Cycle Pharma Ltd v. Dipharma SA

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Cycle Pharmaceuticals LTD (United Kingdom) and Cycle Pharmaceuticals Inc. (Delaware)
  • Defendant: DiPharma S.A. (Switzerland)
  • Plaintiff’s Counsel: DLA Piper LLP
• Case Identification: 1:19-cv-11856, D. Mass., 08/30/2019
• Venue Allegations: Venue is alleged to be proper in the District of Massachusetts because the plaintiff's U.S. headquarters and sales efforts are centralized in Boston.
• Core Dispute: Plaintiff seeks a declaratory judgment that its Nityr® drug product does not infringe Defendant's patents related to a specific crystalline form of the active ingredient nitisinone, and further alleges that Defendant's patents are invalid and unenforceable due to inequitable conduct.
• Technical Context: The case centers on pharmaceutical polymorphism, where a single active pharmaceutical ingredient (API) can exist in different solid-state crystalline forms, potentially affecting drug stability and other properties.
• Key Procedural History: The complaint alleges that this declaratory judgment action was precipitated by Defendant's threats to sue Plaintiff for patent infringement. Plaintiff alleges that Defendant obtained the patents-in-suit by withholding material prior art from the U.S. Patent and Trademark Office and misrepresenting its claimed crystalline form as novel, when it was allegedly identical to the long-known form of nitisinone.

Case Timeline

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

U.S. Patent No. 9,783,485 - "CRYSTALLINE INHIBITOR OF 4-HYDROXYPHENYLPYRUVATE DIOXYGENASE, AND A PROCESS OF SYNTHESIS AND CRYSTALLIZATION THEREOF," issued October 10, 2017

The Invention Explained

• Problem Addressed: The patent's background section identifies the chemical instability of the existing commercial nitisinone formulation, Orfadin®, which requires refrigeration and has a limited 18-month shelf life ('485' Patent, col. 2:30-40). The patent suggests this instability may be attributable to the active pharmaceutical ingredient (API) itself ('485' Patent, col. 2:44-47).
• The Patented Solution: The patent claims to disclose an improved synthesis and crystallization process that produces a "highly pure and stable" form of nitisinone, which it designates "crystalline Form A" ('485' Patent, col. 2:49-52). This form is characterized by a specific X-ray powder diffraction (XRPD) pattern, which provides a structural fingerprint of the crystal lattice ('485' Patent, col. 5:40-51). The complaint includes a diagram of the nitisinone chemical structure, which is the molecule at the center of the dispute (Compl. ¶8).
• Technical Importance: Developing a room-temperature-stable form of a previously refrigerated drug can significantly improve patient logistics, reduce distribution costs, and enhance compliance ('485' Patent, col. 2:37-43).

Key Claims at a Glance

• The complaint identifies independent claims 1 (process), 4 (composition), 11 (product-by-process), and 12 (pharmaceutical composition) as being at issue (Compl. ¶35).
• Independent Claim 4: A composition claim for:
  • 2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione crystalline Form A
  • which has an X-ray powder diffraction pattern with at least five specific peaks at about 2-theta=7.4, 14.7, 15.7, 22.9, and 29.7
  • wherein said values may be plus or minus 0.2° 2-theta and have an intensity of at least 30%
• Independent Claim 12: A claim for a pharmaceutical composition comprising the crystalline form of claim 4.

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U.S. Patent No. 10,093,610 - "CRYSTALLINE INHIBITOR OF 4-HYDROXYPHENYLPYRUVATE DIOXYGENASE," issued October 9, 2018

The Invention Explained

• Problem Addressed: The '610' Patent is a divisional of the application that led to the '485' Patent and shares an identical specification (Compl. ¶34). It therefore addresses the same problem of the alleged instability of prior art nitisinone formulations ('610' Patent, col. 2:30-40).
• The Patented Solution: The patent claims methods of using the "crystalline Form A" of nitisinone, as described in the shared specification, to treat various medical conditions by inhibiting the 4-hydroxyphenylpyruvate dioxygenase (HPPD) enzyme ('610' Patent, col. 7:1-10). The core technical assertion is the use of the purportedly novel and stable crystalline form for therapy.
• Technical Importance: The claimed methods target diseases like hereditary tyrosinemia type 1 (HT-1), where inhibiting the HPPD enzyme is the established mechanism of therapeutic action ('610' Patent, col. 2:18-34).

Key Claims at a Glance

• The complaint identifies independent claims 1, 6, and 10 as being at issue (Compl. ¶36).
• Independent Claim 1: A method of inhibiting the HPPD enzyme in a patient, comprising:
  • administering to a patient in need thereof a therapeutically effective amount of crystalline 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione
  • having an X-ray powder diffraction pattern with at least five specific peaks as defined in claim 4 of the '485' Patent.
• Independent Claim 6: A method of treating specific diseases, including HT-1, by administering the crystalline nitisinone defined in Claim 1.

III. The Accused Instrumentality

• Product Identification: The Plaintiff’s Nityr® tablets, containing 2 mg, 5 mg, or 10 mg of nitisinone (Compl. ¶24).
• Functionality and Market Context: Nityr® is a pharmaceutical product approved by the FDA for the treatment of hereditary tyrosinemia type 1 (HT-1) (Compl. ¶24). The complaint alleges that, unlike the prior art Orfadin® product which requires refrigeration, Nityr® tablets are stable and may be stored at room temperature (Compl. ¶25). Plaintiff's central contention is that the nitisinone API in Nityr® is the same single, stable solid-state form that has been known since the 1990s and was used in Orfadin®, and is not a new crystalline form (Compl. ¶¶ 29-32, 39). The complaint depicts the chemical structure of nitisinone, which is the active ingredient in Nityr® (Compl. ¶8).

IV. Analysis of Infringement Allegations

This is a declaratory judgment action where the Plaintiff (Cycle) seeks a judgment of non-infringement. The following table summarizes Cycle's asserted basis for non-infringement with respect to DiPharma's patents.

'485' Patent Infringement Allegations

'610' Patent Infringement Allegations

• Identified Points of Contention:
  • Factual Question: The central dispute is factual: is the nitisinone API in Plaintiff's Nityr® product, and in the prior art Orfadin® product, structurally identical to the "crystalline Form A" claimed in the '485' and '610' Patents? The complaint alleges they are the same (Compl. ¶¶ 39, 55).
  • Scope Question: Does the term "crystalline Form A" as defined by the XRPD peaks in the patent claims read on the single solid-state form of nitisinone that Plaintiff alleges was already known and in public use?

V. Key Claim Terms for Construction

• The Term: "crystalline Form A"
• Context and Importance: The definition of this term is dispositive. The entire case for both invalidity and non-infringement hinges on whether "crystalline Form A" is a genuinely new polymorph distinct from the prior art form of nitisinone. Practitioners may focus on this term because if it is not novel, the patents may be invalid under 35 U.S.C. §§ 101/102.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The complaint does not present evidence for a broader interpretation. A patentee in this position might argue that the term should be understood to cover any nitisinone meeting the specific XRPD and stability characteristics taught, regardless of minor process variations.
  • Evidence for a Narrower Interpretation: The patents explicitly define "crystalline Form A" by a set of at least five specific peaks in an X-ray powder diffraction pattern ('485' Patent, col. 5:40-51). The abstract and specification repeatedly frame the invention as a "highly pure and stable" product resulting from a specific crystallization process ('485' Patent, Abstract; col. 4:20-22). The complaint argues that this definition is not actually narrow, as it allegedly describes the very same form that was already known and believed to be the only stable form (Compl. ¶¶ 29-32).

VI. Other Allegations

• Indirect Infringement: While not explicitly detailed, the nature of the '610' Patent (a method of use patent) suggests that Defendant's threatened infringement action would include a claim for induced infringement. The complaint alleges that Defendant accused the "approved use" of Nityr® of infringement, which would imply that Plaintiff's labeling and instructions induce physicians and patients to infringe the method claims (Compl. ¶41).
• Willful Infringement: The complaint states that Defendant sent a letter on November 16, 2017, providing notice of the '485' Patent and later threatened to sue (Compl. ¶¶ 40, 42). This alleged pre-suit knowledge would likely form the basis of a willfulness claim by Defendant against Plaintiff.
• Inequitable Conduct: Plaintiff lodges a significant charge of inequitable conduct against Defendant (Compl. ¶¶ 49-63, 72-74). The complaint alleges that Defendant's inventors and prosecutors, with intent to deceive, withheld material information from the PTO, such as prior art regulatory filings stating that nitisinone "does not show polymorphism" (Compl. ¶¶ 30, 52). It further alleges they made material misrepresentations by characterizing "Form A" as a "new crystalline form" when they knew or should have known it was the same as the prior art form (Compl. ¶61).

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

• A core issue will be one of novelty and identity: Is the patented "crystalline Form A" a distinct and novel polymorph of nitisinone, or is it, as the complaint alleges, factually and structurally identical to the single, stable crystalline form known to the prior art? The resolution of this scientific question through competing expert testimony and analytical data (like XRPD) will be paramount.
• A second critical issue will be one of prosecutorial conduct: Did the patentee, as the complaint alleges, breach its duty of candor to the PTO by failing to disclose known prior art that contradicted its assertions of novelty and stability, and did it do so with an intent to deceive? The court's determination on these questions of materiality and intent will decide the potent defense of inequitable conduct.