limitations of the asserted claims of the '124 patent? The resolution will depend on detailed scientific analysis of the respective materials.
  • The case also raises a procedural question: what, if any, preclusive effect will rulings or findings from the prior, consolidated litigation concerning the 90 mg dosage strength have on the current dispute over the 60 mg dosage strength product?