DCT

1:22-cv-00696

Aragon Pharma Inc v. Hetero USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: Aragon Pharmaceuticals, Inc. et al. v. Hetero Labs Limited Unit V et al., 1:22-cv-00696, D. Del., 05/27/2022
  • Venue Allegations: Venue is alleged to be proper as to Hetero USA, Inc. because it is incorporated in Delaware and thus resides in the district. Venue is alleged as proper for Hetero Labs Limited Unit V as it is a foreign corporation with substantial contacts in Delaware, and because its submission of a drug application for sale throughout the U.S., including Delaware, gives rise to the action.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of the prostate cancer drug Erleada® (apalutamide) constitutes an act of infringement of six U.S. patents.
  • Technical Context: The patents relate to the anti-androgen compound apalutamide, specific crystalline forms of the compound, and methods of its use for treating non-metastatic castration-resistant prostate cancer (NM-CRPC), a significant indication in oncology therapeutics.
  • Key Procedural History: The lawsuit was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a Paragraph IV Notice Letter, dated April 18, 2022, in which Defendants stated they were seeking FDA approval to market a generic apalutamide product. The patents-in-suit are listed in the FDA's "Orange Book" as covering the branded drug Erleada®. The Notice Letter included a specific assertion that the proposed generic product would not infringe the patent on crystalline forms because it "is not the claimed polymorphic form."

Case Timeline

Date Event
2006-03-27 Priority Date for ’507 Patent
2012-06-07 Priority Date for ’663 Patent
2012-09-26 Priority Date for ’054, ’314, and ’888 Patents
2013-05-21 Issue Date of ’507 Patent
2016-11-01 Issue Date of ’663 Patent
2017-10-16 Priority Date for ’508 Patent
2018-02-06 Issue Date of ’054 Patent
2018-08-21 Issue Date of ’314 Patent
2020-07-07 Issue Date of ’508 Patent
2020-12-01 Issue Date of ’888 Patent
2022-04-18 Defendant's Paragraph IV Notice Letter Sent
2022-05-27 Complaint Filing Date

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

U.S. Patent No. 8,445,507 - "Androgen Receptor Modulator for the Treatment of Prostate Cancer and Androgen Receptor-Associated Diseases"

The Invention Explained

  • Problem Addressed: The patent's background describes how prostate cancer, though initially responsive to androgen deprivation therapy, often progresses to a "hormone refractory" state where treatments fail ('507 Patent, col. 1:15-30). A key mechanism for this resistance is the overexpression of the Androgen Receptor (AR), which can cause existing anti-androgen drugs like bicalutamide to paradoxically act as agonists, stimulating rather than inhibiting cancer growth ('507 Patent, col. 1:31-50).
  • The Patented Solution: The invention provides a new class of non-steroidal compounds, including the specific compound later named apalutamide, that act as androgen receptor modulators ('507 Patent, Abstract). These compounds are designed to be potent AR antagonists with minimal agonist activity, even in the context of AR overexpression, thereby overcoming the mechanism of resistance that plagues earlier anti-androgens ('507 Patent, col. 2:5-12).
  • Technical Importance: This technology represented an effort to develop a "second-generation" anti-androgen capable of effectively treating castration-resistant prostate cancer, a lethal stage of the disease for which treatment options were limited.

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 22 (Compl. ¶54).
  • Independent Claim 1: A compound claim covering the specific chemical structure of apalutamide or its pharmaceutically acceptable salts ('507 Patent, col. 29:1-25).
  • Independent Claim 22: A method of treatment claim comprising the elements:
    • Administering a compound of claim 1 to a subject in need of treatment
    • Thereby treating a hyperproliferative disorder, wherein the disorder is prostate cancer ('507 Patent, col. 32:2-6).
  • The complaint also asserts dependent claims 2, 3, 11, and 19 and reserves the right to assert others (Compl. ¶54).

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

The Invention Explained

  • Problem Addressed: For a chemical compound to be developed into a viable drug product, it must be manufacturable in a stable and consistent physical form. The patent addresses the technical challenge of identifying and characterizing specific solid-state forms (polymorphs) of apalutamide that possess suitable properties for pharmaceutical development ('663 Patent, col. 1:18-22).
  • The Patented Solution: The invention discloses several distinct crystalline forms of apalutamide, including the polymorph designated "Form B" ('663 Patent, Abstract). The patent provides detailed characterization data for Form B, including its specific X-Ray Powder Diffraction (XRPD) pattern, illustrated in FIG. 2, which serves as a fingerprint to identify this particular solid form ('663 Patent, col. 9:30-41; FIG. 2).
  • Technical Importance: The discovery and patenting of specific, stable crystalline forms of an active pharmaceutical ingredient is a critical step in drug development, ensuring product consistency, stability, and predictable bioavailability.

Key Claims at a Glance

  • The complaint asserts independent claims 1, 13, and 17 (Compl. ¶73).
  • Independent Claim 1: A composition of matter claim to "A crystalline Form B" of apalutamide, which is characterized by at least one of several analytical 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, including 12.1±0.1°, 16.0±0.1°, 16.7±0.1°, 20.1±0.1°, and 20.3±0.1° ('663 Patent, col. 33:1-14).
  • Independent Claim 13: A pharmaceutical composition comprising the crystalline Form B of claim 1 and at least one pharmaceutically acceptable carrier, diluent, or excipient ('663 Patent, col. 34:18-22).
  • Independent Claim 17: A method for treating prostate cancer in a mammal by administering the pharmaceutical composition of claim 13 ('663 Patent, col. 34:33-38).

U.S. Patent No. 9,884,054 - "Anti-androgens for the Treatment of Non-metastatic Castrate-resistant Prostate Cancer"

  • Technology Synopsis: The patent claims a method of treating a specific patient population—male humans with non-metastatic castration-resistant prostate cancer (NM-CRPC)—by administering apalutamide at a specific daily dose ('054 Patent, Abstract). This patent focuses on a particular dosage regimen for a defined clinical indication.
  • Asserted Claims: Independent claim 15 (Compl. ¶93).
  • Accused Features: The use of Defendants' proposed generic apalutamide product at the dosage recommended on its label, which is alleged to be "about 240 mg per day" for the treatment of NM-CRPC (Compl. ¶¶ 93, 94).

U.S. Patent No. 10,052,314 - "Anti-androgens for the Treatment of Non-metastatic Castrate-resistant Prostate Cancer"

  • Technology Synopsis: This patent claims a method of treating NM-CRPC with apalutamide in combination with another therapy ('314 Patent, Abstract). Specifically, the claimed method requires the administration of apalutamide at a particular dose "further compris[ing] administering a gonadotropin releasing hormone (GnRH) agonist" ('314 Patent, col. 17:63-18:2).
  • Asserted Claims: Independent claim 19 (Compl. ¶108).
  • Accused Features: The use of Defendants' proposed generic product in patients who are also receiving a GnRH agonist as part of the standard of care for castration-resistant prostate cancer (Compl. ¶108).

U.S. Patent No. 10,702,508 - "Anti-androgens for the Treatment of Non-metastatic Castration-resistant Prostate Cancer"

  • Technology Synopsis: This patent claims a method of achieving a specific clinical outcome in patients with NM-CRPC ('508 Patent, Abstract). The claimed method of "improving metastasis free survival" requires administering apalutamide in combination with androgen deprivation therapy, "wherein the median metastasis free survival is about 40.5 months" ('508 Patent, col. 83:7-12). This ties the patented method to a specific, quantified clinical result derived from clinical trial data.
  • Asserted Claims: Independent claims 1 and 5 (Compl. ¶122).
  • Accused Features: The use of Defendants' proposed generic product, which is alleged to achieve a median metastasis-free survival of "about 40.5 months" when administered according to its label (Compl. ¶¶ 123, 125).

U.S. Patent No. 10,849,888 - "Anti-androgens for the Treatment of Non-metastatic Castrate-resistant Prostate Cancer"

  • Technology Synopsis: This patent claims a method of treating NM-CRPC with apalutamide in patients who have undergone a specific surgical procedure ('888 Patent, Abstract). The claimed method requires that the administration of apalutamide "further comprises orchiectomy," which is the surgical removal of the testicles ('888 Patent, col. 17:53-61).
  • Asserted Claims: Independent claims 1 and 8 (Compl. ¶139).
  • Accused Features: The use of Defendants' proposed generic product in the sub-population of NM-CRPC patients who have previously undergone an orchiectomy (Compl. ¶140).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is Defendants' "Proposed ANDA Product," a generic drug described in ANDA No. 217185 as "Apalutamide Tablets; Oral 60 mg" (Compl. ¶¶ 2, 44).

Functionality and Market Context

  • The Proposed ANDA Product is a generic pharmaceutical intended to be a therapeutic equivalent to Plaintiffs' branded drug, Erleada® (Compl. ¶2). It contains the same active pharmaceutical ingredient, apalutamide, and is intended for the same indication: treatment of patients with non-metastatic castration-resistant prostate cancer (Compl. ¶¶ 34, 55). The complaint alleges, upon information and belief, that the product contains "some amount of crystalline Form B of apalutamide" (Compl. ¶50). As a generic drug, its market positioning is to serve as a lower-cost, substitutable alternative to the branded product upon receiving FDA approval.

IV. Analysis of Infringement Allegations

’507 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound having the formula [chemical structure of apalutamide] or a pharmaceutically acceptable salt thereof. The Proposed ANDA Product is alleged to contain the compound apalutamide. ¶56 col. 29:1-25

’663 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline Form B of [apalutamide]... The complaint alleges on information and belief that the Proposed ANDA Product and its drug substance contain "some amount of crystalline Form B of apalutamide." ¶74 col. 33:1-3
that is characterized as having at least one of an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2... The complaint alleges the product meets this characterization by referencing the XRPD pattern shown in FIG. 2 of the patent. ¶75 col. 33:3-5
or an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 12.1±0.1° 2-Theta, 16.0±0.1° 2-Theta, 16.7±0.1° 2-Theta, 20.1±0.1° 2-Theta, 20.3±0.1° 2-Theta. The complaint alleges that the crystalline Form B in the accused product is characterized by these specific XRPD peaks. The complaint's allegation includes a chart from the patent, an X-Ray powder diffraction pattern for Crystalline Form B, which serves as a key piece of visual evidence for this limitation (Compl. ¶75; '663 Patent, FIG. 2). ¶75 col. 33:10-14
  • Identified Points of Contention:
    • ’507 Patent: As this is a compound patent and the accused product is a generic version containing the same active ingredient, the primary dispute for this patent may center on validity rather than infringement, though such details are not present in the complaint.
    • ’663 Patent: A central point of contention is explicitly identified in the complaint. Defendants' pre-suit Notice Letter asserted non-infringement on the basis that the Proposed ANDA Product "is not the claimed polymorphic form" (Compl. ¶¶ 47-48). Plaintiffs' allegation that the product contains "some amount" of the claimed Form B creates a direct factual conflict that raises key questions for the court:
      • Technical Question: What is the actual polymorphic composition of the apalutamide in Defendants' product? This will require extensive factual discovery and expert analysis of analytical data (e.g., XRPD, DSC) to determine if any amount of the claimed Form B is present.
      • Scope Questions: What does "substantially the same as shown in FIG. 2" mean? How much deviation from the reference XRPD pattern is permissible? Further, if the accused product contains a mixture of polymorphs, does the presence of "some amount" of Form B satisfy the claim language, or must Form B be the sole or predominant form present?

V. Key Claim Terms for Construction

  • The Term: "crystalline Form B" (from '663 Patent, claim 1)
  • Context and Importance: The definition of this term is dispositive for the infringement analysis of the ’663 Patent. Defendants have staked their non-infringement position on the assertion that their product is not this specific crystalline form. Practitioners may focus on this term because its construction will determine what analytical evidence is required to prove or disprove infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: Claim 1 defines "crystalline Form B" using a disjunctive ("or") list of characteristics, including an XRPD pattern "substantially the same" as FIG. 2, a list of specific peak locations, or unit cell parameters, among others ('663 Patent, col. 33:1-34:17). Plaintiffs may argue that meeting just one of these criteria is sufficient to fall within the claim, and that "substantially the same" allows for some degree of variation from the reference pattern.
    • Evidence for a Narrower Interpretation: The patent specification distinctly identifies and characterizes multiple different crystalline forms (A, C, D, E, etc.) in addition to Form B ('663 Patent, Examples section). Defendants may argue that these distinctions demonstrate an intent to claim each form narrowly and that the definition of Form B must be construed to clearly exclude not only other forms disclosed in the patent but also any other undisclosed forms, such as the one allegedly used by Defendants.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all six patents-in-suit. The inducement allegations are based on the assertion that Defendants' product label and instructions will actively encourage physicians and patients to perform the steps of the patented methods of use (e.g., Compl. ¶¶ 59, 78, 94). The contributory infringement allegations are based on the assertion that apalutamide has no substantial non-infringing uses for the treatment of NM-CRPC and is a material component of the patented inventions (e.g., Compl. ¶¶ 60, 79, 95).
  • Willful Infringement: The complaint does not contain an explicit allegation of willful infringement. However, it does allege that Defendants have had "actual knowledge" of each patent-in-suit "at least as shown by the Notice Letter" sent prior to the lawsuit's filing (e.g., Compl. ¶¶ 62, 81, 97). This allegation of pre-suit knowledge could potentially form the basis for a later willfulness claim.

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

  1. A core question will be one of polymorphic identity: Does Defendants' proposed generic product contain the specific "crystalline Form B" of apalutamide as claimed in the ’663 Patent? This central factual dispute will likely be resolved through a battle of competing analytical chemistry evidence and expert testimony.
  2. A secondary question will be one of claim scope: If Defendants' product is found to contain some amount of Form B, will that be sufficient to infringe the ’663 Patent claims, which recite a composition "comprising" the crystalline form? This raises the legal question of whether the claim requires a minimum level of purity or if the mere presence of the claimed form in a mixture suffices for infringement.
  3. A final set of questions relates to method of use infringement: Assuming the generic product is launched, will its prescribed use for treating non-metastatic castration-resistant prostate cancer inevitably result in direct infringement of the various method patents by doctors and patients, particularly with respect to specific dosages ('054), combination therapies ('314, '888), and quantified clinical outcomes ('508)?