Astellas US LLC v. Hospira Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Astellas US LLC, Astellas Pharma US, Inc., and Gilead Sciences, Inc. (Delaware & Delaware)
  • Defendant: Sandoz Inc. (Colorado)
  • Plaintiff’s Counsel: Fish & Richardson P.C.; Wilmer Cutler Pickering Hale and Dorr LLP
• Case Identification: 1:18-cv-01675, D. Del., 08/05/2019
• Venue Allegations: Venue is asserted as proper, and the complaint notes that in a prior agreement, Sandoz agreed not to contest jurisdiction or venue in the District of Delaware for this action.
• Core Dispute: Plaintiffs allege that Defendant’s proposed generic regadenoson product, submitted for FDA approval via an Abbreviated New Drug Application (ANDA), infringes patents covering the brand-name drug Lexiscan®, its specific crystalline form, and its methods of preparation.
• Technical Context: The technology relates to regadenoson, a selective A₂A-adenosine receptor agonist used as a pharmacologic stress agent in cardiac perfusion imaging for patients unable to perform exercise-based stress tests.
• Key Procedural History: The current action is a consolidated case involving an amended complaint. The original complaint, filed October 25, 2018, asserted U.S. Patent No. 9,085,601 (’601 patent). The '601 patent was subsequently reissued by the USPTO as RE 47,301 (’301 patent) on March 19, 2019, and was substituted into the litigation. This amended complaint also adds U.S. Patent No. 8,524,883 to the suit.

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
2012-10-01	Sandoz sends notice letter regarding its ANDA filing ('183 & '601 Patents)
2013-09-03	U.S. Patent No. 8,524,883 Issues
2015-07-21	U.S. Patent No. 9,085,601 (original of '301) Issues
2015-09-17	Sandoz sends second notice letter regarding its ANDA filing
2018-10-25	Plaintiffs file original complaint against Sandoz
2019-03-19	U.S. Reissue Patent No. RE 47,301 Issues
2019-05-01	Date by which Sandoz allegedly had notice of the '883 patent
2019-08-05	Plaintiffs file First Amended Complaint

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

• Patent Issued: January 31, 2012.

The Invention Explained

• Problem Addressed: The patent’s background section identifies a need for new methods to synthesize the A₂A-adenosine receptor agonist regadenoson on a large scale. Specifically, it notes that prior art methods were suited for small-scale synthesis and utilized protecting groups, which are "undesirable for large scale syntheses" (’183 Patent, col. 1:62-col. 2:1). The patent also recognizes that the compound can exist in multiple different crystalline forms (polymorphs) and that it is desirable to reliably produce the most stable form for pharmaceutical use (’183 Patent, col. 2:2-9).
• The Patented Solution: The patent discloses a synthesis process for regadenoson suitable for large-scale manufacturing and, critically, methods for isolating a specific, stable crystalline monohydrate form of the compound, identified as "Form A" (’183 Patent, Abstract; col. 6:36-47). The specification provides detailed characterization data for this polymorph, including its thermal properties and X-ray powder diffraction (XRPD) pattern, which serves as a fingerprint for the crystal structure (’183 Patent, FIG. 2-3).
• Technical Importance: This technology provides a commercially viable manufacturing path for a highly selective A₂A-adenosine receptor agonist that serves as a key coronary vasodilator in cardiac imaging, offering a critical diagnostic tool for patients who cannot undergo traditional exercise stress tests (’183 Patent, col. 1:25-42).

Key Claims at a Glance

• The complaint asserts independent claim 1 and dependent claims 2-9 (Compl. ¶31).
• Independent Claim 1 requires:
  • 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
  • wherein the monohydrate is in a crystalline form

U.S. Reissue Patent No. RE 47,301 - Process for preparing an A₂A-adenosine receptor agonist and its polymorphs

• Patent Issued: March 19, 2019.

The Invention Explained

• Problem Addressed: The '301 patent, a reissue of U.S. Patent No. 9,085,601, addresses the same problems as the '183 Patent: the need for a large-scale synthesis of regadenoson and a method to isolate its most stable crystalline polymorph for use in pharmaceutical products (’301 Patent, col. 2:5-12).
• The Patented Solution: This patent claims methods for preparing the stable monohydrate form of regadenoson and pharmaceutical compositions containing it. A key aspect of the claimed composition is its purity, specifically being "substantially free of 2-hydrazinoadenosine," an impurity that can arise during synthesis (’301 Patent, claim 11). The claims cover both the process of making the drug substance via specific crystallization techniques and the final drug product composition itself (’301 Patent, claims 6, 11).
• Technical Importance: The patent protects not only the specific crystalline form of the drug but also commercially relevant pharmaceutical formulations and manufacturing methods that ensure a pure and stable final product.

Key Claims at a Glance

• The complaint asserts independent claims 6 and 11, and dependent claims 7-10 and 12-17 (Compl. ¶36).
• Independent Claim 6 (Method) requires:
  • A method for preparing the monohydrate of claim 1 (the crystalline monohydrate compound)
  • Comprising crystallizing the compound
  • In an aqueous protic solvent or an aqueous polar solvent
• Independent Claim 11 (Composition) requires:
  • A pharmaceutical composition
  • Comprising a crystalline monohydrate form of the regadenoson compound
  • That is substantially free of 2-hydrazinoadenosine
  • And 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

• Patent Issued: September 3, 2013.

The Invention Explained

The '883 patent is directed to pharmaceutical compositions containing the stable, crystalline monohydrate form of regadenoson (’883 Patent, col. 2:1-9). The invention focuses specifically on the final formulated drug product, claiming a composition that combines the crystalline monohydrate active ingredient with a pharmaceutically acceptable carrier, such as a buffered aqueous solution, to ensure stability and suitability for intravenous administration (’883 Patent, Abstract; claim 1).

Key Claims at a Glance

• Asserted Claims: Claims 1-5 are asserted, with claim 1 being independent (Compl. ¶44).
• Accused Features: The complaint alleges that processes covered by the claims of the '883 patent are used to prepare the Sandoz ANDA product and that Sandoz intends to make, use, sell, or import a product made by that patented process (Compl. ¶24, ¶44).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is the "Sandoz ANDA product," identified as a 0.4 mg/5 mL (0.08 mg/mL) intravenous solution of regadenoson, which is a proposed generic version of Plaintiffs' Lexiscan® drug product (Compl. ¶2).

Functionality and Market Context

The Sandoz product is intended to be a pharmacologic stress agent for use in radionuclide myocardial perfusion imaging (MPI) for patients unable to undergo adequate exercise stress (Compl. ¶16, ¶21). The complaint alleges that by filing its ANDA, Sandoz has represented to the FDA that its proposed generic product contains the same active ingredient, has the same dosage form and strength, and is bioequivalent to the brand-name Lexiscan® product (Compl. ¶20). The filing seeks approval to market this product prior to the expiration of the patents-in-suit, positioning it as a direct generic competitor (Compl. ¶2).

IV. Analysis of Infringement Allegations

The complaint does not provide a claim chart or detailed, element-by-element infringement allegations. The infringement theory is predicated on 35 U.S.C. § 271(e)(2)(A), where the submission of an ANDA seeking approval for a generic drug constitutes a technical act of infringement. The core allegation is that the product for which Sandoz seeks approval, by its nature as a bioequivalent generic, will meet the limitations of the asserted claims.

’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...	The Sandoz ANDA product is alleged to be an intravenous solution of regadenoson that has the same active ingredient as Lexiscan and is bioequivalent to it.	¶2, ¶20	col. 6:36-47
...which monohydrate is in a crystalline form.	The complaint's theory of infringement rests on the allegation that the Sandoz ANDA product contains or is the specific crystalline monohydrate form of regadenoson claimed in the patent.	¶31, ¶33	col. 6:36-38

’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...	The Sandoz ANDA product is described as a 0.4 mg/5 mL intravenous solution of regadenoson, which Plaintiffs allege constitutes the claimed pharmaceutical composition.	¶2, ¶20	col. 6:22-30
...that is substantially free of 2-hydrazinoadenosine	Based on Sandoz's representation of bioequivalence and its request for approval for human use, Plaintiffs' infringement theory implies the Sandoz product must meet requisite purity standards, including being substantially free of this specified impurity.	¶20, ¶36	col. 19:26-40
...and a pharmaceutically acceptable carrier.	The accused product is an intravenous solution, which by definition includes a pharmaceutically acceptable carrier to deliver the active ingredient.	¶2, ¶17	col. 6:22-30

Identified Points of Contention

• Scope Questions: A primary question will be one of physical form: does the regadenoson active pharmaceutical ingredient (API) in Sandoz's product actually exist in the specific "crystalline monohydrate" form claimed in the patents, or does it utilize an amorphous form or a different polymorph? The scope of this term, particularly in light of the detailed characterization data in the specification for "Form A," will be central.
• Technical Questions: For the '301 patent, a key factual question will be whether Sandoz's manufacturing process uses an "aqueous protic solvent or an aqueous polar solvent" to crystallize the API, as required by method claim 6. Another question will concern the purity of the Sandoz product: what level of 2-hydrazinoadenosine is present, and does this level fall within the scope of the term "substantially free"?

V. Key Claim Terms for Construction

The Term: "crystalline form"

• Context and Importance: This term is foundational to the product claims of both the '183 and '301 patents. Infringement hinges on whether Sandoz's product contains regadenoson in the claimed "crystalline form." Practitioners may focus on this term because the patents disclose multiple polymorphs (Forms A, B, C) and an amorphous material, making the specific form of the API a critical, and potentially dispositive, factual issue.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The plain language "crystalline form" is not explicitly limited to a single polymorph in the claim itself.
  • Evidence for a Narrower Interpretation: The specification provides extensive detail identifying "Form A" as the most stable monohydrate polymorph and provides its specific XRPD pattern (FIG. 3) and thermal analysis data (FIG. 2) (’183 Patent, col. 6:36-47). Plaintiffs may argue that the claim term, when read in light of the specification, should be construed to mean this specific, characterized "Form A."

The Term: "substantially free of 2-hydrazinoadenosine"

• Context and Importance: This purity limitation in claim 11 of the '301 patent is crucial for defining the scope of the claimed pharmaceutical composition. The dispute will likely center on the quantitative threshold for "substantially free." An ANDA filer must demonstrate its product is bioequivalent, but the exact impurity profile could differ and become a basis for a non-infringement argument.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation (i.e., allowing more impurity): The term "substantially" inherently suggests that some amount of the impurity may be present. A defendant might argue this means any amount below a level that affects safety or efficacy.
  • Evidence for a Narrower Interpretation (i.e., requiring higher purity): In a related patent in the same family, claim 9 of the '183 patent claims a form that is "free of any impurity represented by the following structure..." (the same impurity). Plaintiffs may argue that the term "substantially free" in the reissued '301 patent should be interpreted as very close to completely free, representing a high degree of purity required for a pharmaceutical-grade product.

VI. Other Allegations

Indirect Infringement

The complaint alleges inducement and contribution to infringement (Compl. ¶32, ¶37, ¶44). In the context of an ANDA filing, this allegation is typically based on the defendant's proposed product labeling, which would instruct physicians and other healthcare providers to administer the allegedly infringing composition for its approved indication.

Willful Infringement

The complaint does not contain an explicit allegation of willful infringement. However, it pleads facts that could support such a claim by alleging Sandoz had pre-suit knowledge of the asserted patent families. The complaint cites notice letters sent by Sandoz to Plaintiffs dated October 1, 2012, and September 17, 2015, regarding the '183 and '601 (predecessor to '301) patents, and alleges Sandoz had notice of the '883 patent since at least May 1, 2019 (Compl. ¶18, ¶23).

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

This ANDA litigation will likely depend on the resolution of highly technical, fact-based questions that emerge from discovery regarding the specific nature of the Sandoz product and its manufacturing process.

• A core issue will be one of physical characterization: does the regadenoson active pharmaceutical ingredient in Sandoz's proposed generic product exist in the specific "crystalline monohydrate" form (Form A) claimed in the patents-in-suit, or is there a fundamental mismatch in its solid-state properties?
• A second central question will be one of process mapping: can Plaintiffs demonstrate that the process Sandoz uses to manufacture its drug substance, particularly the crystallization step, falls within the scope of the asserted method claims, or has Sandoz developed a non-infringing "design around" manufacturing process?
• A final key evidentiary question will be one of definitional threshold: does the Sandoz product meet the "substantially free of 2-hydrazinoadenosine" limitation in the '301 patent, a determination that may depend on the court's construction of what constitutes a "substantial" absence of the specified impurity in a pharmaceutical context.