Biogen Intl GmbH v. Lupin Atlantis Holdings SA

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Biogen International GmbH (Switzerland) and Biogen MA Inc. (Massachusetts)
  • Defendant: Lupin Atlantis Holdings SA (Switzerland) and Lupin Inc. (Delaware)
  • Plaintiff’s Counsel: Ashby & Geddes; Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.
• Case Identification: 1:17-cv-00853, D. Del., 06/28/2017
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Lupin Inc. is incorporated in Delaware, and Defendant Lupin Atlantis is a foreign corporation subject to suit in any judicial district.
• Core Dispute: Plaintiff alleges that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's Tecfidera® product constitutes infringement of three patents related to pharmaceutical formulations and methods for treating multiple sclerosis.
• Technical Context: The technology concerns the use of dialkyl fumarates, specifically dimethyl fumarate, in orally administered, delayed-release formulations for the treatment of autoimmune diseases like multiple sclerosis.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Notice Letter on June 1, 2017, regarding Defendants' ANDA No. 210226. The complaint notes that this letter did not allege non-infringement of the asserted patents. U.S. Patent No. 8,399,514 survived an inter partes review (IPR2015-01993), with the Patent Trial and Appeal Board finding claims 1-20 patentable, a fact that may influence subsequent validity challenges.

Case Timeline

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

U.S. Patent No. 6,509,376 - Utilization of Dialkyfumarates, Issued January 21, 2003

The Invention Explained

• Problem Addressed: The patent’s background section describes the significant side effects of conventional immunosuppressive agents used to treat autoimmune diseases and prevent transplant rejection, including a weakened immune system and increased risk of malignant diseases (’376 Patent, col. 2:56-59).
• The Patented Solution: The invention is a pharmaceutical preparation containing a dialkyl fumarate, such as dimethyl fumarate, formulated into "micro-tablets or micro-pellets" ('376 Patent, Abstract). This formulation is intended to be administered orally and is designed to improve patient tolerance by preventing the release of the active ingredient in high local concentrations within the gastrointestinal tract, thereby reducing irritation and other side effects associated with earlier formulations ('376 Patent, col. 5:30-55).
• Technical Importance: By creating a more tolerable oral dosage form, the invention sought to enable the long-term therapeutic use of fumaric acid derivatives for chronic conditions like psoriasis and multiple sclerosis, which had previously been hindered by severe side effects ('376 Patent, col. 5:26-34).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶42).
• The essential elements of claim 1 are:
  • A pharmaceutical preparation in the form of microtablets or micropellets.
  • Comprising one or more dialkyl fumarates of a specified chemical formula.
  • Optionally including suitable carriers and excipients.
  • For use in transplantation medicine or for the therapy of specified autoimmune diseases, including multiple sclerosis.
• The complaint reserves the right to assert additional claims (Compl. ¶47).

U.S. Patent No. 7,320,999 - Dimethyl Fumarate for the Treatment of Multiple Sclerosis, Issued January 22, 2008

The Invention Explained

• Problem Addressed: The patent addresses the need for a treatment for multiple sclerosis (MS) that is effective but avoids the disadvantages associated with broad immunosuppression, such as increased risk of infection and malignancy ('999 Patent, col. 2:56-64).
• The Patented Solution: The patent claims a specific method of treating MS by administering a pharmaceutical preparation in which dimethyl fumarate is the "only active ingredient" for that purpose ('999 Patent, Claim 1). This distinguishes the invention from combination therapies and focuses the therapeutic application specifically on dimethyl fumarate for MS, rather than on a broader class of compounds or diseases as in the parent ’376 patent (’999 Patent, col. 3:1-4).
• Technical Importance: The invention provided a targeted monotherapy for MS, claiming a specific use for dimethyl fumarate that could offer therapeutic benefits without the well-known drawbacks of general immunosuppressants.

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶56).
• The essential elements of claim 1 are:
  • A method of treating multiple sclerosis.
  • Comprising treating a patient with an effective amount of a pharmaceutical preparation.
  • Wherein the only active ingredient for treating multiple sclerosis in the preparation is dimethyl fumarate.
• The complaint reserves the right to assert additional claims (Compl. ¶62).

U.S. Patent No. 8,399,514 - Treatment for Multiple Sclerosis, Issued March 19, 2013

Technology Synopsis

This patent describes a method of treating MS by administering a specific oral dose of dimethyl fumarate or monomethyl fumarate. The invention is based on the discovery that these compounds provide a neuroprotective effect by activating the Nrf2 pathway, a cellular mechanism that defends against oxidative stress and is implicated in the pathology of neurodegenerative diseases ('514 Patent, Abstract; col. 1:63-col. 2:19).

Asserted Claims

The complaint asserts independent claim 1 (Compl. ¶71).

Accused Features

The accused infringing act is the filing of an ANDA for a generic dimethyl fumarate product with a proposed label that will allegedly instruct its administration for treating MS at a therapeutically effective amount of about 480 mg per day, as recited in claim 1 of the patent (Compl. ¶¶ 71-72; ’514 Patent, Claim 1).

III. The Accused Instrumentality

Product Identification

Defendants' proposed generic "dimethyl fumarate delayed-release capsules containing 120 mg and 240 mg of dimethyl fumarate" (Compl. ¶39). The product is the subject of ANDA No. 210226 submitted to the FDA (Compl. ¶10).

Functionality and Market Context

The product is a generic equivalent of Biogen’s branded drug, Tecfidera®, and is intended for the treatment of relapsing forms of multiple sclerosis (Compl. ¶3, ¶37). The act of infringement alleged under 35 U.S.C. § 271(e)(2) is the submission of the ANDA itself, which seeks approval to market this generic drug before the expiration of the patents-in-suit (Compl. ¶10).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’376 Patent Infringement Allegations

Identified Points of Contention

• Scope Questions: A central question may be whether the term "microtablets or micropellets" has a specific meaning that Defendants' formulation, as detailed in the confidential ANDA, might not meet. The patent provides preferred size ranges (e.g., 300 to 2,000 µm), which could become a focus of claim construction ('376 Patent, col. 4:49-52).
• Technical Questions: A key factual question will be whether the physical and chemical characteristics of the formulation described in ANDA No. 210226 fall within the scope of claim 1, an issue that will depend on evidence from the ANDA itself.

’999 Patent Infringement Allegations

Identified Points of Contention

• Scope Questions: The interpretation of the phrase "only active ingredient" will be critical. Does this term preclude the presence of excipients that may have ancillary or minor biological effects, or does it simply mean that no other compound is included for the express purpose of treating MS?
• Technical Questions: An evidentiary question will be whether any component of Defendants' formulation, other than dimethyl fumarate, could be legally characterized as an "active ingredient" for MS, potentially allowing Defendants to argue non-infringement of this claim.

V. Key Claim Terms for Construction

Term: "microtablets or micropellets" (’376 Patent, Claim 1)

• Context and Importance: The infringement analysis for the ’376 patent hinges on whether Defendants' proposed generic product, as described in their ANDA, constitutes a "pharmaceutical preparation in the form of microtablets or micropellets." Practitioners may focus on this term because it defines the physical structure of the claimed invention.
• Evidence for a Broader Interpretation: The specification describes the purpose of the formulation is to be administered orally and avoid high local concentrations of the active ingredient, suggesting the term could encompass various forms of small, coated particles that achieve this functional goal ('376 Patent, col. 5:35-55).
• Evidence for a Narrower Interpretation: The specification provides detailed examples of preparing "convex tablets having a gross weight of 10.0 mg and a diameter of 2.0 mm" and gives a preferred mean diameter range of 300 to 2,000 µm ('376 Patent, col. 4:49-52; Example 1). A party could argue the term should be limited to particles within or near these disclosed parameters.

Term: "only active ingredient" (’999 Patent, Claim 1)

• Context and Importance: This limitation is the defining feature of claim 1 of the ’999 patent, distinguishing it as a monotherapy. A dispute over its meaning is central to infringement, as a defendant could argue its formulation contains other components with some biological activity.
• Evidence for a Broader Interpretation: A party may argue that in the context of pharmaceutical regulations, an "active ingredient" is a component intended to furnish pharmacological activity. This would suggest that inactive excipients, regardless of any minor biological effects, do not negate the "only active ingredient" status of dimethyl fumarate.
• Evidence for a Narrower Interpretation: The patent does not provide an explicit definition of the term. A party could argue that if any other component in the formulation—even one classified as an excipient—has any demonstrable therapeutic effect for MS or its symptoms, the "only" limitation is not met.

VI. Other Allegations

Indirect Infringement

The complaint alleges induced infringement of the ’999 and ’514 method patents. It asserts that Defendants will take active steps to encourage infringement by physicians and patients by marketing the generic product with a label, copied from the FDA-approved Tecfidera® label, that instructs the infringing use (Compl. ¶¶ 59, 74). Contributory infringement is also alleged, on the basis that the dimethyl fumarate product is a material part of the invention and not a staple article of commerce with substantial non-infringing uses (Compl. ¶¶ 60, 75).

Willful Infringement

The complaint does not use the term "willful infringement" but alleges that Defendants have "actual knowledge" of the patents-in-suit as a result of the June 1, 2017 Notice Letter (Compl. ¶¶ 41, 55, 70). Furthermore, the prayer for relief requests a declaration that the case is "exceptional" under 35 U.S.C. § 285, which is the statutory basis for an award of attorney fees and can be predicated on willful or egregious conduct (Compl. p. 16).

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

• A core issue will be one of definitional scope: can the phrase "only active ingredient" in the ’999 patent be construed to read on a formulation containing multiple excipients, or can Defendants avoid infringement by demonstrating a secondary therapeutic effect from one of those excipients?
• A second key issue will be one of factual correspondence: does the specific formulation disclosed in Defendants' confidential ANDA meet the "microtablets or micropellets" limitation of the ’376 patent, and will discovery reveal a physical form and size that falls squarely within the patent's teachings or resides in a grey area?
• Finally, a central question for the '514 patent will be one of proof of infringement: given that the patent survived an IPR and its validity is strengthened, will infringement of the method claim (requiring administration of ~480 mg/day) be established simply by Defendants' proposed label instructions, or will the court require additional evidence related to the underlying Nrf2 activation mechanism described in the specification?