DCT
1:21-cv-00032
Astellas US LLC v. Mylan Pharma Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Astellas US LLC (Delaware); Astellas Pharma US, Inc. (Delaware); and Gilead Sciences, Inc. (Delaware)
- Defendant: Mylan Pharmaceuticals Inc. (West Virginia)
- Plaintiff’s Counsel: Thomas Combs & Spann, PLLC
- Case Identification: 1:21-cv-00032, N.D.W. Va., 03/04/2021
- Venue Allegations: Venue is asserted on the basis that Defendant is a corporation organized under the laws of West Virginia with its principal place of business in the judicial district, and therefore resides in the district.
- Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of the cardiac stress agent Lexiscan® (regadenoson) constitutes an act of infringement of three patents covering the drug's specific crystalline form, methods of its preparation, and resulting pharmaceutical compositions.
- Technical Context: The technology relates to pharmaceutical chemistry, specifically a stable crystalline monohydrate of a selective A2A-adenosine receptor agonist and processes for its large-scale, high-purity manufacture.
- Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following a notice letter from Mylan, dated January 21, 2021, informing Plaintiffs of its ANDA filing. U.S. Reissue Patent No. RE 47,301 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 Issued |
| 2013-09-03 | U.S. Patent No. 8,524,883 Issued |
| 2019-03-19 | U.S. Reissue Patent No. RE 47,301 Issued |
| 2021-01-21 | Mylan Sends Notice Letter Regarding ANDA Filing |
| 2021-03-04 | 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"
The Invention Explained
- Problem Addressed: The patent's background section notes that prior methods for synthesizing the active pharmaceutical ingredient regadenoson were not suitable for large-scale manufacturing because they required the use of protecting groups, a step which is undesirable in commercial production ('183 Patent, col. 2:58-65).
- The Patented Solution: The patent discloses a synthesis process suitable for large-scale manufacturing that avoids the use of protecting groups ('183 Patent, col. 2:58-65). The invention also identifies that the resulting compound can exist in several different crystalline structures (polymorphs) and establishes that a specific monohydrate form ("Form A") is the most stable and therefore the most desirable form for a final drug product ('183 Patent, col. 6:35-49).
- Technical Importance: The invention provided a pathway for commercially viable manufacturing and identified a stable crystalline form of the drug, which is critical for ensuring consistent purity, shelf-life, and bioavailability in a pharmaceutical product ('183 Patent, col. 2:1-10).
Key Claims at a Glance
- The complaint asserts independent claims 1 and 8, as well as dependent claims 2-3 and 9 (Compl. ¶33).
- Independent Claim 1 recites:
- 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.
- Independent Claim 8 recites:
- The monohydrate of claim 1,
- wherein the crystalline form has a ¹H NMR spectrum as shown in FIG. 1.
U.S. Reissue Patent No. RE 47,301 - "Process for preparing an A2A-adenosine receptor agonist and its polymorphs"
The Invention Explained
- Problem Addressed: As with the related ’183 Patent, the background identifies a need for new methods of synthesis for the regadenoson compound that can produce large quantities in good yield and high purity without the use of protecting groups ('301 Patent, col. 2:1-12).
- The Patented Solution: The patent claims a pharmaceutical composition produced by a process that ensures high purity. This is achieved by dissolving a specific crystalline monohydrate form of regadenoson, which is "substantially free" of the impurity 2-hydrazinoadenosine, into a pharmaceutically acceptable carrier ('301 Patent, cl. 6).
- Technical Importance: The invention addresses the critical need in drug manufacturing for a final product with high purity and a stable, well-defined composition, which is essential for patient safety, therapeutic efficacy, and regulatory approval ('301 Patent, cl. 11, 17).
Key Claims at a Glance
- The complaint asserts independent claims 6 and 17 (Compl. ¶38).
- Independent Claim 6 recites:
- A pharmaceutical composition of an A2A-adenosine receptor agonist produced by a process comprising the step of:
- dissolving a crystalline monohydrate form of the regadenoson compound that is substantially free of 2-hydrazinoadenosine in a pharmaceutically acceptable carrier.
- Independent Claim 17 recites:
- A pharmaceutical composition comprising 99.6% pure regadenoson,
- dissolved in a pharmaceutically acceptable carrier.
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"
- Technology Synopsis: This patent claims a method of preparing a pharmaceutical composition by combining a specific crystalline monohydrate of regadenoson with a carrier ('883 Patent, cl. 1). The invention focuses on ensuring the starting material is a stable crystalline monohydrate that is substantially free of impurities, thereby yielding a high-purity final drug product ('883 Patent, cl. 3).
- Asserted Claims: The complaint asserts independent claim 1 and dependent claims 2-5 (Compl. ¶46).
- Accused Features: The complaint alleges on information and belief that Mylan uses processes covered by the ’883 Patent to prepare its ANDA product (Compl. ¶25, ¶44).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is Mylan’s proposed generic intravenous solution of regadenoson (0.4 mg/5 mL), for which it filed Abbreviated New Drug Application (ANDA) No. 213856 with the FDA (Compl. ¶¶ 1-2).
Functionality and Market Context
- The Mylan ANDA product contains the same active ingredient, regadenoson, at the same dosage and strength as Plaintiffs' branded Lexiscan® product (Compl. ¶21). It is intended for the same use as a pharmacologic stress agent to increase blood flow in coronary arteries during cardiac nuclear stress tests for patients unable to exercise (Compl. ¶¶ 16-17, 22). The complaint alleges that Mylan intends to market its generic product prior to the expiration of the patents-in-suit (Compl. ¶20).
IV. Analysis of Infringement Allegations
The complaint does not contain detailed infringement contentions or claim charts, as is common in initial ANDA complaints. The infringement theory is based on the statutory act of filing an ANDA for a drug claimed in a patent. The following chart summarizes the allegations, which are premised on the representation that Mylan’s product is bioequivalent to and has the same active ingredient as Lexiscan® (Compl. ¶21).
’183 Patent 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, | Mylan’s ANDA product is alleged to contain the same active ingredient as Lexiscan®, which Plaintiffs allege is the claimed regadenoson compound. | ¶21, ¶33 | col. 2:3-7 |
| which monohydrate is in a crystalline form. | By seeking approval for a generic version of Lexiscan®, Mylan’s product is alleged to be the claimed stable crystalline monohydrate form of the active ingredient. | ¶33 | col. 6:35-39 |
’301 Patent Infringement Allegations
| Claim Element (from Independent Claim 6) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition of an A2A-adenosine receptor agonist produced by a process comprising the following step: | Mylan’s ANDA filing seeks approval to market a pharmaceutical composition containing the regadenoson agonist. | ¶21, ¶38 | col. 20:49-51 |
| dissolving 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 | On information and belief, the manufacturing process for Mylan’s ANDA product is alleged to involve dissolving the specified high-purity crystalline monohydrate of regadenoson. | ¶25, ¶38 | col. 20:52-58 |
| in a pharmaceutically acceptable carrier. | The Mylan ANDA product is described as an intravenous solution, which by definition comprises an active ingredient dissolved in a carrier. | ¶2, ¶21 | col. 20:58-59 |
No probative visual evidence provided in complaint.
Identified Points of Contention
- Scope Questions: A central question for the '183 Patent is whether the term "crystalline form" is met by Mylan's product. The dispute may focus on whether Mylan uses the specific "Form A" polymorph described in the patent or an alternative, potentially non-infringing form (e.g., a different polymorph or an amorphous solid). For the '301 and '883 Patents, a dispute may arise over the scope of "substantially free," and what quantitative level of impurity falls outside that definition.
- Technical Questions: The core of the case will likely be a factual dispute over the exact physical and chemical properties of Mylan's proposed product and the specifics of its manufacturing process. The complaint alleges infringement on "information and belief" (Compl. ¶25), raising the question of what evidence, to be revealed from Mylan's confidential ANDA, will show regarding the product's crystalline structure, purity levels, and manufacturing steps.
V. Key Claim Terms for Construction
The Term: "crystalline form" ('183 Patent, cl. 1)
- Context and Importance: The infringement analysis for the '183 Patent hinges on whether Mylan’s product is the claimed "crystalline form" of the regadenoson monohydrate. A common strategy in ANDA litigation is to design a generic product using a different, non-infringing polymorph or an amorphous version of the active ingredient. Practitioners may focus on this term because its construction could determine whether Mylan's product falls within the scope of the claims.
- Intrinsic Evidence for a Broader Interpretation: The specification discloses the existence of "at least three different crystalline forms, referred to herein as Form A, Form B, Form C, and an amorphous product" ('183 Patent, col. 6:35-39). Plaintiffs may argue that the term "crystalline form" in the independent claim should be given its plain and ordinary meaning, covering any crystalline structure of the monohydrate, not just the preferred embodiment.
- Intrinsic Evidence for a Narrower Interpretation: The patent specification heavily emphasizes the stability and desirability of "Form A" and provides its specific X-ray diffraction pattern data in FIG. 3 ('183 Patent, col. 6:45-49). A defendant could argue that, in the context of the patent, "crystalline form" of the monohydrate should be construed as being limited to the specifically disclosed and characterized "Form A."
The Term: "substantially free of 2-hydrazinoadenosine" ('301 Patent, cl. 6)
- Context and Importance: This purity limitation is critical for the infringement analysis of the process-related claims in the '301 and '883 Patents. The dispute will likely center on the permissible threshold of the 2-hydrazinoadenosine impurity. If Mylan's product contains the impurity at a level deemed to be more than incidental, it may not infringe.
- Intrinsic Evidence for a Broader Interpretation (less strict): The patent does not provide a specific numerical percentage for "substantially free." Plaintiffs may argue the term should be interpreted according to its plain meaning, implying a level of purity that does not compromise the safety or efficacy of the final drug product.
- Intrinsic Evidence for a Narrower Interpretation (more strict): The patent's specification repeatedly highlights the goal of high purity. One example describes a purified product with 99.6% purity ('301 Patent, col. 15:1-14). A defendant may argue that this example defines the standard required to be "substantially free" of impurities.
VI. Other Allegations
Indirect Infringement
- The complaint alleges inducement and contributory infringement, asserting that Mylan's actions in seeking FDA approval for its product, which will have a label instructing its use, will actively encourage and contribute to infringement by end-users (e.g., physicians and hospitals) upon commercial launch (Compl. ¶¶ 34-35, 39-40).
Willful Infringement
- The complaint does not explicitly plead willfulness. However, it lays a foundation for such a claim by alleging Mylan had notice of the patents-in-suit. Mylan's notice letter dated January 21, 2021, establishes pre-suit knowledge of the '183 and '301 patents (Compl. ¶19), and the complaint alleges actual or constructive notice of the '883 patent prior to the ANDA filing (Compl. ¶31).
VII. Analyst’s Conclusion: Key Questions for the Case
This case presents several critical questions for the court, revolving around the specific nature of the accused generic product, which will be detailed in Mylan's confidential ANDA submission.
- A central factual question will be one of composition: Does Mylan’s proposed generic product comprise the specific crystalline monohydrate of regadenoson as claimed in the '183 patent, or does it utilize a different, non-infringing solid-state form?
- A key evidentiary issue will be one of process and purity: Does the manufacturing process detailed in Mylan’s ANDA align with the steps claimed in the '301 and '883 patents, and does the resulting product meet the claimed purity limitations, particularly the requirement of being "substantially free of 2-hydrazinoadenosine"?
- The outcome may also depend on a question of claim scope: How will the court construe the term "substantially free," and will the level of purity in Mylan's product fall within that judicially determined definition?