DCT

1:18-cv-01232

AstraZeneca LP v. Hisun Pharmaceutical Co Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-01232, D. Del., 08/10/2018
  • Venue Allegations: Venue is alleged to be proper for Hisun Pharmaceutical (Hangzhou) Co., Ltd. as a foreign corporation that may be sued in any judicial district. For Hisun Pharmaceuticals USA, Inc., venue is alleged to be proper because it is incorporated in Delaware and thus resides in the district for patent venue purposes.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff’s BRILINTA® (ticagrelor) product constitutes an act of infringement of three U.S. patents covering the ticagrelor compound, methods of its use, and its specific crystalline forms.
  • Technical Context: The technology relates to antiplatelet drugs known as P2T receptor antagonists, which are used to reduce the rate of cardiovascular death, myocardial infarction, and stroke.
  • Key Procedural History: The complaint notes that U.S. Patent No. RE 46,276 is a reissue of U.S. Patent No. 6,525,060, which was surrendered on January 17, 2017. A prior lawsuit between the parties (Civ. Action No. 15-cv-1042-RGA) concerning a generic ticagrelor product was previously dismissed without prejudice and did not involve the patents currently in suit.

Case Timeline

Date Event
1998-12-04 Earliest Priority Date for '276 and '419 Patents
2000-06-02 Earliest Priority Date for '124 Patent
2007-07-31 '419 Patent Issued
2007-09-04 '124 Patent Issued
2009-11-18 Hisun USA files certificate of incorporation in Delaware
2015-09-30 Date of prior Notice Letter in unrelated matter
2017-01-17 '060 Patent Surrendered; '276 Reissue Patent Issued
2018-06-28 Date of Hisun's Notice of Certification Letter to AstraZeneca
2018-08-10 Complaint Filed

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

U.S. Patent No. RE 46,276 - "Triazolo(4,5-D)pyrimidine Compounds," issued January 17, 2017

The Invention Explained

  • Problem Addressed: The patent describes a need for effective anti-thrombotic agents to prevent arterial thrombosis, which can lead to myocardial infarction and unstable angina, by inhibiting platelet aggregation (RE46,276 Patent, col. 1:29-42). Existing agents like aspirin were noted to have limited efficacy because they only block one pathway of platelet activation (RE46,276 Patent, col. 1:57-68).
  • The Patented Solution: The invention provides a class of triazolo[4,5-d]pyrimidine compounds that function as antagonists of the P2T receptor on platelet membranes. By blocking this receptor, the compounds inhibit ADP-induced platelet aggregation, a key mechanism in thrombosis (RE46,276 Patent, col. 2:7-20). The patent claims specific compounds, including ticagrelor, and pharmaceutical compositions containing them.
  • Technical Importance: The development of P2T receptor antagonists provided a new therapeutic mechanism for preventing platelet aggregation that was distinct from and potentially more comprehensive than that of aspirin (RE46,276 Patent, col. 2:11-16).

Key Claims at a Glance

  • The complaint asserts independent claims 18 and 19, among others.
  • Independent Claim 18 claims:
    • A compound chosen from a group of two specified chemical structures, one of which is the compound known as ticagrelor.
  • Independent Claim 19 claims:
    • An oral pharmaceutical composition comprising the ticagrelor compound.
    • In combination with a pharmaceutically acceptable diluent, adjuvant, and/or carrier suitable for oral administration.
    • Wherein the composition is in the form of a tablet, pill, capsule, liquid, powder, or granule.
  • The complaint reserves the right to assert infringement of other claims, including dependent claims (Compl. ¶46).

U.S. Patent No. 7,250,419 - "Trisubstituted Triazolopyrimidines for use in Platelet Aggregation Inhibition," issued July 31, 2007

The Invention Explained

  • Problem Addressed: Building on earlier work, the patent identifies a need for P2T antagonists that not only possess high potency but also exhibit "surprisingly high metabolic stability and bioavailibility" (’419 Patent, col. 2:20-23). These properties are critical for developing a drug with a predictable and effective therapeutic dose for prolonged use in humans.
  • The Patented Solution: The invention discloses and claims specific triazolo[4,5-d]pyrimidine compounds, including the compound ticagrelor, that possess this advantageous combination of potency and metabolic stability (’419 Patent, col. 2:20-26). The patent covers the compound itself, its salts, and methods of using it to treat conditions such as myocardial infarction.
  • Technical Importance: Achieving high metabolic stability and bioavailability in a drug candidate is a significant technical hurdle that can differentiate a laboratory compound from a viable commercial therapeutic (’419 Patent, col. 2:20-26).

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 6, among others.
  • Independent Claim 1 claims:
    • A compound selected from the group consisting of the ticagrelor compound.
    • And pharmaceutically acceptable salts thereof.
  • Independent Claim 6 claims:
    • A method of treatment of myocardial infarction.
    • Which comprises administering to a person suffering therefrom a therapeutically effective amount.
    • Of a compound according to claim 2 (which is the ticagrelor compound).
  • The complaint reserves the right to assert infringement of other claims, including dependent claims (Compl. ¶46).

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 challenges in pharmaceutical manufacturing and formulation related to the physical properties of an active drug substance (’124 Patent, col. 1:15-34). It discloses that the ticagrelor compound can exist in several distinct, stable, substantially crystalline forms (Polymorphs I, II, III, and IV) as well as a substantially amorphous form, each with unique physical characteristics relevant to processing, stability, and shelf-life (’124 Patent, col. 2:35-44).
  • Asserted Claims: The complaint asserts independent claims 1, 11, and 22, among others (Compl. ¶46).
  • Accused Features: The complaint alleges that Defendant’s filing of its ANDA for generic ticagrelor tablets, and the future manufacture and sale of such tablets, will infringe the ’124 patent (Compl. ¶¶83, 88). This is based on the allegation that the active ingredient in the generic product will be one of the claimed crystalline or amorphous forms of ticagrelor.

III. The Accused Instrumentality

Product Identification

  • Defendant’s proposed generic ticagrelor tablets, for which it filed Abbreviated New Drug Application (ANDA) No. 208575 with the U.S. Food and Drug Administration (FDA) (Compl. ¶1).

Functionality and Market Context

  • The complaint alleges that the proposed generic product contains ticagrelor, the same active ingredient as Plaintiff's BRILINTA® product (Compl. ¶58). It is further alleged that the generic product will have the same dosage form and strength, will be bioequivalent to BRILINTA®, and will be marketed for the same approved indications, which include reducing the rate of myocardial infarction (Compl. ¶¶58-59). The filing of the ANDA is a formal step to obtain FDA approval to market this generic drug in the United States prior to the expiration of Plaintiff's patents (Compl. ¶42).
    No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

RE46,276 Infringement Allegations

Claim Element (from Independent Claim 19) Alleged Infringing Functionality Complaint Citation Patent Citation
An oral pharmaceutical composition comprising [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol The complaint states that Defendant's Notice Letter admits that the chemical name for the active ingredient in its proposed ANDA product is ticagrelor, the compound recited in the claim. ¶49 col. 28:20-25
in combination with a pharmaceutically acceptable diluent, adjuvant, and/or carrier suitable for oral administration, The proposed generic product is an oral tablet, which necessarily includes pharmaceutically acceptable excipients such as diluents or carriers for administration. ¶49 col. 28:25-27
wherein said oral pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, powder, or granule. The complaint alleges that Defendant admits in its Notice Letter that its proposed ticagrelor ANDA product will be a tablet for oral use. ¶49 col. 28:27-28

7,250,419 Infringement Allegations

Claim Element (from Independent Claim 6) Alleged Infringing Functionality Complaint Citation Patent Citation
a method of treatment of myocardial infarction Defendant is seeking approval to market its generic product for the same indications as BRILINTA®, which includes use "to reduce the rate of...myocardial infarction." ¶¶54-55, 59 col. 26:22-23
which comprises administering to a person suffering therefrom a therapeutically effective amount The product label for the generic drug, which under FDA regulations is required to copy the BRILINTA® label, will instruct for administration of a "therapeutically effective amount" for the approved indications. ¶¶54-55, 66 col. 26:23-24
of a compound according to claim 2. The complaint alleges that Defendant's Notice Letter admits its product contains ticagrelor, the compound recited in claim 2 of the patent. ¶52 col. 26:24-25

Identified Points of Contention

  • Validity vs. Infringement: The complaint alleges that Defendant’s Notice Letter does not deny that its product would infringe the asserted claims if they are found valid (Compl. ¶46). This suggests the primary legal battle will concern Defendant’s asserted defenses of invalidity and/or unenforceability, rather than non-infringement of the compound and method claims in the ’276 and ’419 patents.
  • Technical Questions (Polymorph Form): For the ’124 patent, a central question of fact will be whether the specific crystalline or amorphous form of the ticagrelor active pharmaceutical ingredient in Defendant's proposed product falls within the scope of the asserted claims. This will likely require competing expert analyses of the final manufactured product, which is not yet on the market.

V. Key Claim Terms for Construction

  • The Term: "substantially crystalline form" (and by extension, "Polymorph I," "Polymorph II," etc.)
  • Context and Importance: This term from the ’124 patent is critical because infringement will depend on whether Defendant's generic product contains a form of ticagrelor that meets this definition. The patent claims four distinct polymorphs and an amorphous form. Practitioners may focus on this term because the scope of "substantially" will determine how much deviation from the ideal, reference polymorph is permitted before a product is considered non-infringing.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent specifies that polymorphs are defined by XRPD patterns containing "specific peaks of high intensity at" various angles "±0.1°" (’124 Patent, e.g., col. 3:49-54). The explicit inclusion of a tolerance (±0.1°) could support an interpretation that does not require an exact match to the reference data. The patent also states that an "anhydrous form" may still contain some residual solvent, suggesting "substantially" does not mean "entirely" pure (’124 Patent, col. 3:11-15).
    • Evidence for a Narrower Interpretation: The patent provides distinct definitions for four different polymorphs and an amorphous form, each characterized by a unique set of XRPD peaks or the lack thereof (’124 Patent, col. 3:49-col. 4:21). A party could argue that for a product to be a specific polymorph, it must exhibit the key "high intensity" peaks identified for that polymorph and not the characteristic peaks of other polymorphs, thereby narrowing the scope of any single polymorph claim.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement of the method claims of the ’276, ’419, and ’124 patents. The basis for inducement is the allegation that Defendant will, upon approval, copy the FDA-approved labeling for BRILINTA®, which instructs and encourages physicians to prescribe and patients to use the generic product in a manner that directly infringes the method claims (e.g., to treat myocardial infarction) (Compl. ¶¶66, 79, 92). The complaint also pleads contributory infringement, alleging the ticagrelor tablets are a material part of the invention, are not staple articles of commerce, and are knowingly sold for an infringing use (Compl. ¶¶67, 80, 93).
  • Willful Infringement: The complaint does not contain a formal count for willful infringement or a specific request for enhanced damages under 35 U.S.C. § 284. However, it does allege that Defendant has "actual knowledge" of each patent-in-suit as a result of receiving the Paragraph IV Notice Letter, a prerequisite for any future willfulness claim based on post-suit conduct (Compl. ¶¶61, 74, 87).

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

  • A central issue will be one of validity: as this is a Hatch-Waxman action triggered by a Paragraph IV certification, the case will likely turn on whether Defendant can 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 lack of enablement, as asserted in its Notice Letter.
  • A key evidentiary question will be one of physical form: for the asserted claims of the ’124 patent, the infringement analysis will depend entirely on the outcome of a technical, factual dispute over whether the active pharmaceutical ingredient in Defendant’s final, manufactured generic product is in a "substantially crystalline" or "substantially amorphous" form as defined and claimed in the patent.
  • A potential legal question may concern reissue scope: because the ’276 patent is a reissue, the court may need to address whether any of the reissued claims are invalid under the recapture rule, which prevents a patentee from reclaiming through reissue subject matter that was surrendered during the original prosecution to overcome a prior art rejection.