DCT

2:22-cv-03212

Aragon Pharma Inc v. Hetero Labs Ltd Unit V

Log In
Key Events
Amended Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:22-cv-03212, D.N.J., 10/18/2023
  • Venue Allegations: Venue is alleged to be proper as Defendant Hetero USA has a regular and established place of business in Piscataway, New Jersey, and Defendants have not contested venue for the purposes of this action.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) for a generic version of the prostate cancer drug Erleada® (apalutamide) constitutes an act of infringement of six patents covering the apalutamide compound, its specific crystalline forms, and methods of its use for treating non-metastatic castration-resistant prostate cancer.
  • Technical Context: The technology concerns second-generation anti-androgen therapeutics, a class of drugs that represents a significant advancement in the treatment of castration-resistant prostate cancer by overcoming resistance mechanisms that limit the effectiveness of earlier treatments.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 217185 and issuance of a Paragraph IV notice letter on April 18, 2022, certifying that the patents-in-suit are invalid, unenforceable, or not infringed. This First Amended Complaint was filed to add infringement allegations regarding U.S. Reissue Patent No. RE49,353, which issued on January 3, 2023, as a reissue of a previously asserted patent.

Case Timeline

Date Event
2007-01-26 ’507 Patent Priority Date
2012-06-07 ’663 Patent Priority Date
2012-09-26 ’054 and RE353 Patent Priority Date
2013-05-21 ’507 Patent Issue Date
2016-11-01 ’663 Patent Issue Date
2017-10-16 ’508 Patent Priority Date
2018-01-16 ’888 Patent Priority Date
2018-02-06 ’054 Patent Issue Date
2020-07-07 ’508 Patent Issue Date
2020-12-01 ’888 Patent Issue Date
2022-02-14 Defendants' ANDA Submission Date (approx.)
2022-04-18 Defendants' Paragraph IV Notice Letter Date
2023-01-03 RE353 Patent Issue Date
2023-10-18 First Amended 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 advanced prostate cancer often becomes "hormone refractory," where the cancer progresses despite treatments that lower androgen levels. A key mechanism for this resistance is the overexpression of the Androgen Receptor (AR), which can cause first-generation anti-androgen drugs like bicalutamide to paradoxically act as agonists, thereby promoting rather than inhibiting cancer growth (’507 Patent, col. 1:15-46).
  • The Patented Solution: The invention provides a new class of non-steroidal androgen receptor modulators designed to be potent antagonists with minimal or no agonist activity, even in cancer cells that overexpress the AR. The core of the invention is the specific chemical structure of the compound that became known as apalutamide, which is designed to effectively inhibit AR function and overcome treatment resistance (’507 Patent, Abstract; col. 2:20-27).
  • Technical Importance: This technology provided a second-generation anti-androgen capable of treating castration-resistant prostate cancer (CRPC) that had progressed on earlier therapies, addressing a critical unmet need in oncology (’507 Patent, col. 1:47-51).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 2, and 3, along with dependent claims 11, 19, and 22 (Compl. ¶69).
  • Independent Claim 1: A compound according to a specific chemical structure (Formula II), which covers the apalutamide molecule.
  • Independent Claim 2: A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or adjuvant.
  • Independent Claim 3: A method for treating a hyperproliferative disorder in a subject, said method comprising administering a compound of claim 1 to the subject.

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 drug, its solid-state physical properties must be well-characterized and controlled. Different crystalline forms, or polymorphs, of the same compound can have different stabilities, solubilities, and dissolution rates, which directly impacts the drug's manufacturing, formulation, and clinical performance (’663 Patent, col. 1:44-58).
  • The Patented Solution: The patent discloses the discovery and characterization of specific crystalline forms of apalutamide, including the polymorph designated "Form B." This form is defined by its unique X-Ray Powder Diffraction (XRPD) pattern, which provides a distinct structural fingerprint, ensuring consistency and predictability for pharmaceutical use (’663 Patent, Abstract; col. 2:25-34). The XRPD pattern for Form B is depicted in the patent’s FIG. 2, which is referenced in the complaint as a basis for infringement allegations (Compl. ¶90).
  • Technical Importance: Identifying a stable and reproducible crystalline form is a critical step in drug development that enables consistent manufacturing of the active pharmaceutical ingredient and reliable performance of the final drug product (’663 Patent, col. 1:59-63).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 13, and 17 (Compl. ¶88).
  • Independent Claim 1: Crystalline Form B of [apalutamide] that is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2.
  • Independent Claim 13: A pharmaceutical composition comprising apalutamide and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients, in which the apalutamide in the composition comprises the crystalline Form B of claim 1.
  • Independent Claim 17: A method of treating prostate cancer in a mammal comprising administering to said mammal a pharmaceutical composition of claim 13.

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

Technology Synopsis

This patent addresses the specific medical need of patients with non-metastatic castration-resistant prostate cancer (NM-CRPC). It claims a method of treating this patient population by orally administering apalutamide at a dose of about 240 mg per day (’054 Patent, Abstract).

Asserted Claims

Claims 6 and 15 are asserted; claim 6 is independent (Compl. ¶107).

Accused Features

The complaint alleges that Defendants' proposed generic product will be labeled for and used by physicians to treat NM-CRPC at the claimed daily dose, thereby inducing infringement of the method claims (Compl. ¶108).

U.S. Reissue Patent No. RE49,353 - "Anti-androgens for the Treatment of Non-metastatic Castrate-resistant Prostate Cancer"

Technology Synopsis

As a reissue of a prior patent, this patent refines the method of treating NM-CRPC with apalutamide by additionally requiring the concurrent administration of a gonadotropin releasing hormone (GnRH) agonist. This covers the common clinical practice of combination therapy for maintaining chemical castration (’RE353 Patent, Abstract).

Asserted Claims

Claims 1 and 19 are asserted; claim 1 is independent (Compl. ¶122).

Accused Features

The complaint alleges that physicians will prescribe the accused product for use in combination with GnRH agonists as part of the standard of care, thereby inducing infringement (Compl. ¶123).

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

Technology Synopsis

This patent claims a method for achieving a specific, positive clinical outcome: improving metastasis-free survival (MFS) in NM-CRPC patients. The claim is tied to the quantitative result observed in clinical trials, specifying that administration of apalutamide in combination with androgen deprivation therapy results in a median MFS of about 40.5 months (’508 Patent, Abstract). The complaint references the clinical trial data that underlies this claim, which is graphically depicted in the ’508 Patent's FIG. 3 (Compl. ¶138).

Asserted Claims

Claims 1, 2, 5, and 7 are asserted; claim 1 is independent (Compl. ¶137).

Accused Features

The complaint alleges that the proposed product will be prescribed to achieve improved MFS and that its label will include the MFS data, thereby inducing infringement (Compl. ¶¶ 138, 140).

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

Technology Synopsis

This patent covers a method of treating NM-CRPC with apalutamide where the patient has undergone an orchiectomy (surgical castration). This method is an alternative to the use of GnRH agonists for androgen deprivation therapy (’888 Patent, Abstract).

Asserted Claims

Claims 1 and 8 are asserted; claim 1 is independent (Compl. ¶154).

Accused Features

The complaint alleges that the accused product will be prescribed to patients who have had an orchiectomy, which will induce infringement of the claimed method (Compl. ¶155).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendants’ "Proposed ANDA Product," identified as "Apalutamide Tablets; Oral 60 mg" (Compl. ¶¶ 2, 49). This product is a proposed generic version of Plaintiffs' branded drug, Erleada® (Compl. ¶2).

Functionality and Market Context

The Proposed ANDA Product is a tablet for oral administration containing the active pharmaceutical ingredient apalutamide (Compl. ¶¶ 39-40, 71). The product is intended for the treatment of non-metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer (Compl. ¶39). The lawsuit arises from Defendants' submission of Abbreviated New Drug Application No. 217185 to the FDA, which is a statutory act of infringement under 35 U.S.C. § 271(e)(2) intended to facilitate the resolution of patent disputes before the commercial launch of a generic drug (Compl. ¶¶ 2, 9).

IV. Analysis of Infringement Allegations

U.S. Patent No. 8,445,507 Infringement Allegations

Claim Element (from Independent Claims 1, 2, 3) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of claim 1. The Proposed ANDA Product contains the compound apalutamide. ¶71 col. 12:46-67
A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or adjuvant. The Proposed ANDA Product is a pharmaceutical composition formulated as a tablet, which comprises apalutamide and pharmaceutically acceptable excipients. ¶72 col. 25:6-10
A method for treating a hyperproliferative disorder...said method comprising administering...a compound of claim 1. The Proposed ANDA Product will be used by physicians and patients to treat prostate cancer, a hyperproliferative disorder. ¶73 col. 23:21-25

U.S. Patent No. 9,481,663 Infringement Allegations

Claim Element (from Independent Claims 1, 13, 17) Alleged Infringing Functionality Complaint Citation Patent Citation
Crystalline Form B of [apalutamide] that is characterized as having an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2... The Proposed ANDA Product contains crystalline Form B of apalutamide characterized by an XRPD pattern as shown in FIG. 2 of the patent or by specific characteristic peaks. ¶90 col. 2:25-34
A pharmaceutical composition comprising apalutamide and at least one additional ingredient...in which the apalutamide in the composition comprises the crystalline Form B of claim 1. The Proposed ANDA Product is a pharmaceutical composition that comprises crystalline Form B of apalutamide along with other ingredients. ¶91 col. 21:13-17
A method of treating prostate cancer in a mammal...comprising administering...a pharmaceutical composition of claim 13... The Proposed ANDA Product, a composition containing crystalline Form B, will be administered by physicians and patients to treat prostate cancer. ¶92 col. 21:51-57

Identified Points of Contention

  • Scope Questions: For the method-of-use patents (’054, ’RE353, ’508, ’888), a central question may be whether the instructions and intended uses on the Defendants' proposed product label will be found to actively encourage physicians to perform each and every step of the claimed methods, thereby satisfying the requirements for induced infringement.
  • Technical Questions: A primary technical dispute is explicitly identified for the ’663 Patent. Defendants' notice letter stated that the Proposed ANDA Product "will not literally infringe the claims of the 663 Patent because the Proposed ANDA Product 'is not the claimed polymorphic form'" (Compl. ¶52). This raises the evidentiary question of whether the crystalline form of apalutamide in the accused product is, in fact, "crystalline Form B" as defined by the claim, either literally or under the doctrine of equivalents. The complaint's allegation that the product contains "some amount" of Form B may suggest a potential dispute over issues of polymorphic purity or the presence of mixed forms (Compl. ¶89).

V. Key Claim Terms for Construction

The Term

"substantially the same as shown in FIG. 2" (’663 Patent, claim 1)

Context and Importance

The construction of this term is central to the infringement analysis of the ’663 Patent. Defendants have asserted that their product is not the "claimed polymorphic form" (Compl. ¶52). The dispute will therefore focus on how much deviation, if any, is permitted between the XRPD pattern of the accused product and the pattern shown in the patent's FIG. 2 while still falling within the scope of the claim.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The use of the word "substantially" inherently suggests that the claim is not limited to an exact, identical match. The specification may note that XRPD patterns can exhibit variations due to factors like "particle size [or] preferred orientation," which could support construing "substantially the same" to cover patterns with minor, scientifically understood differences (’663 Patent, col. 22:5-15).
  • Evidence for a Narrower Interpretation: The patent provides an alternative definition for Form B by listing specific characteristic peaks with precise numerical ranges (e.g., "12.1±0.1° 2-Theta") (’663 Patent, col. 2:30-34). A party could argue that "substantially the same as shown in FIG. 2" should be interpreted narrowly to mean a pattern that, at a minimum, includes these specifically enumerated peaks, rather than one that just bears a general resemblance to the figure.

VI. Other Allegations

Indirect Infringement

The complaint alleges inducement of infringement for all six asserted patents. The factual basis for these allegations is that Defendants' product, upon approval, will be sold with a label and instructions that will cause physicians and patients to administer the drug in a manner that directly infringes the various method claims (e.g., for treating NM-CRPC, in combination with GnRH agonists, or to achieve improved metastasis-free survival) (Compl. ¶¶ 74, 93, 109, 124, 139, 156). The complaint also alleges contributory infringement, stating the Proposed ANDA Product is not a staple article suitable for substantial non-infringing use (Compl. ¶¶ 75, 94, 110, 125, 142, 157).

Willful Infringement

While the complaint does not contain a formal count for willful infringement, it lays a factual predicate by alleging that Defendants have had "actual knowledge" of the patents-in-suit. This knowledge is alleged to arise from the patents' listing in the FDA's Orange Book and from the Paragraph IV notice letters that Defendants themselves sent to the Plaintiffs (Compl. ¶¶ 48, 65, 77, 96, 112, 127, 144, 159).

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

  • A core issue will be one of physical characterization: does the crystalline form of apalutamide in Defendants' proposed generic product fall within the scope of the claims covering "Form B" in the ’663 patent? This will likely involve a detailed factual analysis of competing expert testimony and XRPD data to determine if the accused product is "substantially the same as" the patented form.
  • A second key question will be one of induced infringement: for the five asserted method-of-use patents, will the language on the Defendants' proposed product label be found to provide specific instructions or encouragement for physicians and patients to perform all the steps of the claimed methods, thereby establishing the requisite intent for inducement?
  • A third question concerns the scope of the compound claims: given the number of patents covering different facets of the same drug (the compound, a specific crystal form, and multiple methods of use), the case will test the extent to which a patent portfolio can create overlapping layers of protection around a single successful therapeutic product, potentially raising questions about obviousness-type double patenting that may be explored later in the litigation.