DCT
1:17-cv-01073
AstraZeneca LP v. Invagen Pharma Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: AstraZeneca (Delaware, Sweden, UK)
- Defendant: InvaGen Pharmaceuticals Inc. (New York)
- Plaintiff’s Counsel: McCarter & English, L.L.P.; Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.
- Case Identification: 1:17-cv-01073, D. Del., 08/02/2017
- Venue Allegations: Venue is alleged to be proper in the District of Delaware based on Defendant’s submission of a regulatory notice letter into the state, its intent to market and sell the accused product in Delaware, its continuous business transactions within the state, and its prior litigation conduct in the district without objecting to jurisdiction.
- Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of the cardiovascular drug BRILINTA® (ticagrelor) constitutes an act of patent infringement.
- Technical Context: The technology concerns triazolopyrimidine compounds that function as P2T receptor antagonists to inhibit platelet aggregation, which are used to prevent thrombotic events such as heart attacks and strokes.
- Key Procedural History: The complaint notes a prior lawsuit (15-cv-1001-RGA) between the same parties concerning Defendant's ANDA for a 90 mg dosage strength of the same generic drug. The current action was triggered by Defendant’s submission of a Paragraph IV certification in a supplemental ANDA for a 60 mg dosage strength, asserting that Plaintiff's patents are invalid, unenforceable, or will not be infringed.
Case Timeline
| Date | Event |
|---|---|
| 1998-12-04 | Priority Date (’276 Patent, ’419 Patent) |
| 2000-06-02 | Priority Date (’124 Patent) |
| 2007-07-31 | Issue Date (U.S. 7,250,419) |
| 2007-09-04 | Issue Date (U.S. 7,265,124) |
| 2017-01-17 | Issue Date (U.S. RE 46,276) |
| 2017-06-29 | InvaGen sends Notice Letter for 60 mg ticagrelor ANDA |
| 2017-08-02 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. RE 46,276 - “Triazolo(4,5-D)pyrimidine compounds,” issued Jan. 17, 2017
The Invention Explained
- Problem Addressed: The patent’s background describes how platelet adhesion and aggregation can lead to arterial thrombosis, resulting in serious conditions like myocardial infarction and unstable angina, and notes the limitations of existing anti-thrombotic agents (RE46,276 Patent, col. 1:31-41). A need existed for more effective P2T receptor antagonists, which play a key role in mediating thrombosis (RE46,276 Patent, col. 2:8-16).
- The Patented Solution: The invention provides a class of novel triazolo[4,5-d]pyrimidine compounds, defined by a general chemical structure (Formula I), that act as P2T receptor antagonists to inhibit platelet aggregation (RE46,276 Patent, Abstract; col. 2:36-50). The patent discloses specific chemical substitutions to this core structure that yield the desired therapeutic effect.
- Technical Importance: The invention disclosed a new chemical class of P2T antagonists designed to offer significant improvements over other anti-thrombotic agents available at the time (RE46,276 Patent, col. 2:13-21).
Key Claims at a Glance
- The complaint alleges infringement of at least one claim without specifying which ones (Compl. ¶32). Independent claim 1 is representative of the patented subject matter.
- Independent Claim 1 recites:
- A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof;
- wherein R¹ is a C3-5 alkyl optionally substituted by one or more halogen atoms;
- R² is a phenyl group, optionally substituted by one or more fluorine atoms;
- R³ and R⁴ are both hydroxy;
- R is XOH, where X is CH₂, OCH₂CH₂ or a bond; and
- a set of provisos constraining the specific combinations of these substituent groups.
U.S. Patent No. 7,250,419 - “Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition,” issued Jul. 31, 2007
The Invention Explained
- Problem Addressed: The patent addresses the same underlying medical problem of arterial thrombosis driven by platelet aggregation (Compl. ¶2:33-42). It further highlights the need for anti-thrombotic agents that combine high potency with high metabolic stability and bioavailability to achieve an advantageous therapeutic dose for prolonged treatment (’419 Patent, col. 2:17-26).
- The Patented Solution: The invention claims methods of using a specific triazolopyrimidine compound, ticagrelor, to inhibit platelet aggregation in a patient (’419 Patent, col. 14:52-56). The patent identifies this specific compound from a broader class as having a superior combination of potency and metabolic stability, making it suitable for clinical use (’419 Patent, col. 2:19-26).
- Technical Importance: The patent claimed the specific therapeutic use of what would become the active ingredient in BRILINTA®, providing a method for treating or preventing various thrombotic cardiovascular diseases (’419 Patent, col. 9:1-51).
Key Claims at a Glance
- The complaint alleges infringement of at least one claim (Compl. ¶36). Independent claim 13 is a representative method claim.
- Independent Claim 13 recites:
- A method of inhibiting platelet aggregation in a person;
- which comprises administering a therapeutically effective amount of the compound [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, or a pharmaceutically acceptable salt thereof, to said person.
Multi-Patent Capsule: U.S. Patent No. 7,265,124 - “Cristalline and amorphous form of a triazolo (4,5-D) pyridimine compound,” issued Sep. 4, 2007
- Technology Synopsis: This patent addresses technical challenges in pharmaceutical manufacturing related to the physical properties of a drug substance, such as chemical and solid-state stability (’124 Patent, col. 1:19-29). It discloses and claims specific stable crystalline forms (polymorphs) and an amorphous form of the ticagrelor compound, which are essential for creating a commercially viable, pure, and stable drug product (’124 Patent, col. 1:30-44).
- Asserted Claims: The complaint alleges infringement of at least one claim (Compl. ¶40). Representative independent claims include claim 1, which claims one of several specified polymorphs of the compound of formula (I).
- Accused Features: The accused instrumentality is InvaGen's proposed generic ticagrelor drug, which is alleged to be, or to contain, an infringing form of the ticagrelor compound (Compl. ¶¶ 39-40).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendant InvaGen's proposed generic drug product containing 60 mg of ticagrelor in an oral tablet form, for which it seeks FDA approval via Abbreviated New Drug Application (ANDA) No. 208537 (Compl. ¶1, ¶25).
Functionality and Market Context
The product is a generic version of Plaintiff’s BRILINTA® drug, intended for use as a P2T receptor antagonist to inhibit platelet aggregation (Compl. ¶1, ¶23). It is indicated for reducing the rate of cardiovascular death, myocardial infarction, and stroke in certain patient populations (Compl. ¶23). The complaint alleges that InvaGen intends to commercially manufacture, use, and sell this product in the United States upon receiving FDA approval, prior to the expiration of the patents-in-suit (Compl. ¶26). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint does not provide a detailed element-by-element infringement analysis. The infringement allegations are premised on the statutory act of infringement under 35 U.S.C. § 271(e)(2)(A), where the submission of an ANDA seeking approval to market a patented drug or use a patented method before patent expiration constitutes infringement.
RE46,276 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 | The ticagrelor active pharmaceutical ingredient in Defendant's ANDA product is alleged to be a compound falling within the scope of Formula (I). | ¶1, ¶31-32 | col. 2:36-50 |
| wherein R¹ is C3-5 alkyl optionally substituted...; R² is a phenyl group optionally substituted...; R³ and R⁴ are both hydroxy; R is XOH...; and provisos | The specific chemical structure of ticagrelor in Defendant's ANDA product is alleged to satisfy the substituent definitions and provisos of the asserted claim. | ¶1, ¶31-32 | col. 2:51-64 |
U.S. 7,250,419 Infringement Allegations
| Claim Element (from Independent Claim 13) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of inhibiting platelet aggregation in a person | Defendant's proposed product label for its generic ticagrelor tablets allegedly instructs and encourages medical professionals and patients to use the drug for its anti-platelet aggregation effects. | ¶23, ¶35-36 | col. 14:52-53 |
| which comprises administering a therapeutically effective amount of the compound [ticagrelor]... to said person. | Defendant's filing of an ANDA for a generic equivalent of BRILINTA®, with a label mirroring the approved indications, is alleged to constitute an act of infringement for this claimed method of administration. | ¶1, ¶35-36 | col. 14:53-56 |
Identified Points of Contention
- Validity: The central point of contention in this ANDA litigation will likely be the validity of the asserted patents. Defendant's Paragraph IV certification asserts that the patents are invalid and/or unenforceable (Compl. ¶27), raising the question of whether the claimed compound, methods, and forms were obvious or anticipated by prior art.
- Polymorph Form: For the ’124 patent, a key technical question will be whether the specific crystalline or amorphous form of ticagrelor in Defendant’s proposed commercial product will meet the physical characterization limitations (e.g., XRPD peaks) of the asserted claims.
- Induced Infringement: For the ’419 method of use patent, a potential issue is whether Defendant's proposed product label will contain instructions that direct users to perform all steps of the claimed method, thereby establishing the requisite intent for induced infringement.
V. Key Claim Terms for Construction
The complaint does not identify any specific claim terms as being in dispute. However, based on the subject matter, the following terms may become central to the case.
The Term: "inhibiting platelet aggregation" (’419 Patent, Claim 13)
Context and Importance: This term defines the scope of the patented method. The dispute may turn on the degree or mechanism of inhibition required to fall within the claim. Practitioners may focus on this term because Defendant could argue that its product's effect, or the instructions on its label, do not meet the standard of "inhibition" as defined by the patent.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language itself does not impose any specific quantitative limit, which may support a broad construction covering any level of clinically relevant inhibition.
- Evidence for a Narrower Interpretation: The specification discusses achieving "high potency" and "prolonged inhibition" as an advantage of the invention (’419 Patent, col. 2:20-26). The patent also describes specific pharmacological assays for measuring activity, which a party could argue should be used to limit the scope of the term to a particular threshold of effectiveness (’419 Patent, col. 14:2-45).
The Term: "A compound of formula (I)" characterized by specific X-ray powder diffraction peaks (e.g., "specific peaks of high intensity at 5.3° (±0.1°)...") (’124 Patent, Claim 1)
Context and Importance: This language defines the patented crystalline polymorph. The infringement analysis for the ’124 patent will depend entirely on whether Defendant’s product meets these specific physical characterization requirements.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The use of "(±0.1°)" provides a defined range of error, but a party might argue for additional flexibility based on standard experimental variance in XRPD measurements.
- Evidence for a Narrower Interpretation: The patent defines multiple distinct polymorphs (I, II, III, and IV), each with its own set of peaks (’124 Patent, col. 3:17-4:19). This may support a strict interpretation of the peak lists to maintain clear distinctions between the claimed forms. The specification also notes that the quoted figures "are not to be taken as absolute values," but this is qualified by discussion of equipment-specific variations, not a broad allowance for deviation (’124 Patent, col. 3:41-45; col. 8:59-67).
VI. Other Allegations
- Indirect Infringement: The complaint alleges infringement of the ’419 method of use patent. The filing of an ANDA for a generic drug with a label that instructs users on the patented method is the basis for a claim of induced infringement under 35 U.S.C. § 271(b). The complaint alleges Defendant will infringe by, inter alia, offering to sell and selling the generic product, which implies inducing infringement by end-users who follow the product label (Compl. ¶36).
- Willful Infringement: The complaint does not explicitly use the word "willful." However, it alleges facts that may support a future claim for enhanced damages under 35 U.S.C. § 284. The complaint establishes Defendant’s pre-suit knowledge of the patents through its Paragraph IV certification letter (Compl. ¶27) and through prior litigation between the parties over the same drug and related patents (Compl. ¶29).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue for all three patents will be one of validity: can Defendant meet its burden to prove, by clear and convincing evidence, that the claims covering the ticagrelor compound, its specific method of use for inhibiting platelet aggregation, and its claimed crystalline forms are invalid in light of the prior art?
- A key evidentiary question will be one of physical identity: for the ’124 patent, does the specific solid-state form of the ticagrelor active ingredient in Defendant’s proposed commercial product exhibit the X-ray powder diffraction peaks and other physical properties required by the asserted polymorph claims?
- A dispositive legal question for the method of use patent will be inducement: assuming the ’419 patent is valid, do the instructions on Defendant's proposed product label provide sufficient evidence of an affirmative intent to encourage or instruct physicians and patients to perform the patented method of inhibiting platelet aggregation?