Sanofi Aventis US LLC v. Apotex Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Sanofi-Aventis U.S. LLC (Delaware), Aventisub LLC (Delaware), Sanofi (France), and Genzyme Corporation (Massachusetts)
  • Defendant: Apotex, Inc. (Canada) and Apotex Corp. (Delaware)
  • Plaintiff’s Counsel: RatnerPrestia; McDonnell Boehnen Hulbert & Berghoff LLP
• Case Identification: Sanofi-Aventis U.S. LLC v. Apotex, Inc., 1:16-cv-01312, D. Del., 12/27/2016
• Venue Allegations: Venue is alleged based on Defendants' business activities in Delaware, including the development, marketing, and distribution of generic pharmaceuticals, and the intent to sell the accused product in the state upon FDA approval. The complaint also notes that Defendants have previously submitted to the jurisdiction of the Delaware court in other matters.
• Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of the drug Aubagio® (teriflunomide) constitutes an act of infringement of two patents related to methods of treating multiple sclerosis.
• Technical Context: The technology concerns pharmaceutical methods for treating multiple sclerosis (MS), an autoimmune disease, using the active ingredient teriflunomide, and managing potential drug interactions when it is co-administered with other medications.
• Key Procedural History: This lawsuit was filed under the Hatch-Waxman Act, triggered by a Paragraph IV certification in which Defendant Apotex asserted that Plaintiffs’ patents are invalid, unenforceable, or will not be infringed by its proposed generic product. The complaint notes that U.S. Patent No. 6,794,410 underwent ex parte reexamination, which resulted in the allowance of new claims, including claims now asserted in this litigation.

Case Timeline

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

U.S. Patent No. 6,794,410 (as reexamined) - “Use of (Z)-2-cyano-3-hydroxy-but-2-enoic Acid-(4'-trifluoromethylphenyl)-amide for Treating Multiple Sclerosis”

• Patent Identification: U.S. Patent No. 6,794,410, issued September 21, 2004. A reexamination certificate was issued on July 31, 2013 (Compl. ¶22; ’410 Patent, front page).

The Invention Explained

• Problem Addressed: The patent describes multiple sclerosis (MS) as a debilitating neurological illness and notes that, at the time of the invention, existing therapies had significant limitations, including adverse side effects, limited impact on disease progression, and the potential to induce neutralizing antibodies that decrease efficacy, creating a "strong need for new drugs" (’410 Patent, col. 2:48-57).
• The Patented Solution: The invention claims a method of treating MS by administering the compound teriflunomide. The patent specification explains that MS is suspected to be a T-cell-mediated autoimmune reaction and that teriflunomide has been shown to have "antiproliferative effects on a wide variety of immune cells," which provides a mechanism for its therapeutic effect (’410 Patent, col. 2:22-34, col. 2:62-65).
• Technical Importance: The invention provided a method of treatment using a new oral therapy for MS, a field where many existing treatments were injectable and had known therapeutic limitations (’410 Patent, col. 2:42-57).

Key Claims at a Glance

• The complaint asserts infringement of "at least one of the claims, including but not limited to claim 10" (Compl. ¶53). Claim 10 is an independent claim added during reexamination.
• Independent Claim 10:
  • A method of treating multiple sclerosis which comprises
  • orally administering to a patient that has manifested clinical disease
  • a therapeutically effective amount of a compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.
• The complaint reserves the right to assert additional claims (Compl. ¶53).

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

• Patent Identification: U.S. Patent No. 9,186,346, issued November 17, 2015 (Compl. ¶23; ’346 Patent, front page).

The Invention Explained

• Problem Addressed: The patent addresses a specific adverse drug-drug interaction. It states that when teriflunomide is administered with rosuvastatin (a widely used cholesterol-lowering drug), it "causes an increase in the plasma concentration of rosuvastatin" (’346 Patent, col. 2:56-59). This elevated exposure to rosuvastatin could create a safety risk for patients.
• The Patented Solution: The invention provides a method to manage this interaction by co-administering teriflunomide with a specifically reduced dose of rosuvastatin. The patent claims methods where the rosuvastatin dose is either "at the amount of about 50% of the normal dose" or, more specifically, "at a dose that does not exceed 10 mg once daily" (’346 Patent, col. 5:12-14, col. 5:24-26).
• Technical Importance: The claimed method provides a specific dosing instruction that allows patients with both MS and high cholesterol to be treated concurrently with both drugs while mitigating the risk from the identified interaction.

Key Claims at a Glance

• The complaint asserts infringement of "at least one of the claims, including but not limited to claim 5" (Compl. ¶71). Claim 5 is an independent claim.
• Independent Claim 1:
  • 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 which is at the amount of about 50% of the normal dose of rosuvastatin.
• 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 additional claims (Compl. ¶71).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are Apotex’s proposed generic "Teriflunomide ANDA Products" in 7 mg and 14 mg tablet form, which are intended to be generic versions of the branded drug Aubagio® (teriflunomide) (Compl. ¶9).

Functionality and Market Context

The complaint alleges that Apotex's product is a generic drug that Apotex has asserted is bioequivalent to Aubagio® (Compl. ¶35). Apotex is allegedly seeking FDA approval to market the product for the same indication: "the treatment of patients with relapsing forms of multiple sclerosis" (Compl. ¶¶ 37-38). The infringement allegations are based on the filing of ANDA No. 209601 and the anticipated commercial manufacture, use, and sale of the generic product with its accompanying prescribing information upon FDA approval (Compl. ¶¶ 9, 41). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’410 Patent Infringement Allegations

’346 Patent Infringement Allegations

Identified Points of Contention

• Evidentiary Question: A central issue for both patents is what the final, FDA-approved label for Apotex's product will instruct. The complaint's allegations regarding the label's contents are based on "information and belief" and the expectation that it will "substantially copy" the branded drug's label (Compl. ¶¶ 39, 41). The actual language of the proposed label will be a key piece of evidence determining whether Apotex will induce infringement of these method claims.
• Scope Question: For the ’410 patent, a question may arise regarding the scope of "patient that has manifested clinical disease." For the ’346 patent, the dispute will turn on whether the label's language regarding the rosuvastatin interaction meets the specific dosage limitations recited in the claims.

V. Key Claim Terms for Construction

For the ’410 Patent

• The Term: "patient that has manifested clinical disease" (from reexamined claim 10)
• Context and Importance: This phrase was added during reexamination and defines the patient population. Its construction is critical because infringement requires that the accused product be indicated for this specific group. Practitioners may focus on this term to see if any ambiguity was introduced during reexamination that could provide a non-infringement argument.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification describes MS broadly and lists its four clinical patterns (relapsing-remitting, secondary progressive, etc.), all of which describe a patient who has manifested the disease (’410 Patent, col. 2:10-16). This could support a construction covering any patient with a formal MS diagnosis.
  • Evidence for a Narrower Interpretation: Other reexamined claims refer more specifically to an "acute episode of MS" (e.g., claims 2, 5, and 8). An argument could be made that "manifested clinical disease" should be construed in light of these more specific limitations, potentially narrowing its meaning to patients experiencing active symptoms rather than those in remission.

For the ’346 Patent

• The Term: "normal dose of rosuvastatin" (from claim 1)
• Context and Importance: This term is the baseline for the dosage reduction required by claim 1 ("about 50% of the normal dose"). Its definition is essential for determining infringement. Practitioners may focus on this term because its potential ambiguity could be a basis for an indefiniteness challenge under 35 U.S.C. § 112.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation (or supporting definiteness): The patent provides an explicit definition: "'Normal dose of rosuvastatin' means a dose of rosuvastatin that would be recommended for a patient to take or a doctor would prescribe... if the patient is not taking teriflunomide concurrently." (’346 Patent, col. 2:25-29). This could be argued to provide clear guidance to a skilled artisan.
  • Evidence for a Narrower Interpretation (or supporting indefiniteness): The specification offers multiple examples of what a "normal dose" could be, including the general FDA-approved range of 5-40 mg daily or the specific dose a patient was taking before starting teriflunomide (’346 Patent, col. 2:29-32). The existence of multiple potential reference points for a single patient could be argued to render the term indefinite, as the "normal dose" and the resulting 50% reduction could vary.

VI. Other Allegations

• Indirect Infringement: The complaint is premised on a theory of induced infringement, alleging that Apotex, by seeking approval for its generic product with a specific label, intends for physicians and patients to use the drug in a way that directly infringes the patented methods (Compl. ¶¶ 45, 50, 62). The complaint also alleges contributory infringement, asserting that the teriflunomide products are not staple articles of commerce suitable for substantial non-infringing use because they are "especially made or adapted for use in infringing" the claims (Compl. ¶¶ 65, 83).
• Willful Infringement: The complaint alleges that Apotex had notice of the patents, at the latest, upon sending its Paragraph IV certification letter (Compl. ¶¶ 28, 54, 72). It further alleges that infringement is and will be "deliberate," seeking a finding that this is an "exceptional case" warranting treble damages and attorneys' fees (Compl. ¶¶ 56, 69, 74, 87).

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

1. A central issue will be one of induced infringement based on label instructions: Does the specific language of Apotex’s proposed product label direct medical professionals and patients to administer teriflunomide in a way that satisfies all limitations of the asserted method claims? The outcome will depend heavily on the content of a document—the proposed label—that is not yet public.
2. A key legal question will be the definiteness of the '346 patent's claims: Can the term "normal dose," which the specification defines using multiple potential reference points, be considered sufficiently clear to one of ordinary skill in the art? A finding of indefiniteness could invalidate the core claims of the patent covering the drug interaction.
3. The case may also turn on a question of prosecution history estoppel for the '410 patent: What arguments and claim amendments did the patentee make during reexamination to overcome prior art? These actions may have narrowed the enforceable scope of the reexamined claims in a way that provides Apotex with a non-infringement defense.