Apotex Inc v. Astellas Pharma

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Apotex Inc. (Canada)
  • Defendant: Gilead Sciences, Inc. (Delaware); Astellas Pharma US, Inc. (Delaware)
  • Plaintiff’s Counsel: Rakoczy Molino Mazzochi Siwik LLP; Clark Hill LLP
• Case Identification: 3:18-cv-06475, N.D. Cal., 10/23/2018
• Venue Allegations: Venue is alleged to be proper based on Defendant Gilead Sciences, Inc.'s principal place of business being located within the district, and Defendant Astellas Pharma US, Inc.'s alleged continuous and systematic business contacts, including the sale and marketing of pharmaceutical products, within the state and judicial district.
• Core Dispute: Plaintiff seeks a declaratory judgment that its proposed generic regadenoson injection product does not infringe patents related to a process for preparing the drug substance regadenoson and its specific crystalline forms (polymorphs).
• Technical Context: The technology concerns pharmaceutical chemistry, specifically methods for the large-scale synthesis of an A₂A-adenosine receptor agonist used as a coronary vasodilator in cardiac imaging, and the isolation of its stable polymorphs.
• Key Procedural History: This declaratory judgment action arises under the Hatch-Waxman Act. Plaintiff Apotex Inc., a subsequent applicant, filed an Abbreviated New Drug Application (ANDA) with a "Paragraph IV Certification" asserting non-infringement of the patents-in-suit. After Defendants did not file an infringement suit within the statutory 45-day window following receipt of Apotex's notice letter, Apotex initiated this action. The complaint notes that a judgment of non-infringement could cause a forfeiture of the 180-day market exclusivity period held by an unidentified "First Filer," thereby accelerating Apotex's ability to enter the market.

Case Timeline

Date	Event
2006-02-03	Priority Date for ’183 Patent and ’601 Patent
2012-01-31	’183 Patent Issue Date
2012-03-08	’183 Patent submitted for Orange Book listing
2012-04-10	First Paragraph IV Certification submitted by a third party for LEXISCAN
2015-07-21	’601 Patent Issue Date
2018-09-04	Defendants receive Apotex’s Paragraph IV Notice Letter
2018-10-23	Complaint Filing Date

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 methods to synthesize the A₂A-adenosine receptor agonist regadenoson, noting that prior methods were suited for small-scale syntheses and that the use of "protecting groups" is "undesirable for large scale syntheses" ('183 Patent, col. 1:56-65).
• The Patented Solution: The invention provides a synthesis process suitable for large-scale manufacturing of regadenoson that avoids the use of protecting groups ('183 Patent, col. 1:64-65). Additionally, the patent discloses that the compound can exist in at least three different crystalline forms (polymorphs) and an amorphous form, and it provides methods for isolating a specific, stable "monohydrate" crystalline form ('183 Patent, col. 2:1-12, col. 6:36-48).
• Technical Importance: The patent notes that the compound is a highly selective A₂A-adenosine receptor agonist undergoing clinical trials as a coronary vasodilator, making an efficient and pure large-scale synthesis critical for commercial pharmaceutical production ('183 Patent, col. 1:50-55).

Key Claims at a Glance

• The complaint broadly seeks a declaration of non-infringement of "any valid or enforceable claim" of the patent (Compl. ¶71). The patent’s independent claims appear to be Claims 1 and 6.
• Independent Claim 1 (Composition):
  • 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 6 (Method):
  • A method for preparing the monohydrate of claim 1
  • comprising crystallizing (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-methylcarboxamide
  • in an aqueous protic solvent or an aqueous polar solvent.

U.S. Patent No. 9,085,601 - PROCESS FOR PREPARING AN A2A-ADENOSINE RECEPTOR AGONIST AND ITS POLYMORPHS

• Issued: July 21, 2015

The Invention Explained

• Problem Addressed: The '601 Patent, which shares a specification with the '183 Patent, addresses the same technical problem: the need for a large-scale synthesis of regadenoson that avoids the use of protecting groups common in small-scale methods ('601 Patent, col. 2:1-4).
• The Patented Solution: The invention provides syntheses for large-scale preparation of the regadenoson compound and its polymorphs, with a focus on obtaining the product as a stable monohydrate, which was found to be the most stable of at least three different crystalline forms ('601 Patent, Abstract; col. 2:6-14).
• Technical Importance: As with the '183 Patent, the invention is framed as important for the commercial production of a selective A₂A agonist being developed for use in cardiac imaging ('601 Patent, col. 1:55-60).

Key Claims at a Glance

• The complaint broadly seeks a declaration of non-infringement of "any valid or enforceable claim" of the patent (Compl. ¶76). The patent’s sole independent claim is Claim 1.
• Independent Claim 1 (Product-by-Process):
  • A pharmaceutical composition prepared from 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
  • by adding at least one pharmaceutically acceptable carrier.

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is Plaintiff's "Proposed Regadenoson Product," identified as a "generic regadenoson injection, 0.4 mg/5 mL (0.08 mg/mL) prefilled syringe product" (Compl. ¶1).

Functionality and Market Context

• The complaint describes the product as a generic version of Defendants' LEXISCAN (regadenoson) injection product (Compl. ¶¶35-39). Plaintiff Apotex filed an Abbreviated New Drug Application (ANDA) with the FDA seeking approval to commercially manufacture and sell this product in the United States (Compl. ¶42). The complaint does not provide specific technical details regarding the composition, polymorphic form of the active ingredient, or manufacturing process of the Proposed Regadenoson Product.

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not allege infringement but instead seeks a declaratory judgment of non-infringement. It states that Apotex certified to the FDA and notified Defendants that its product "will not be infringed by the manufacture, use, or sale of the Proposed Regadenoson Product" (Compl. ¶44). The complaint asserts that the product would not infringe any claim of the patents-in-suit, either literally or under the doctrine of equivalents (Compl. ¶¶71, 76). However, the complaint itself does not set forth the specific technical basis or non-infringement theories for this assertion, noting only that its Paragraph IV notice letter "included non-infringement defenses" (Compl. ¶46). As no claim chart or detailed technical comparison is provided, a tabular analysis is not possible.

• Identified Points of Contention: Based on the patent claims and the nature of the accused product, the central infringement questions will likely revolve around the following:
  • Scope Questions ('183 Patent): Does Apotex's active pharmaceutical ingredient (API) exist in the specific "crystalline monohydrate" form required by Claim 1? A key dispute may arise over whether Apotex uses a different, non-infringing form, such as an amorphous solid, a different polymorph, or a non-monohydrate solvate.
  • Technical Questions ('601 Patent): Does Apotex’s manufacturing process fall within the scope of the '601 Patent's product-by-process claim? A central question will be whether Apotex's final drug product is "prepared from" the claimed crystalline monohydrate, even if that form is not present in the final injectable solution.

V. Key Claim Terms for Construction

• The Term: "crystalline form" ('183 Patent, Claim 1)

  • Context and Importance: The infringement analysis for the '183 Patent will likely depend entirely on whether Apotex's regadenoson API meets the definition of a "crystalline form" of the claimed monohydrate. If Apotex uses a non-crystalline (amorphous) form, it would likely not infringe this claim.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification discloses the existence of at least three different crystalline forms (Form A, B, and C) as well as an amorphous material ('183 Patent, col. 6:36-39). The use of the general term "crystalline form" without limitation to a specific polymorph (e.g., "Form A") could support a construction that covers any crystalline structure of the claimed monohydrate.
    • Evidence for a Narrower Interpretation: The specification repeatedly identifies "Form A" as a monohydrate and describes it as "the most stable of the various polymorphs" ('183 Patent, col. 6:45-48). A defendant may argue that the claims should be interpreted in light of these preferred embodiments, potentially limiting the scope to the specifically disclosed and characterized crystalline forms.

• The Term: "prepared from" ('601 Patent, Claim 1)

  • Context and Importance: This term is part of a product-by-process claim, which defines a product by the method used to make it. The construction of this term is critical to determining whether the manufacturing history of Apotex's product is relevant to infringement. Practitioners may focus on this term because infringement could exist even if the starting material (the crystalline monohydrate) is transformed and no longer present in the final accused product.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent specification describes a multi-step synthesis process ('183 Patent, Reaction Scheme III, col. 10). A plaintiff could argue that "prepared from" should be read broadly to encompass any process in which the claimed crystalline monohydrate is used at any stage, even as an early intermediate that is subsequently modified.
    • Evidence for a Narrower Interpretation: A defendant could argue that "prepared from" implies a more direct relationship, such as requiring the claimed crystalline monohydrate to be the immediate precursor that is mixed with the "pharmaceutically acceptable carrier" to form the final composition, and not a distant intermediate.

VI. Other Allegations

• Indirect Infringement: The complaint seeks a declaration that its product would not infringe the patents-in-suit "either directly or indirectly" (Compl. ¶¶71, 76). However, it provides no specific factual allegations regarding inducement or contributory infringement for analysis.

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

The resolution of this declaratory judgment action will likely depend on the evidence presented regarding the undisclosed nature of Apotex's product and process, centered on two key technical questions and one procedural driver.

• A core issue will be one of material composition: does the active pharmaceutical ingredient in Apotex’s generic product exist in the specific "crystalline monohydrate" form required by the ’183 Patent, or does it utilize a non-infringing alternative such as an amorphous solid or a different polymorph?
• A related question will be one of process scope: for the ’601 Patent, is Apotex’s final drug product "prepared from" the claimed crystalline starting material, a question whose answer depends on both the facts of Apotex’s manufacturing process and the court’s construction of that product-by-process limitation?
• A primary driver for the litigation appears to be commercial strategy: the complaint is structured to leverage the Hatch-Waxman Act's provisions, where a favorable non-infringement ruling for Apotex could trigger the forfeiture of a competitor's 180-day exclusivity period, highlighting that the timing and motivation for the suit may be as much about market-entry dynamics as about resolving a direct technical dispute with the Defendants.