Aragon Pharma Inc v. Lupin Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiffs: Aragon Pharmaceuticals, Inc. (Delaware); Janssen Biotech, Inc. (Pennsylvania); Sloan-Kettering Institute for Cancer Research (New York)
  • Defendants: Lupin Limited (India); Lupin Pharmaceuticals, Inc. (Delaware)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Akin Gump Strauss Hauer & Feld LLP
• Case Identification: 1:22-cv-00637, D. Del., 05/13/2022
• Venue Allegations: Plaintiffs allege venue is proper in the District of Delaware because Defendant Lupin Pharmaceuticals, Inc. is incorporated in Delaware and thus resides in the district. Venue over Defendant Lupin Limited, a foreign corporation, is alleged to be proper in any judicial district. The complaint further alleges that the Defendants cooperate as a unitary entity for distributing drug products in Delaware and throughout the United States.
• Core Dispute: Plaintiffs allege that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to market a generic version of the prostate cancer drug Erleada® constitutes an act of infringement of a patent claiming a specific crystalline form of the active ingredient, apalutamide.
• Technical Context: The technology concerns pharmaceutical polymorphs—different solid-state crystalline structures of the same chemical compound—which can have distinct physical properties affecting a drug's stability, solubility, and manufacturing consistency.
• Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 217084 with a Paragraph IV certification, asserting that the patent-in-suit is invalid, unenforceable, or not infringed. In a pre-suit Notice Letter, Defendants stated their proposed generic product would not literally infringe because it does not contain the claimed "crystalline Form B" of apalutamide and would not infringe under the doctrine of equivalents because the patent owner allegedly disclosed but did not claim an amorphous form of the compound.

Case Timeline

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 9,481,663 - “Crystalline Forms of an Androgen Receptor Modulator”

• Patent Identification: U.S. Patent No. 9,481,663, issued November 1, 2016 (the “’663 Patent”).

The Invention Explained

• Problem Addressed: The patent background describes the role of the androgen receptor in the progression of prostate cancer, including the development of "castration resistant" forms of the disease that no longer respond to conventional anti-androgen therapies (’663 Patent, col. 5:5-32). While not explicitly stated as a problem, the patent's focus on identifying specific solid-state forms of the therapeutic compound implies a need for a version of the active pharmaceutical ingredient with consistent and advantageous physical properties for formulation and manufacturing.
• The Patented Solution: The patent discloses the identification and characterization of multiple distinct crystalline forms (polymorphs) of the androgen receptor modulator apalutamide (’663 Patent, Abstract). The invention provides specific, reproducible crystalline structures, such as "Form B," defined by unique physical characteristics like their X-Ray Powder Diffraction (XRPD) patterns, which are suitable for use in pharmaceutical compositions (’663 Patent, col. 2:1-2, Fig. 2).
• Technical Importance: Isolating and claiming a specific polymorph of a drug substance is critical in pharmaceutical development to ensure batch-to-batch consistency, predictable dissolution rates, and stable shelf life, which are essential for product safety and efficacy.

Key Claims at a Glance

• The complaint asserts independent claim 1 and dependent claims 13 and 17 (’Compl. ¶50).
• The essential elements of independent claim 1 are:
  • A crystalline Form B of the compound 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (apalutamide)
  • that is characterized as having at least one of several specified properties, including:
    • an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2; or
    • an XRPD pattern with characteristic peaks at specific 2-Theta angles (12.1°, 16.0°, 16.7°, 20.1°, 20.3°, each ±0.1°).

III. The Accused Instrumentality

Product Identification

• Defendants' "Proposed ANDA Product," identified as "apalutamide oral tablets, 60 mg," a proposed generic version of Erleada® (Compl. ¶¶2, 38).

Functionality and Market Context

• The Proposed ANDA Product is intended for oral administration to treat patients with non-metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer (Compl. ¶34). It contains the active pharmaceutical ingredient apalutamide and is positioned to be a generic market competitor to the branded drug Erleada® upon FDA approval (Compl. ¶¶2, 34). The complaint alleges, "on information and belief," that the drug substance in the Proposed ANDA Product "contains some amount of crystalline Form B of apalutamide" (Compl. ¶¶46-47).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’663 Patent Infringement Allegations

Identified Points of Contention

• Evidentiary Question: The central dispute appears to be factual: does the Proposed ANDA Product contain the claimed "crystalline Form B" of apalutamide? The complaint's allegations are based "on information and belief," and it notes that Defendants declined to provide technical information, suggesting this will be a primary focus of discovery and expert analysis (Compl. ¶¶44, 46).
• Scope Question: How the term "substantially the same" is interpreted will be critical. This raises the question of what degree of variation between the accused product's XRPD pattern and the patent's Figure 2 is permissible for a finding of literal infringement.

V. Key Claim Terms for Construction

The Term: "crystalline Form B"

• Context and Importance: This term defines the patented subject matter. The entire infringement analysis hinges on whether the accused product contains this specific polymorph.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The claim defines "Form B" by a list of alternative characteristics connected by "at least one of," which may support an argument that satisfying any single criterion (e.g., matching the specified XRPD peaks) is sufficient to meet the limitation (’663 Patent, col. 38:12-16).
  • Evidence for a Narrower Interpretation: The specification provides a detailed description of Form B, including specific methods of its creation and multiple analytical characterizations (e.g., DSC, TGA) (’663 Patent, col. 9:28-col. 10:48; col. 25:29-41). A party could argue that these details implicitly limit the scope of "Form B" to a material exhibiting a combination of these described properties, not just one.

The Term: "substantially the same"

• Context and Importance: This term qualifies the comparison between the accused product's XRPD pattern and the pattern shown in Figure 2 of the patent. Its construction will define the boundary for literal infringement.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: A party may argue that this language is intended to account for normal, minor experimental variations in analytical measurements (e.g., peak intensity, slight shifts in position) that are well understood by those skilled in the art of crystallography (’663 Patent, col. 34:65-col. 35:2).
  • Evidence for a Narrower Interpretation: A party may argue that "substantially" cannot be used to encompass a product that is a different crystalline form or an amorphous solid, even if there is some coincidental overlap in their respective XRPD patterns.

VI. Other Allegations

Indirect Infringement

• The complaint alleges that Defendants will induce infringement of method claim 17 by labeling the Proposed ANDA Product for the treatment of prostate cancer, thereby encouraging and instructing physicians and patients to perform the claimed method (Compl. ¶¶55, 62). Contributory infringement is also alleged on the basis that the product is not a staple article of commerce and is specifically designed for the infringing use (Compl. ¶64).

Willful Infringement

• The complaint does not plead a separate count for willful infringement, but it alleges that Defendants have had actual knowledge of the ’663 Patent at least since sending their Notice Letter (Compl. ¶57). It further requests that the case be declared "exceptional" to permit an award of attorneys' fees under 35 U.S.C. § 285 (Compl. ¶67).

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

• A primary issue will be one of compositional identity: does the Defendants' proposed generic product, in fact, contain any amount of the specific "crystalline Form B" as claimed in the ’663 Patent? Resolution will likely depend on conflicting analytical evidence and expert testimony regarding the solid-state characterization of the accused product.
• A central legal question will be one of definitional scope: how will the court construe the claim term "substantially the same" when comparing XRPD patterns? This determination will set the legal standard for infringement and influence the entire case.
• Should literal infringement not be found, a key question will be the viability of the doctrine of equivalents: can Plaintiffs prove their claim is infringed by an equivalent, particularly in light of Defendants' stated defense that the disclosure of an amorphous form without claiming it dedicated that alternative to the public domain?