Bial Portela & Ca SA v. Lupin Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Bial - Portela & Ca Sa., Bial - Holding, SA. (Portugal), and Sunovion Pharmaceuticals Inc. (Delaware)
  • Defendant: Lupin Limited (India) and Lupin Pharmaceuticals, Inc. (Delaware)
  • Plaintiff’s Counsel: Ashby & Geddes; Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:18-cv-00312, D. Del., 02/23/2018
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Lupin Pharmaceuticals is a Delaware corporation.
• Core Dispute: Plaintiffs allege that Defendants’ filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs’ anticonvulsant drug APTIOM® constitutes an act of infringement of six U.S. patents.
• Technical Context: The technology concerns pharmaceutical compositions, methods of manufacturing, and therapeutic uses of eslicarbazepine acetate, a voltage-gated sodium channel blocker for the treatment of epilepsy.
• Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendants’ submission of ANDA No. 211246, which included a Paragraph IV certification alleging that Plaintiffs’ patents are invalid, unenforceable, or would not be infringed by the proposed generic product. Plaintiffs filed this complaint within the 45-day statutory window after receiving Defendants’ notice letter, triggering an automatic 30-month stay on FDA approval of the ANDA.

Case Timeline

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

U.S. Patent No. 8,372,431 - "Pharmaceutical composition comprising licarbazepine acetate,"

• Issued: February 12, 2013

The Invention Explained

• Problem Addressed: The patent’s background section states that the active pharmaceutical ingredient (API), eslicarbazepine acetate, has an "extremely low bulk density" and "poor flowability," which makes it difficult to handle on an industrial scale and challenging to compress into tablets of a reasonable size that dissolve properly (’431 Patent, col. 5:4-14).
• The Patented Solution: The invention is a specific pharmaceutical formulation and a wet granulation process for manufacturing it. This process increases the bulk density of the API-excipient mixture from approximately 0.28 g/mL to over 0.60 g/mL, which improves its handling and compressibility for tablet formation (’431 Patent, col. 3:18-31). The formulation also specifies that the disintegrant (croscarmellose sodium) be split between the internal granules and the external mixture, a configuration discovered to improve tablet dissolution (’431 Patent, col. 3:1-6).
• Technical Importance: This process enables the consistent, large-scale manufacturing of eslicarbazepine acetate into a stable, effective oral solid dosage form, overcoming a significant hurdle in bringing the drug to market (’431 Patent, col. 4:30-34).

Key Claims at a Glance

• The complaint does not identify specific asserted claims. Independent claim 1 is representative of the formulation patents.
• Independent Claim 1 requires:
  • A pharmaceutical composition "consisting of" specific ingredients
  • 80-90 wt% eslicarbazepine acetate
  • 3-10 wt% povidone (a binder)
  • 3-10 wt% croscarmellose sodium (a disintegrant)
  • 0.1-3 wt% magnesium stearate (a lubricant)
  • The composition must exhibit a dissolution of at least 60% at about 30 minutes under specified test conditions

U.S. Patent No. 9,206,135 - "Asymmetric catalytic reduction of oxcarbazepine,"

• Issued: December 8, 2015

The Invention Explained

• Problem Addressed: Prior art methods for synthesizing the active metabolite of eslicarbazepine acetate involved an asymmetric reduction of oxcarbazepine. These methods were inefficient for large-scale production because they required high amounts of an expensive ruthenium catalyst, leading to high costs and undesirable levels of ruthenium contamination in the final product (’135 Patent, col. 2:8-30).
• The Patented Solution: The patent discloses an improved synthesis process that uses a specific ruthenium catalyst system while carefully controlling the reaction pH between 6.5 and 8 (’135 Patent, col. 4:62-col. 5:2). This pH control dramatically increases the efficiency of the catalyst, allowing for a much higher substrate-to-catalyst ratio. This results in higher yields, a purer final product with very low ruthenium levels, and a more economically viable and safer process for industrial manufacturing (’135 Patent, Abstract; col. 3:1-14).
• Technical Importance: This invention provides a commercially viable and efficient manufacturing process for producing an optically pure form of a key anticonvulsant drug, which is critical for the development of single-enantiomer therapeutics (’135 Patent, col. 2:60-65).

Key Claims at a Glance

• The complaint does not identify specific asserted claims. Independent claim 1 is representative of the patents directed to the compound and its purity.
• Independent Claim 1 requires:
  • A compound being (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide (eslicarbazepine acetate)
  • Comprising about 2 ppm of ruthenium or less

U.S. Patent No. 9,566,244 - "Pharmaceutical composition comprising licarbazepine acetate,"

• Issued: February 14, 2017
• Technology Synopsis: This patent, like the ’431 Patent, addresses the technical challenges of formulating the low-density eslicarbazepine acetate API into a commercially viable tablet. It claims a pharmaceutical composition made via a granulation process that includes specific types and amounts of excipients, resulting in a tablet with defined physical and dissolution properties (’244 Patent, Abstract).
• Asserted Claims: The complaint does not specify which claims are asserted.
• Accused Features: Defendants' proposed generic eslicarbazepine acetate tablets are alleged to embody the claimed pharmaceutical composition (Compl. ¶¶84, 86).

U.S. Patent No. 9,643,929 - "Asymmetric catalytic reduction of oxcarbazepine,"

• Issued: May 9, 2017
• Technology Synopsis: This patent is in the same family as the ’135 Patent and addresses the same problem of creating an efficient, low-contamination synthesis for eslicarbazepine acetate. It claims the final compound itself, characterized by a very low level of residual ruthenium (about 2 ppm or less), which is achieved through the patented pH-controlled manufacturing process (’929 Patent, Abstract; col. 3:1-14).
• Asserted Claims: The complaint does not specify which claims are asserted.
• Accused Features: Defendants’ proposed generic product is alleged to be the claimed compound with the specified low level of ruthenium impurity (Compl. ¶¶95, 97).

U.S. Patent No. 9,750,747 - "Treatments involving eslicarbazepine acetate or eslicarbazepine,"

• Issued: September 5, 2017
• Technology Synopsis: This patent claims methods of treating certain disorders, such as epilepsy, in patients who are susceptible to absence seizures. The invention is based on the discovery that, unlike other drugs in its class that can aggravate absence seizures, eslicarbazepine acetate does not and can be used safely in this patient population (’747 Patent, col. 1:52-col. 2:2).
• Asserted Claims: The complaint does not specify which claims are asserted.
• Accused Features: The intended use of Defendants' generic product, as will be described in its labeling, is alleged to induce infringement of the patented method of treatment (Compl. ¶¶111-113).

U.S. Patent No. 9,763,954 - "Therapeutical uses of eslicarbazepine,"

• Issued: September 19, 2017
• Technology Synopsis: This patent claims methods of treating intractable epilepsy in patients who have previously been treated with oxcarbazepine. The invention is based on the discovery that eslicarbazepine is not a substrate for certain drug-efflux transporters (like P-glycoprotein) in the brain, making it effective in patients who have developed resistance to other drugs, such as oxcarbazepine, that are affected by these transporters (’954 Patent, Abstract; col. 4:8-13).
• Asserted Claims: The complaint does not specify which claims are asserted.
• Accused Features: Defendants' proposed label is alleged to encourage physicians to prescribe the generic product for patients in a manner that directly infringes the claimed therapeutic method (Compl. ¶¶126-128).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Lupin's Generic Product," identified as Eslicarbazepine Acetate Tablets in 200, 400, 600, and 800 mg dosage forms, for which Defendants filed ANDA No. 211246 with the FDA (Compl. ¶¶11, 53).

Functionality and Market Context

The product is a generic version of Plaintiffs’ branded drug, APTIOM®, and is intended to be used for treating partial-onset seizures (Compl. ¶¶3, 34, 53). The complaint alleges that Defendants have represented to the FDA that their generic product is "pharmaceutically and therapeutically equivalent" to APTIOM® tablets (Compl. ¶60). The filing of the ANDA signifies Defendants' intent to manufacture, market, and sell this generic product in the United States upon receiving FDA approval (Compl. ¶53).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain detailed infringement allegations or claim charts. The infringement theory, typical for ANDA litigation, is that because the accused generic product is represented as pharmaceutically and therapeutically equivalent to the branded product, it will necessarily meet the limitations of the patents covering the branded product's composition, method of manufacture, and approved uses.

8,372,431 Patent Infringement Allegations

9,206,135 Patent Infringement Allegations

• Identified Points of Contention:
  • Scope Questions: For the ’431 Patent, a central question will be the scope of the term "consisting of." If Lupin's formulation contains any additional excipients not recited in claim 1, such as fillers or glidants, it may raise a strong non-infringement defense.
  • Technical Questions: For the ’135 Patent, the dispute may focus on the term "about 2 ppm." The analysis will require claim construction to define the permissible range of "about" and factual evidence from Lupin's ANDA and product samples to determine the actual level of ruthenium impurity.

V. Key Claim Terms for Construction

• Term: "consisting of" (from ’431 Patent, Claim 1)

  • Context and Importance: Practitioners may focus on this term because it is a closed-ended transition phrase in claim drafting. Unlike "comprising," it presumptively excludes any elements not specified. The infringement analysis for the ’431 Patent may turn on whether Lupin’s generic formulation contains only the four listed ingredients (and ordinary impurities) or includes additional, unlisted excipients.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party might argue that while the claim is closed, the specification's discussion of other optional excipients like fillers, glidants, and sweeteners suggests the inventors did not intend to disavow all other formulations (’431 Patent, col. 6:8-25). This is generally a difficult argument against the established legal meaning of the term.
    • Evidence for a Narrower Interpretation: The plain language of the claim is the strongest evidence. The inventors chose the highly restrictive term "consisting of" rather than the open-ended "comprising," indicating a clear intent to limit the composition to only the specified four components.

• Term: "about 2 ppm" (from ’135 Patent, Claim 1)

  • Context and Importance: This term defines the purity threshold that distinguishes the patented compound. The entire infringement question for this patent may depend on the numerical range assigned to "about" and whether Lupin's product falls within that range.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent does not provide an explicit definition for "about." A party arguing for a broader scope could contend that the term must be interpreted in light of the inherent variability of manufacturing processes and the precision of analytical measurement techniques known at the time of the invention.
    • Evidence for a Narrower Interpretation: The patent specification repeatedly highlights the problem of high ruthenium levels in the prior art and touts the invention’s ability to produce a product with low contamination (’135 Patent, col. 2:20-27). A party could argue that "about 2 ppm" represents a specific, important upper limit that characterizes the invention and should be construed narrowly.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that upon FDA approval, Defendants will actively induce and contribute to infringement (Compl. ¶62). For the method-of-use patents (’747 and ’954), the allegations of inducement are based on the premise that Defendants' proposed package insert and marketing materials will instruct or encourage physicians and patients to use the generic product in a manner that directly infringes the claimed methods (Compl. ¶¶111-113, 127-128).
• Willful Infringement: The complaint does not contain a formal count for willful infringement. However, it does allege that Defendants have had knowledge of the patents-in-suit as evidenced by their January 9, 2018 notice letter, which could form the basis for a later claim of post-filing willfulness (Compl. ¶¶77, 114, 129).

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

• A core issue will be one of compositional identity: for the formulation patents ('431, '244), does the precise combination of active ingredient and excipients in Lupin's proposed generic product, as specified in its confidential ANDA, fall within the scope of the patent claims, particularly in view of the restrictive "consisting of" language in claim 1 of the ’431 patent?
• A second central question will be one of definitional threshold: for the compound purity patents ('135, '929), can the term "about 2 ppm or less" of ruthenium be construed to read on the measured impurity levels in Lupin's final product, and what evidence will establish that level?
• Finally, the case will present a key question of induced infringement: for the method-of-use patents ('747, '954), will the language in Lupin’s proposed FDA-approved label inevitably instruct medical professionals to prescribe the generic drug for indications or to patient populations in a way that directly practices the steps of the patented therapeutic methods?