DCT

1:22-cv-00678

Aragon Pharma Inc v. Sandoz Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-00678, D. Del., 05/24/2022
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because the defendant, Sandoz Inc., is a Delaware corporation and therefore resides in the judicial district.
  • Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of the prostate cancer drug Erleada® infringes five patents related to the active ingredient apalutamide, its specific crystalline forms, pharmaceutical compositions, and methods of use.
  • Technical Context: The technology lies in the field of oncology therapeutics, specifically small-molecule androgen receptor modulators designed to treat both hormone-sensitive and hormone-refractory prostate cancer.
  • Key Procedural History: The action was initiated under the Hatch-Waxman Act following Defendant’s April 13, 2022 Notice Letter, which informed Plaintiffs of its ANDA submission containing a Paragraph IV certification of non-infringement, invalidity, or unenforceability for the patents-in-suit. The complaint notes Defendant’s specific non-infringement position for one patent is that its product does not contain "crystalline Form B" of apalutamide, a position Plaintiffs contest on information and belief.

Case Timeline

Date Event
2006-03-27 Earliest Priority Date for ’507, ’689, ’159, ’261 Patents
2012-06-07 Earliest Priority Date for ’663 Patent
2013-05-21 ’507 Patent Issued
2014-08-12 ’689 Patent Issued
2016-07-12 ’159 Patent Issued
2016-11-01 ’663 Patent Issued
2018-06-05 ’261 Patent Issued
2022-04-13 Defendant's ANDA Notice Letter Date
2022-05-24 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"

  • Patent Identification: U.S. Patent No. 8,445,507, "Androgen Receptor Modulator for the Treatment of Prostate Cancer and Androgen Receptor-Associated Diseases," issued May 21, 2013.

The Invention Explained

  • Problem Addressed: The patent’s background section describes the clinical challenge of hormone-refractory prostate cancer (HRPC), where standard anti-androgen therapies fail. It identifies a key mechanism for this failure: the overexpression of the androgen receptor (AR), which can convert existing anti-androgen drugs from antagonists (inhibitors) into agonists (stimulators), thereby promoting cancer growth (’507 Patent, col. 1:26-44).
  • The Patented Solution: The invention provides a class of non-steroidal thiohydantoin compounds designed to be potent AR antagonists that retain their inhibitory activity, with minimal agonistic effects, even when the AR is overexpressed. The compound apalutamide (disclosed as compound A52) is an exemplary embodiment intended to overcome the limitations of prior anti-androgens and effectively treat both early-stage and advanced, hormone-refractory prostate cancer (’507 Patent, col. 2:5-13, col. 13:15-25).
  • Technical Importance: This technology represents a second-generation approach to androgen receptor inhibition, aiming to create a more durable and effective treatment for advanced prostate cancer that is less susceptible to the common resistance mechanism of AR overexpression (’507 Patent, col. 1:56-62).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 3, 11, and 22, along with dependent claims 2 and 19 (Compl. ¶43).
  • Claim 1: A compound having the specific chemical structure of apalutamide, or a pharmaceutically acceptable salt thereof.
  • Claim 3: A method for treating prostate cancer in a subject by administering a compound of claim 1.
  • Claim 11: A pharmaceutical composition comprising the compound of claim 2, where the compound is specified as having the structure of apalutamide.
  • Claim 22: The compound of claim 1, wherein the compound has the specific chemical structure of apalutamide.

U.S. Patent No. 8,802,689 - "Androgen Receptor Modulator for the Treatment of Prostate Cancer and Androgen Receptor-Associated Diseases"

  • Patent Identification: U.S. Patent No. 8,802,689, "Androgen Receptor Modulator for the Treatment of Prostate Cancer and Androgen Receptor-Associated Diseases," issued August 12, 2014.

The Invention Explained

  • Problem Addressed: This patent, a continuation of the application leading to the ’507 Patent, addresses the same problem: the progression of prostate cancer to a hormone-refractory state where existing anti-androgens become ineffective or even agonistic due to Androgen Receptor (AR) overexpression (’689 Patent, col. 1:55-65).
  • The Patented Solution: The patent claims methods of treating prostate cancer by administering the same class of thiohydantoin compounds, specifically apalutamide, which were developed to function as pure AR antagonists without the agonist activity that plagues earlier drugs in the context of AR overexpression (’689 Patent, Abstract; col. 2:10-19).
  • Technical Importance: By claiming a method of treatment, this patent provides a distinct layer of protection for the use of the apalutamide compound specifically for treating prostate cancer, complementing the compound protection of the parent ’507 Patent (’689 Patent, col. 1:15-18).

Key Claims at a Glance

  • The complaint asserts "at least claim 2," which is dependent on independent claim 1 (Compl. ¶62).
  • Claim 1: A method for treating prostate cancer in a subject comprising administering to the subject a compound having the specific chemical structure of apalutamide.
  • Claim 2 (dependent): The method of claim 1, wherein the subject is a patient in need of such treatment.

U.S. Patent No. 9,388,159 - "Substituted Diazaspiroalkanes as Androgen Receptor Modulators"

  • Patent Identification: U.S. Patent No. 9,388,159, "Substituted Diazaspiroalkanes as Androgen Receptor Modulators," issued July 12, 2016.
  • Technology Synopsis: This patent, also in the same family, claims diazaspiroalkane compounds, including apalutamide, that modulate the androgen receptor. The invention is directed at treating androgen receptor-associated conditions like prostate cancer by providing compounds that overcome the agonist-switching problem of prior anti-androgens in hormone-refractory disease (’159 Patent, Abstract; col. 2:1-17).
  • Asserted Claims: Independent claims 1 (compound), 12 (composition), and 17 (composition) (Compl. ¶79).
  • Accused Features: The complaint alleges that Defendant's Proposed ANDA Product contains apalutamide and constitutes a pharmaceutical composition formulated for oral administration, thereby infringing the asserted claims (Compl. ¶¶81-82).

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

  • Patent Identification: U.S. Patent No. 9,481,663, "Crystalline Forms of an Androgen Receptor Modulator," issued November 1, 2016.
  • Technology Synopsis: This patent moves beyond the chemical entity to protect specific solid-state forms of apalutamide. The invention addresses the technical challenge of developing a stable and consistent active pharmaceutical ingredient for formulation by claiming specific crystalline polymorphs, particularly "Form B," which is defined by a unique X-ray powder diffraction (XRPD) pattern (’663 Patent, Abstract; col. 2:4-10).
  • Asserted Claims: Independent claims 1 (crystalline Form B), 13 (composition containing Form B), and 17 (method of use) (Compl. ¶96).
  • Accused Features: The complaint alleges, on information and belief, that the Defendant's Proposed ANDA Product and its drug substance contain "some amount" of the claimed crystalline Form B, identifiable by its characteristic XRPD peaks (Compl. ¶¶97-98).

U.S. Patent No. 9,987,261 - "Substituted Diazaspiroalkanes as Androgen Receptor Modulators"

  • Patent Identification: U.S. Patent No. 9,987,261, "Substituted Diazaspiroalkanes as Androgen Receptor Modulators," issued June 5, 2018.
  • Technology Synopsis: This patent protects specific pharmaceutical formulations of apalutamide. The invention claims tablets comprising the compound within a specified dosage range, providing protection for the final drug product as formulated for patient administration (’261 Patent, Abstract; col. 2:45-51).
  • Asserted Claims: Independent claims 8, 10, and 12 (all relating to tablets) (Compl. ¶115).
  • Accused Features: The complaint alleges that Defendant's product is a tablet comprising apalutamide in a dosage range covered by the claims, along with a pharmaceutically acceptable carrier (Compl. ¶117).

III. The Accused Instrumentality

Product Identification

  • Defendant Sandoz Inc.’s proposed generic drug product submitted to the FDA under ANDA No. 216431 (Compl. ¶2).

Functionality and Market Context

  • The accused product is identified as "Apalutamide Tablets, 60 mg," a generic version of the branded drug Erleada® (Compl. ¶¶2, 30). The filing of the ANDA signifies Defendant's intent to manufacture and sell this product for the same indications as Erleada®, namely the treatment of non-metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer, prior to the expiration of the patents-in-suit (Compl. ¶¶2, 21). The product's active pharmaceutical ingredient is apalutamide, a small-molecule androgen receptor modulator (Compl. ¶¶21-22).
  • No probative visual evidence provided in complaint.

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: [structure of apalutamide is shown]. The Proposed ANDA Product contains apalutamide. ¶45 col. 13:15-25
or a pharmaceutically acceptable salt thereof. The complaint does not provide sufficient detail for analysis of this element. ¶45 col. 16:15-18

’689 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating prostate cancer in a subject The Proposed ANDA Product is intended for the treatment of prostate cancer. ¶64 col. 1:15-18
comprising administering to the subject a compound of formula: [structure of apalutamide is shown]. The Proposed ANDA Product contains apalutamide and will be administered to patients for treating prostate cancer. ¶64 col. 24:39-44

Identified Points of Contention

  • Factual Dispute (Polymorph Presence): A primary point of contention, explicitly raised in the complaint, concerns the ’663 Patent. Defendant's Notice Letter allegedly asserts that its product will not infringe because it does not contain crystalline Form B of apalutamide (Compl. ¶34). Plaintiffs counter this by alleging, on information and belief, that the product does contain "some amount" of Form B (Compl. ¶97). This sets up a central factual dispute that may depend on the sensitivity of analytical techniques (e.g., XRPD) to detect the presence of the claimed polymorph, potentially in a mixture of forms.
  • Scope Questions (Claim Construction): For the ’663 Patent, the interpretation of terms such as "substantially the same as shown in FIG. 2" and the tolerance of the enumerated "characteristic peaks" (e.g., 12.1±0.1° 2-Theta) may become a key claim construction issue to determine the scope of protection for Form B (’663 Patent, col. 39:7-21).
  • Legal Dispute (Validity): The complaint notes that Defendant’s ANDA includes a Paragraph IV Certification that the patents-in-suit are "invalid, unenforceable, or not infringed" (Compl. ¶33). While the complaint does not detail Defendant's invalidity arguments, this certification indicates that a primary defense against the compound, composition, and method-of-use claims will be challenges to their patentability, likely on grounds such as obviousness or lack of enablement.

V. Key Claim Terms for Construction

  • The Term: "crystalline Form B of apalutamide that is characterized as having at least one of an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2...or an X-ray powder diffraction (XRPD) pattern with characteristic peaks at [specific 2-Theta values]" (from Claim 1 of the ’663 Patent).
  • Context and Importance: The infringement analysis for the ’663 patent will turn entirely on the meaning of this term. As Defendant has asserted its product does not contain Form B, the scope afforded to this definition will be critical. Practitioners may focus on this term because its construction will determine whether minor variations in the accused product's XRPD pattern from the patent's reference standard constitute infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: Plaintiffs may argue that the use of the term "substantially" and the disjunctive "or" between the graphical pattern and the list of peaks indicates that the claims are not limited to an exact replica of the XRPD pattern in FIG. 2. They may point to specification language acknowledging potential variability in XRPD measurements to argue for a broader scope that covers patterns with minor shifts or differences in peak intensity.
    • Evidence for a Narrower Interpretation: Defendant may argue that the patent provides a very specific definition of Form B by listing characteristic peaks to a precision of ±0.1° 2-Theta. This explicit recitation could be used to argue that "substantially the same" must be interpreted narrowly and that any product whose XRPD pattern deviates meaningfully from these precise peaks does not infringe.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced and contributory infringement for all asserted method-of-use claims. The basis for these allegations is that Defendant, by filing an ANDA for a generic version of Erleada®, intends for its product to be used to treat prostate cancer and will market it with a label instructing physicians and patients to perform the patented methods of treatment (Compl. ¶¶48, 65, 101).
  • Willful Infringement: The complaint does not contain an explicit count for willful infringement. It does, however, allege that Defendant has "actual knowledge" of the patents-in-suit, as evidenced by its Paragraph IV certification and Notice Letter (Compl. ¶¶51, 68, 85, 104, 120). The prayer for relief requests a declaration that the case is "exceptional" under 35 U.S.C. § 285, which could provide a basis for an award of attorney fees (Compl. p. 23).

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

  • A central evidentiary question will be one of polymorphic identity: Does Sandoz's proposed generic product contain "crystalline Form B" of apalutamide as defined in the ’663 patent? The resolution of this issue will likely depend on sophisticated analytical testing and expert testimony regarding the interpretation of techniques like X-ray powder diffraction.
  • The primary legal question will be one of patent validity: Are the claims covering the apalutamide compound, its specific crystalline form, various pharmaceutical compositions, and its methods of use valid over the prior art? This question, raised by Defendant's Paragraph IV certification, will be the main line of defense against infringement allegations for at least four of the five patents-in-suit.
  • A key issue of definitional scope will concern the ’663 patent: How broadly will the court construe the term "substantially the same" in the context of an XRPD pattern? This determination will define the literal scope of the polymorph claims and dictate how much variation from the patent's reference standard is permissible for a finding of infringement.