DCT
1:20-cv-00347
Astellas US LLC v. Gland Pharma Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Astellas US LLC, Astellas Pharma US, Inc., and Gilead Sciences, Inc. (Delaware, Illinois, California)
- Defendant: Gland Pharma Limited (India)
- Plaintiff’s Counsel: Fish & Richardson P.C.
- Case Identification: 1:20-cv-00347, D. Del., 03/09/2020
- Venue Allegations: Plaintiffs allege venue is proper in the District of Delaware because Defendant Gland Pharma Limited committed an act of infringement by filing its ANDA with the intent to market and sell the generic product in Delaware, and has purposefully availed itself of the rights of Delaware law through systematic and continuous business contacts within the state.
- Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the cardiac stress agent Lexiscan® constitutes an act of infringement of three patents related to the drug’s active ingredient, its specific crystalline form, and its manufacturing process.
- Technical Context: The technology involves regadenoson, an A2A-adenosine receptor agonist used as a pharmacologic stress agent for myocardial perfusion imaging in patients unable to undergo adequate exercise stress.
- Key Procedural History: The action was initiated under the Hatch-Waxman Act following a notice letter dated February 24, 2020, in which Gland Pharma informed the Plaintiffs of its ANDA filing containing a Paragraph IV certification of non-infringement and/or invalidity for the asserted patents. The patents-in-suit are listed in the FDA’s Orange Book for Lexiscan®. U.S. Patent No. RE47,301 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 |
| 2015-07-21 | U.S. Patent No. 9,085,601 (of which '301 is a reissue) Issued |
| 2019-03-19 | U.S. Reissue Patent No. RE47,301 Issued |
| 2020-02-24 | Gland Pharma Sends Lexiscan Notice Letter to Plaintiffs |
| 2020-03-09 | 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 (’183 Patent)
The Invention Explained
- Problem Addressed: The patent’s background section identifies the need for new, efficient methods to synthesize large quantities of a specific A2A-adenosine receptor agonist (regadenoson) with high yield and purity, noting that previously disclosed methods were unsuitable for large-scale synthesis because they utilized protecting groups (’183 Patent, col. 1:56-col. 2:2).
- The Patented Solution: The patent discloses a synthesis process suitable for large-scale manufacturing that avoids protecting groups (’183 Patent, col. 2:14-20). Additionally, the invention identifies that the compound can exist in several different crystalline forms (polymorphs), and it specifically claims the most stable of these forms: a monohydrate that is desirable for a final pharmaceutical product (’183 Patent, col. 2:3-9).
- Technical Importance: Developing a scalable, high-purity synthesis process and identifying the most stable crystalline form of an active pharmaceutical ingredient are critical steps for enabling commercial manufacturing and ensuring product consistency and safety (’183 Patent, col. 1:56-61).
Key Claims at a Glance
- The complaint asserts independent claims 1 and 8, along with dependent claims 2-3 and 9 (Compl. ¶32).
- 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.
- Independent Claim 8:
- The monohydrate of claim 1,
- wherein the crystalline form has a ¹H NMR spectrum as shown in FIG. 1.
- The complaint reserves the right to assert additional claims (Compl. ¶32).
U.S. Reissue Patent No. RE 47,301 - "Process for preparing an A2A-adenosine receptor agonist and its polymorphs," Issued March 19, 2019 (’301 Patent)
The Invention Explained
- Problem Addressed: As with the ’183 Patent, this patent addresses the need for methods to produce and formulate a stable, high-purity A2A-adenosine receptor agonist suitable for pharmaceutical use in cardiac imaging (’301 Patent, col. 2:5-12).
- The Patented Solution: This reissue patent claims pharmaceutical compositions that contain the specific, stable crystalline monohydrate form of regadenoson. The claims focus not just on the compound itself, but on the final drug formulation, specifying characteristics such as high purity (e.g., being substantially free of a known impurity) and dissolution in a carrier (’301 Patent, col. 2:37-41; Claims 6, 11, 17).
- Technical Importance: Formulating a drug with a specific, stable polymorph at high purity is essential for ensuring consistent bioavailability, shelf-life, and patient safety in a commercial pharmaceutical product (’301 Patent, col. 2:15-23).
Key Claims at a Glance
- The complaint asserts independent claims 6, 11, and 17 (Compl. ¶37).
- Independent Claim 6:
- A pharmaceutical composition of an A2A-adenosine receptor agonist produced by a process comprising the following step:
- 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 in a pharmaceutically acceptable carrier.
- 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.
- Independent Claim 17:
- A pharmaceutical composition comprising 99.6% pure (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl)pyrazol-4-yl)-N-methylcarboxamide 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-aminopu- rin-2-yl}pyrazol-4-yl)-N-methylcarboxamide," Issued September 3, 2013 (’883 Patent)
- Technology Synopsis: This patent claims methods of preparing a pharmaceutical composition containing the active ingredient regadenoson (’883 Patent, col. 1:19-24, Claim 1). The invention focuses on the process of combining the stable crystalline monohydrate form of the drug with a pharmaceutically acceptable carrier, such as a buffered aqueous solution, to create the final drug product (’883 Patent, Abstract; col. 2:44-50).
- Asserted Claims: The complaint asserts independent claim 1 and dependent claims 2-5 (Compl. ¶45).
- Accused Features: Plaintiffs allege that Gland’s process for manufacturing its generic regadenoson product, as described in its ANDA, infringes the methods claimed in the ’883 Patent (Compl. ¶¶ 17, 24, 45).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Gland Pharma's generic 0.4 mg/5 mL (0.08 mg/mL) intravenous solution of regadenoson, which is the subject of Abbreviated New Drug Application (ANDA) No. 207320 (the "Gland ANDA product") (Compl. ¶2).
Functionality and Market Context
The product is a generic version of Plaintiffs' Lexiscan® drug (Compl. ¶2). It is intended for use as a pharmacologic stress agent in radionuclide myocardial perfusion imaging (MPI) for patients unable to perform an adequate exercise stress test (Compl. ¶16). The complaint alleges that the Gland ANDA product contains the same active ingredient as Lexiscan, has the same dosage form and strength, is bioequivalent, and is intended for the same approved medical indication (Compl. ¶¶ 20, 21).
IV. Analysis of Infringement Allegations
The complaint is filed pursuant to 35 U.S.C. § 271(e)(2), where the act of infringement is the submission of the ANDA seeking approval to market a generic drug prior to the expiration of the patents-in-suit. As is typical in such pleadings, the complaint does not provide detailed infringement charts. The allegations are based on the premise that for Gland’s product to be approved as a generic equivalent of Lexiscan®, it must necessarily meet the limitations of the asserted claims.
No probative visual evidence provided in complaint.
’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, which monohydrate is in a crystalline form. | The Gland ANDA product is alleged to be a generic version of Lexiscan® and to contain the same active ingredient, which Plaintiffs contend is the claimed crystalline monohydrate form of regadenoson. | ¶¶2, 20, 32 | col. 6:39-48 |
’301 Patent 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 ... that is substantially free of 2-hydrazinoadenosine; | The Gland ANDA product is alleged to be a pharmaceutical composition containing the crystalline monohydrate form of regadenoson. To gain FDA approval as a generic, it must meet purity specifications, which Plaintiffs allege means it is substantially free of the 2-hydrazinoadenosine impurity. | ¶¶20, 37 | col. 2:40-44 |
| and a pharmaceutically acceptable carrier. | The Gland ANDA product is described as an intravenous solution, which by definition is a pharmaceutical composition containing a pharmaceutically acceptable carrier. | ¶2 | col. 6:22-31 |
Identified Points of Contention
- Scope Questions: The primary dispute, as previewed in Gland's notice letter, will be whether the product as described in the confidential ANDA filing falls within the scope of the asserted claims (Compl. ¶22). A central question is one of polymorphic identity: does Gland's proposed generic product contain the specific crystalline monohydrate claimed in the ’183 and ’301 patents, or does it utilize a different, non-infringing polymorph or an amorphous form?
- Technical Questions: For the ’883 process patent, a key question will be whether the manufacturing process detailed in Gland’s ANDA is the same as, or technically equivalent to, the process claimed in the patent (Compl. ¶¶ 24, 45). For the ’301 composition patent, a potential point of contention is the meaning of "substantially free," and whether the level of the 2-hydrazinoadenosine impurity in Gland's product falls below the threshold required by that term.
V. Key Claim Terms for Construction
"crystalline form" (’183 Patent, Claim 1)
- Context and Importance: The patents describe multiple polymorphs (Forms A, B, C) and an amorphous form of regadenoson. Infringement of the asserted claims hinges on whether Gland’s product contains the specific crystalline structure claimed. Practitioners may focus on this term because Gland could potentially avoid infringement by using a different, non-claimed polymorph or an amorphous version of the drug.
- Intrinsic Evidence for a Broader Interpretation: The term "crystalline form" itself is general. A party could argue it should be given its plain and ordinary meaning, covering any form that exhibits a crystal lattice structure.
- Intrinsic Evidence for a Narrower Interpretation: The specification explicitly identifies "Form A" as a monohydrate and the most stable polymorph, providing detailed characterization data, including a specific X-ray powder diffraction pattern in FIG. 3 (’183 Patent, col. 6:39-48, col. 7:5-18). A party could argue that, in the context of the patent, "crystalline form" as used in the claims covering the monohydrate is implicitly limited to this specifically identified and characterized Form A.
"substantially free of 2-hydrazinoadenosine" (’301 Patent, Claim 11)
- Context and Importance: This is a term of degree that will be critical to determining infringement. The parties will likely dispute the purity threshold required to be "substantially free" of this specific process impurity.
- Intrinsic Evidence for a Broader Interpretation (less stringent): A party advocating for a broader scope might argue the term means the impurity is reduced to a level that is pharmaceutically acceptable or does not interfere with the drug's safety and efficacy, without requiring a specific numerical limit. The ’301 patent also includes claim 9, which requires the form to be "free of any impurity represented by the following structure," suggesting that "substantially free" was intended to mean something different and less absolute than "free."
- Intrinsic Evidence for a Narrower Interpretation (more stringent): A party advocating for a narrower scope could point to the patent’s emphasis on creating a high-purity product and the disclosure of a specific process to remove the 2-hydrazinoadenosine impurity (’183 Patent, col. 16:1-17, incorporated by reference into the ’301 patent). This could support an argument that "substantially free" implies a very low, if not undetectable, level of the impurity.
VI. Other Allegations
Indirect Infringement
The complaint alleges that upon approval, Gland's commercial manufacture, use, sale, and importation of the ANDA product would induce and/or contribute to infringement by others (e.g., healthcare providers) (Compl. ¶¶ 33, 38, 45). The basis for these allegations is the future marketing of the product and the instructions for its use that will be included on its label.
Willful Infringement
The complaint does not contain a formal count for willful infringement. However, it alleges that Gland had "actual and/or constructive notice" of the ’883 patent prior to its ANDA filing (Compl. ¶30) and that Gland's own notice letter establishes pre-suit knowledge of the ’183 and ’301 patents (Compl. ¶18). These allegations may form the basis for a future claim of post-filing willful infringement.
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of chemical and physical identity: Does the regadenoson formulation described in Gland's confidential ANDA filing contain the specific crystalline monohydrate (Form A) claimed by the ’183 and ’301 patents, or does it utilize a different, non-infringing polymorph or an amorphous solid form?
- A second key question will be one of process equivalence: Does the manufacturing process disclosed in Gland's ANDA fall within the scope of the method claims of the ’883 patent, either literally or under the doctrine of equivalents?
- Finally, the case will turn on the question of validity raised by Gland in its Paragraph IV certification. The court will likely need to resolve disputes over whether the claimed compound, compositions, and processes were obvious or anticipated in light of the prior art existing at the time of the invention.