DCT

2:14-cv-00980

Spectrum Pharma Inc v. EuroHealth Intl SARL

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:14-cv-00980, D. Nev., 06/18/2014
  • Venue Allegations: Venue is alleged to be proper in the District of Nevada because the Defendant conducts business in the state, including holding a license from the Nevada Board of Pharmacy to act as a pharmaceutical wholesaler and distributing drug products throughout Nevada.
  • Core Dispute: Plaintiffs allege that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic levoleucovorin product constitutes an act of infringement of a patent covering a highly purified pharmaceutical composition of the drug.
  • Technical Context: The lawsuit concerns pharmaceutical formulations of levoleucovorin, a drug used in cancer therapy, with the central issue relating to the claimed purity level of a specific stereoisomer of the active molecule.
  • Key Procedural History: The patent-in-suit is listed in the FDA's "Orange Book" in connection with Plaintiff Spectrum's commercial product, Fusilev®. Defendant provided Plaintiffs with a notice letter containing a Paragraph IV certification, asserting that its proposed generic product would not infringe the patent or that the patent is invalid. This lawsuit was filed under the Hatch-Waxman Act within the 45-day statutory period following that notice, which may trigger a 30-month stay on the FDA’s approval of the defendant's generic product.

Case Timeline

Date Event
1986-09-03 '829 Patent Priority Date
2002-12-31 '829 Patent Issue Date
2008-03-07 Plaintiff's Fusilev® New Drug Application (NDA) Approved
2011-11-07 Fusilev® Granted Orphan-Drug Exclusivity for a Specific Use
2014-06-11 Plaintiff Received Defendant's Paragraph IV Notification (approx.)
2014-06-18 Complaint Filing Date
2022-03-07 Alleged '829 Patent Expiration Date

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

U.S. Patent No. 6,500,829 - Substantially Pure Diastereoisomers of Tetrahydrofolate Derivatives, issued December 31, 2002

The Invention Explained

  • Problem Addressed: The patent's background explains that leucovorin, a drug used as a "rescue agent" to mitigate the toxicity of methotrexate cancer therapy, was commercially available as a 50/50 mixture of two distinct molecular forms, known as the (6S) and (6R) diastereoisomers (’829 Patent, col. 1:30-36). The patent asserts that only the "natural" (6S) diastereoisomer provides the desired therapeutic effect, while the "non-natural" (6R) isomer is not only ineffective but may also be harmful by inhibiting DNA biosynthesis (’829 Patent, col. 1:59-col. 2:11). Existing methods for separating these isomers were described as having low yields or being difficult to perform (’829 Patent, col. 2:12-23).
  • The Patented Solution: The invention claims a pharmaceutical composition containing a "substantially pure" form of the beneficial (6S) isomer. The patent specification describes a process to achieve this purity by attaching a "chiral auxiliary group" to the mixed isomers, which creates a new pair of molecules that are more easily separated (e.g., via butanol extraction, as depicted in FIG. 4), and then removing the auxiliary group to yield the purified final product (’829 Patent, Abstract; col. 2:49-60).
  • Technical Importance: The technology addressed a stated clinical need for a leucovorin formulation that maximized the concentration of the therapeutically active (6S) isomer while minimizing the presence of the potentially detrimental (6R) isomer (’829 Patent, col. 2:9-11).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claim 2 (Compl. ¶22).
  • The essential elements of independent claim 1 are:
    • A pharmaceutical composition for therapeutic use for methotrexate rescue or folate deficiency.
    • The composition "consists essentially of" a therapeutically effective amount of a (6S) diastereoisomer of leucovorin (or its salts/esters).
    • The compound comprises a mixture of (6S) and (6R) isomers and "consists of at least 92% by weight of the (6S) diastereoisomer".
    • The compound is in combination with a pharmaceutically acceptable carrier.
  • The complaint reserves the right to assert additional claims of the '829 Patent (Compl. ¶24).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is "Ben Venue's Product," identified as "levoleucovorin calcium for injection, 50 mg/vial," which is the subject of Abbreviated New Drug Application (ANDA) No. 206263 submitted to the FDA (Compl. ¶15).

Functionality and Market Context

  • The product is a generic version of the Plaintiffs' Fusilev® pharmaceutical product (Compl. ¶1, ¶10). By filing the ANDA, Defendant Ben Venue has represented to the FDA that its product has the same active ingredient, route of administration, dosage form, and strength as Fusilev®, and that it is bioequivalent (Compl. ¶17). The product is intended for therapeutic uses that include combination chemotherapy in the palliative treatment of advanced metastatic adenocarcinoma of the colon and rectum (Compl. ¶13). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

'829 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition for therapeutic use which consists essentially of a therapeutically effective amount sufficient for the treatment of human beings for methotrexate rescue or folate deficiency, Defendant's ANDA seeks approval to market a generic version of Fusilev®, which is used for the claimed therapeutic purposes. The proposed product labeling is alleged to instruct for these uses. ¶17, ¶24 col. 1:49-59
of a pharmaceutically acceptable compound which is a (6S) diastereoisomer selected from the group consisting of (6S) leucovorin (5-formyl-(6S)-tetrahydrofolic acid) and pharmaceutically acceptable salts and esters of (6S) leucovorin; Defendant's product is identified as "levoleucovorin calcium for injection," which is a pharmaceutically acceptable salt of (6S) leucovorin. The ANDA represents that the product has the same active ingredient as Fusilev®. ¶15, ¶17 col. 10:59-62
wherein the compound consists of a mixture of (6S) and (6R) diastereoisomers and consists of at least 92% by weight of the (6S) diastereoisomer, the balance of said compound consisting of the (6R) diastereoisomer; The complaint alleges infringement of claim 1, which contains this purity limitation. By seeking approval for a product that is bioequivalent to Fusilev®, the Defendant's product as described in its ANDA will allegedly meet this requirement. ¶17, ¶21-22 col. 10:62-66
in combination with a pharmaceutically acceptable carrier. The accused product is a lyophilized powder for injection, a formulation which, by its nature, includes pharmaceutically acceptable carriers. ¶15, ¶21 col. 10:66-col. 11:1
  • Identified Points of Contention:
    • Technical Questions: A central factual question is whether the composition described in Ben Venue's confidential ANDA submission meets the "at least 92% by weight of the (6S) diastereoisomer" limitation. The litigation will depend on the technical specifications of the proposed generic product.
    • Scope Questions: The complaint states that Ben Venue's Paragraph IV certification asserts non-infringement (Compl. ¶18). This raises the question of Ben Venue's theory for avoiding the claim language. It may be that Ben Venue argues its product does not meet the 92% purity threshold, or it may advance a claim construction argument, for example regarding the meaning of "consists essentially of," to place its specific formulation outside the claim scope.

V. Key Claim Terms for Construction

  • The Term: "consists essentially of"
    • Context and Importance: This transitional phrase is a term of art that is narrower than "comprising" but broader than "consisting of." The infringement analysis may turn on whether any unlisted ingredients or impurities in the accused generic product "materially affect the basic and novel properties" of the claimed high-purity composition. Practitioners may focus on this term because Defendant could argue that additional excipients in its formulation are material and thus place the product outside the claim's scope.
    • Evidence for a Broader Interpretation: A party could argue that the "basic and novel properties" are simply the therapeutic efficacy of the (6S) isomer for methotrexate rescue, a property not materially affected by standard carriers (Compl. ¶21; ’829 Patent, col. 1:59-col. 2:11).
    • Evidence for a Narrower Interpretation: A party could argue that the term should be interpreted narrowly in light of the specific purification methods disclosed, which yield a particular composition whose properties could be materially affected by other substances not contemplated by the patent (’829 Patent, col. 2:49-60; Example 1).
  • The Term: "at least 92% by weight of the (6S) diastereoisomer"
    • Context and Importance: This limitation defines the core quantitative requirement of the invention. The infringement case will likely hinge on whether the product specified in the ANDA satisfies this numerical threshold.
    • Intrinsic Evidence for Interpretation: The patent specification provides direct antecedent basis for this value. Example 1(ii) and the accompanying FIG. 4 describe a separation process involving butanol extraction that yields a "(6S) diastereoisomer (2nd crop) [92% isomerically pure]" (’829 Patent, Fig. 4). This example provides concrete support for the specific purity level recited in the claim.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that the future commercial manufacture, use, or sale of the product would constitute indirect infringement under 35 U.S.C. §§ 271(b) and (c) (Compl. ¶24). The basis for this allegation is that the proposed labeling for the ANDA product will instruct physicians and patients to use the product for the claimed therapeutic indications, thereby inducing infringement.
  • Willful Infringement: The complaint does not use the term "willful," but it alleges the case is "exceptional" and requests treble damages, which are associated with findings of willful infringement (Compl. ¶27; Request for Relief ¶G). The factual basis for such a claim is the Defendant's knowledge of the '829 Patent, as evidenced by the patent's listing in the FDA Orange Book and the Defendant's filing of a Paragraph IV certification specifically addressing the patent (Compl. ¶14, ¶18).

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

  • A primary issue will be one of chemical composition: Does the product as specified in Ben Venue's confidential ANDA filing in fact meet the quantitative limitation of "at least 92% by weight of the (6S) diastereoisomer" as required by claim 1? The resolution of this factual question will be central to the infringement analysis.
  • A key legal question will be one of claim scope: If the purity level is met, the dispute may shift to the proper construction of the term "consists essentially of." The court will need to determine the "basic and novel properties" of the invention and whether any additional components in the accused generic product materially alter those properties.
  • An overarching question will relate to patent validity: Defendant's Paragraph IV notice alleges that the '829 patent is invalid (Compl. ¶18). Consequently, the litigation will likely involve a significant dispute over whether the claimed composition, defined by its specific level of isomeric purity, was non-obvious and novel over the prior art at the time of the invention.