DCT
1:20-cv-01182
Astellas US LLC v. Meitheal Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Astellas US LLC; Astellas Pharma US, Inc.; and Gilead Sciences, Inc. (Delaware, Delaware, Delaware)
- Defendant: Meitheal Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Fish & Richardson P.C.; Wilmer Cutler Pickering Hale and Dorr LLP; Mayer Brown LLP
- Case Identification: 1:20-cv-01182, D. Del., 09/04/2020
- Venue Allegations: Venue is based on Defendant's incorporation in Delaware and an agreement by Defendant not to contest jurisdiction or venue in the District of Delaware.
- Core Dispute: Plaintiffs allege that Defendant's filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' Lexiscan® drug product constitutes infringement of three patents covering the drug's active ingredient, its crystalline form, and methods of preparation.
- Technical Context: The technology concerns regadenoson, an A2A-adenosine receptor agonist used as a pharmacologic stress agent in cardiac imaging for patients unable to undergo exercise-based stress tests.
- Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendant Meitheal's filing of ANDA No. 212806 and its associated notification letter to Plaintiffs, which asserted that the '183 and '301 patents are invalid, unenforceable, and/or will not be infringed. The '301 patent is a reissue of U.S. Patent No. 9,085,601.
Case Timeline
| Date | Event |
|---|---|
| 2006-02-03 | Priority Date for ’183, ’301, and ’883 Patents |
| 2012-01-31 | U.S. Patent No. 8,106,183 Issues |
| 2013-09-03 | U.S. Patent No. 8,524,883 Issues |
| 2015-07-21 | U.S. Patent No. 9,085,601 (Reissued as '301) Issues |
| 2019-03-19 | U.S. Reissue Patent No. RE47,301 Issues |
| 2020-08-17 | Meitheal sends Lexiscan Notice Letter to Plaintiffs |
| 2020-09-04 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,106,183 - Process for preparing an A2A-adenosine receptor agonist and its polymorphs
- Issued: January 31, 2012
The Invention Explained
- Problem Addressed: The patent describes a need for new, convenient methods to synthesize large quantities of the A2A-adenosine receptor agonist regadenoson in good yield and high purity, noting that prior methods were suited for small-scale synthesis and undesirably used protecting groups (’183 Patent, col. 1:56-col. 2:2).
- The Patented Solution: The invention provides a synthesis for large-scale preparation of regadenoson and identifies that the compound can exist in at least three different crystalline forms (polymorphs), the most stable of which is a monohydrate (’183 Patent, col. 2:3-9, col. 6:35-49). The patent claims this stable monohydrate crystalline form, which is desirable for the final drug product (’183 Patent, col. 2:3-9).
- Technical Importance: For pharmaceutical development, identifying and isolating a stable crystalline polymorph is critical for ensuring product consistency, stability, and predictable dissolution properties, which are key regulatory and manufacturing requirements.
Key Claims at a Glance
- The complaint asserts independent claims 1 and 9, as well as dependent claims 2-3 and 8 (Compl. ¶34).
- Independent Claim 1:
- A monohydrate of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide,
- which monohydrate is in a crystalline form.
- Plaintiffs reserve the right to assert additional claims.
U.S. Reissue Patent No. RE47,301 - Process for preparing an A2A-adenosine receptor agonist and its polymorphs
- Issued: March 19, 2019
The Invention Explained
- Problem Addressed: As with the '183 patent, this patent addresses the need for large-scale, high-purity synthesis of the regadenoson compound and its polymorphs, particularly the stable monohydrate form suitable for a final drug product (’301 Patent, col. 2:3-14).
- The Patented Solution: The patent claims pharmaceutical compositions that contain the specific crystalline monohydrate form of regadenoson, either produced by a specific process or simply combined with a pharmaceutically acceptable carrier (’301 Patent, col. 20:56-65). This shifts the focus from the compound itself to the formulated drug product containing it.
- Technical Importance: Patenting the final formulated drug product provides a distinct layer of protection beyond the active pharmaceutical ingredient (API) itself, covering the commercial product as sold.
Key Claims at a Glance
- The complaint asserts independent claims 6, 11, and 17 (Compl. ¶39).
- Independent Claim 11:
- A pharmaceutical composition comprising a crystalline monohydrate form of the compound (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide that is substantially free of 2-hydrazinoadenosine;
- and a pharmaceutically acceptable carrier.
- Plaintiffs reserve the right to assert additional claims.
U.S. Patent No. 8,524,883 - Monohydrate of (1-{9-[4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide
- Issued: September 3, 2013
- Technology Synopsis: This patent claims methods of preparing pharmaceutical compositions containing the stable monohydrate form of regadenoson (’883 Patent, col. 10:1-20). The invention covers the process of combining the specific crystalline monohydrate with a carrier, such as a buffered aqueous solution, to create the final drug product (’883 Patent, col. 19:26-34).
- Asserted Claims: Claims 1-5 (Compl. ¶47). Independent claim 1 is asserted.
- Accused Features: The complaint alleges that Meitheal's preparation of its ANDA product will involve the claimed method of combining the regadenoson monohydrate with a carrier to form a pharmaceutical composition (Compl. ¶19, ¶26).
III. The Accused Instrumentality
Product Identification
The "Meitheal ANDA product," which is a generic 0.4 mg/5 mL (0.08 mg/mL) intravenous solution of regadenoson (Compl. ¶2).
Functionality and Market Context
- The complaint alleges that Meitheal's ANDA product is a generic version of Plaintiffs' Lexiscan® drug (Compl. ¶2).
- By filing its ANDA, Meitheal has represented to the FDA that its product has the same active ingredient, dosage form, and strength as Lexiscan, and is bioequivalent to it (Compl. ¶22).
- Meitheal is seeking FDA approval to market its product for the same indication as Lexiscan: radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress (Compl. ¶18, ¶23).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The infringement allegations are based on 35 U.S.C. § 271(e)(2), where the submission of an ANDA for a generic drug to be marketed before patent expiration is a technical act of infringement.
U.S. Patent No. 8,106,183 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A monohydrate of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide, | Based on information and belief, the Meitheal ANDA product contains the same active ingredient as Lexiscan, which is the claimed regadenoson monohydrate. | ¶22 | col. 19:12-20 |
| which monohydrate is in a crystalline form. | Based on information and belief, because the Meitheal ANDA product is represented as bioequivalent to Lexiscan, its active ingredient is the same stable, crystalline monohydrate form claimed by the patent. | ¶22 | col. 6:45-49 |
U.S. Reissue Patent No. RE47,301 Infringement Allegations
| Claim Element (from Independent Claim 11) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition comprising a crystalline monohydrate form of the compound (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide | Based on information and belief, the Meitheal ANDA product is a pharmaceutical composition that contains the claimed crystalline monohydrate of regadenoson. | ¶2, ¶22 | col. 21:10-17 |
| that is substantially free of 2-hydrazinoadenosine; | Based on information and belief, the manufacturing process for the Meitheal ANDA product results in a final product that is substantially free of the specified impurity, as required for a bioequivalent pharmaceutical product. | ¶22, ¶26 | col. 21:14-16 |
| and a pharmaceutically acceptable carrier. | The Meitheal ANDA product is an intravenous solution, which necessarily includes a pharmaceutically acceptable carrier for the active ingredient. | ¶2, ¶19 | col. 21:17-18 |
Identified Points of Contention
- Scope Questions: A central question will be whether Meitheal's manufacturing process for its ANDA product inevitably results in the specific crystalline "monohydrate" form (Form A) claimed in the ’183 and ’301 patents. Meitheal may argue it uses a different process that produces an alternative, non-infringing polymorph or form of regadenoson.
- Technical Questions: For the '301 patent, a factual dispute may arise over the meaning of "substantially free of 2-hydrazinoadenosine." The parties may contest the threshold level of the specified impurity in the Meitheal ANDA product and whether it falls within the scope of this limitation.
V. Key Claim Terms for Construction
- The Term: "monohydrate"
- Context and Importance: This term is the central feature of the asserted claims in the '183, '301, and '883 patents. Its construction will determine whether Meitheal's active ingredient, even if chemically identical as regadenoson, is the same patented crystalline form. Practitioners may focus on this term because polymorph patents often rise or fall on the precise definition of the claimed crystalline structure.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term "polymorph" is defined broadly in the specification to include "amorphous and solvates" of the compound, which could support an argument that the claims are not strictly limited to a single crystalline structure (’183 Patent, col. 6:31-35).
- Evidence for a Narrower Interpretation: The specification explicitly identifies a specific monohydrate, "Form A," as the most stable polymorph and provides detailed analytical data for it, including X-ray diffraction patterns and thermal analysis (e.g., FIG. 1, 2, 3). This detailed description of a specific embodiment may be used to argue for a narrower construction limited to the characteristics of Form A (’183 Patent, col. 6:39-49). Claim 9 of the '183 patent, which claims the monohydrate of claim 1 being free of a specific impurity, further reinforces the focus on a particular, purified form.
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement and contributory infringement for all three patents. The basis alleged is that upon approval, Meitheal's marketing, sale, and labeling of its generic product for the same indication as Lexiscan will cause and encourage physicians and patients to use it in an infringing manner (Compl. ¶35-36, ¶40-41, ¶47).
- Willful Infringement: The complaint does not include a specific count for willful infringement, but it does allege that Meitheal had "actual and/or constructive notice" of the '883 patent prior to filing its ANDA (Compl. ¶32). This allegation could form the basis for a later willfulness claim.
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of polymorphic identity: Can Plaintiffs demonstrate that the regadenoson in Meitheal's ANDA product, as it will be commercially manufactured, is necessarily the specific crystalline "monohydrate" (Form A) described and claimed in the patents-in-suit, or will Meitheal be able to show it utilizes a non-infringing form?
- A key evidentiary question will be one of process-product relationship: For the '883 patent's method claims, can Plaintiffs prove that Meitheal's process for formulating its final drug product performs the claimed steps? Similarly, for the '301 patent, what evidence will emerge regarding the purity of Meitheal's product and whether it is "substantially free" of the specified impurity?
- A central legal and factual question, stemming from Meitheal's notice letter, will be validity: Do the asserted claims meet the requirements of patentability, or can Meitheal prove, as it has asserted, that the claims are invalid, for instance, on grounds of obviousness or lack of adequate written description for the claimed crystalline form?