DCT

1:17-cv-00034

Sanofi Aventis US LLC v. Zydus Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-00034, D. Del., 01/11/2017
  • Venue Allegations: Plaintiffs allege venue is proper in the District of Delaware because Defendants intend to market and sell the accused products in the state, maintain business contacts there, and have previously submitted to the court's jurisdiction in other matters.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) for a generic version of the multiple sclerosis drug Aubagio® (teriflunomide) constitutes an act of infringement of two patents covering a stable formulation of the drug and a method for managing its interaction with rosuvastatin.
  • Technical Context: The dispute centers on pharmaceutical chemistry and clinical pharmacology related to teriflunomide, an oral medication used for treating relapsing forms of multiple sclerosis.
  • Key Procedural History: The litigation was triggered under the Hatch-Waxman Act by Defendants' submission of ANDA No. 209668 to the U.S. Food and Drug Administration. On or about November 28, 2016, Defendants sent Plaintiffs a Notice Letter containing a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2010-07-12 U.S. Patent No. 8,802,735 Priority Date
2013-03-12 U.S. Patent No. 9,186,346 Priority Date
2014-08-12 U.S. Patent No. 8,802,735 Issued
2015-11-17 U.S. Patent No. 9,186,346 Issued
2016-11-28 Defendants sent Paragraph IV Notice Letter
2017-01-11 Complaint Filed

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

U.S. Patent No. 8,802,735 - “(Z)-2-cyano-3-hydroxy-but-2-enoic Acid-(4'-trifluoromethylphenyl)-amide Tablet Formulations with Improved Stability”

The Invention Explained

  • Problem Addressed: The patent's background describes that solid pharmaceutical formulations of teriflunomide were observed during stability studies to have a "strong increase in one degradant," identified as 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide ('735 Patent, col. 2:1-3). The formation of such degradants can compromise the drug's safety, efficacy, and shelf life.
  • The Patented Solution: The invention addresses this stability issue by claiming pharmaceutical compositions with specific chemical properties. One approach disclosed is to create a formulation with a low pH, which is claimed to limit the formation of the degradant ('735 Patent, col. 4:56-62). Another disclosed approach, not asserted via the specifically identified claim in the complaint, involves omitting colloidal silicon dioxide from the formulation ('735 Patent, col. 2:25-29).
  • Technical Importance: Ensuring the chemical stability of a drug product over its shelf life is a fundamental requirement for regulatory approval and patient safety, making innovations in formulation science critical to pharmaceutical development ('735 Patent, col. 2:18-23).

Key Claims at a Glance

  • The complaint asserts infringement of at least Claim 10 ('735 Patent, col. 17:34-38; Compl. ¶55).
  • Independent Claim 10:
    • A solid pharmaceutical composition
    • comprising a therapeutically effective amount of teriflunomide or a pharmaceutically acceptable basic addition salt thereof,
    • wherein the pH of the solid pharmaceutical composition is no more than about 2.2.
  • The complaint reserves the right to assert other claims.

U.S. Patent No. 9,186,346 - “Methods for Reducing the Risk of an Adverse Teriflunomide and Rosuvastatin Interaction in Multiple Sclerosis Patients”

The Invention Explained

  • Problem Addressed: The patent discloses that when teriflunomide is administered together with rosuvastatin (a widely used cholesterol-lowering medication), it "causes an increase in the plasma concentration of rosuvastatin" ('346 Patent, col. 3:55-59). Elevated levels of rosuvastatin can increase the risk of adverse effects for the patient.
  • The Patented Solution: The invention provides a method for managing this drug-drug interaction. The method involves co-administering teriflunomide with a reduced dose of rosuvastatin, specifically a dose that does not exceed 10 mg once daily, which is approximately 50% of the typical normal dose ('346 Patent, col. 2:1-3; col. 3:61-65).
  • Technical Importance: Identifying and managing drug-drug interactions is a critical aspect of clinical practice, as it allows physicians to safely prescribe multiple medications to patients with comorbid conditions, such as multiple sclerosis and high cholesterol ('346 Patent, col. 3:14-17).

Key Claims at a Glance

  • The complaint asserts infringement of at least Claim 5 ('346 Patent, col. 6:20-29; Compl. ¶63).
  • Independent Claim 5:
    • A method for treating multiple sclerosis while managing the risk of teriflunomide and rosuvastatin interaction in a patient having multiple sclerosis,
    • wherein rosuvastatin is co-administered with teriflunomide,
    • comprising administering to the patient about 7 or 14 mg of teriflunomide daily,
    • and administering to the patient rosuvastatin at a dose that does not exceed 10 mg once daily.
  • The complaint reserves the right to assert other claims.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendants' proposed "Teriflunomide ANDA Products" in 7 mg and 14 mg tablet dosages, for which Defendants seek FDA approval via ANDA No. 209668 (Compl. ¶10).

Functionality and Market Context

  • The products are a proposed generic version of Plaintiffs' branded drug Aubagio® (teriflunomide), indicated for the treatment of patients with relapsing forms of multiple sclerosis (Compl. ¶10, ¶25).
  • The complaint alleges the ANDA Products contain teriflunomide as the active ingredient and are asserted to be bioequivalent to Aubagio® (Compl. ¶36, ¶37).
  • Regarding the '735 Patent, the complaint alleges, on information and belief, that the accused products are formulated to "have a pH of no more than 2.2" (Compl. ¶39).
  • Regarding the '346 Patent, the complaint alleges, on information and belief, that the accused products will be accompanied by prescribing information that instructs co-administration with rosuvastatin in a manner where the rosuvastatin dose "will not exceed 10 mg once daily" (Compl. ¶40, ¶44).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

'735 Patent Infringement Allegations

Claim Element (from Independent Claim 10) Alleged Infringing Functionality Complaint Citation Patent Citation
A solid pharmaceutical composition Defendants' Teriflunomide ANDA Products are solid tablets. ¶10 col. 2:39-45
comprising a therapeutically effective amount of teriflunomide... The ANDA Products contain a therapeutically effective amount (7 mg or 14 mg) of teriflunomide. ¶10, ¶39 col. 1:17-21
wherein the pH of the solid pharmaceutical composition is no more than about 2.2. The complaint alleges the ANDA Products are formulated to have a pH of no more than 2.2. ¶39 col. 4:56-62
  • Identified Points of Contention:
    • Evidentiary Question: A central factual dispute will concern the actual pH of Defendants' proposed generic tablets. The complaint makes this allegation on "information and belief," suggesting that confirmation will depend on evidence produced during discovery from the ANDA filing.
    • Scope Question: How the court construes "about 2.2" may become relevant. The primary dispute, however, appears to be the factual question of whether the accused products meet this limitation at all.

'346 Patent Infringement Allegations

Claim Element (from Independent Claim 5) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating multiple sclerosis while managing the risk of teriflunomide and rosuvastatin interaction... The proposed prescribing information for the ANDA Products will allegedly instruct users on treating MS while managing this specific drug interaction. ¶44, ¶45 col. 3:41-44
wherein rosuvastatin is co-administered with teriflunomide... The proposed prescribing information will allegedly instruct users on the co-administration of the two drugs. ¶45 col. 2:18-24
comprising administering to the patient about 7 or 14 mg of teriflunomide daily... The ANDA Products are 7 mg and 14 mg teriflunomide tablets intended for daily administration. ¶10 col. 3:36-39
and administering to the patient rosuvastatin at a dose that does not exceed 10 mg once daily. The complaint alleges the proposed prescribing information will instruct that when the ANDA product is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg once daily. ¶40, ¶44 col. 5:24-26
  • Identified Points of Contention:
    • Evidentiary Question: The infringement allegation for this method claim is based on inducement. The central question will be whether the language in Defendants' proposed product label and prescribing information instructs, encourages, or promotes the performance of all steps of the claimed method. The content of that label will be the key piece of evidence.
    • Legal Question: The analysis will turn on whether Defendants' actions, particularly the act of seeking approval for a product with a specific label, demonstrate the specific intent required to establish induced infringement under 35 U.S.C. § 271(b).

V. Key Claim Terms for Construction

  • The Term: "pH of the solid pharmaceutical composition" ('735 Patent, Claim 10)

  • Context and Importance: The infringement allegation for the '735 Patent hinges entirely on whether the accused product meets the specific pH limitation of "no more than about 2.2." The method used to measure the pH of a solid tablet is not standardized and could be a point of contention.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Narrower Interpretation: The patent specification provides an explicit, and potentially definitional, description of the measurement protocol: "The pH determination is performed by suspending one tablet in about 1 ml of purified water. The pH of the supernatant is determined with a pH sensitive probe" ('735 Patent, col. 4:52-55). A party could argue that this specific protocol is the only valid way to assess whether a product meets the claim limitation.

  • The Term: "managing the risk" ('346 Patent, Claim 5)

  • Context and Importance: This phrase appears in the preamble of the claim. Whether this preamble is construed as a binding limitation on the claim's scope could be important. A defendant might argue that its proposed label does not "manage" a risk but merely provides information.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent's summary and detailed description equate "managing the risk" with the act of reducing the rosuvastatin dose by about 50% when co-administered with teriflunomide ('346 Patent, col. 2:1-3; col. 3:61-65). This suggests that instructing the dose reduction is itself the claimed act of "managing the risk."

VI. Other Allegations

  • Indirect Infringement: The complaint's theory against the '346 Patent is primarily one of induced infringement. It alleges that Defendants will provide prescribing information that will instruct physicians and patients to perform the patented method of co-administering teriflunomide with a limited dose of rosuvastatin (Compl. ¶44-45, ¶52). The complaint further alleges that Defendants know this use will infringe and specifically intend for physicians and patients to follow these instructions (Compl. ¶47, ¶49).
  • Willful Infringement: The complaint alleges that Defendants had knowledge of the patents-in-suit and that their infringement has been "deliberate" (Compl. ¶28, ¶59, ¶65). This allegation is based on the patents being listed in the FDA's Orange Book and Defendants' receipt of the notice of the lawsuit, establishing pre- and post-suit knowledge.

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

The resolution of this case appears to depend on two distinct types of evidence corresponding to the two asserted patents.

  • A core issue will be one of empirical fact: Does Zydus's proposed generic formulation, as described in its confidential ANDA submission, actually possess the physical-chemical property of a pH "no more than about 2.2" as required by Claim 10 of the '735 patent, particularly when measured using the specific protocol disclosed in the patent's specification?
  • A second core issue will be one of induced infringement: Does the instructional language in Zydus’s proposed product label direct, encourage, or promote the co-administration of its teriflunomide product with rosuvastatin in the specific dosing regimen claimed by the '346 patent, thereby establishing the requisite intent for inducement?