Bial Portela & Ca SA v. Hetero Labs Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:

  • Plaintiff: Bial - Portela & Ca Sa., Bial - Holding, SA. (Portugal), and Sunovion Pharmaceuticals Inc. (Delaware)
  • Defendant: Hetero Labs Ltd, Hetero Labs Ltd UNIT-V (India), and Hetero USA Inc. (Delaware)
  • Plaintiff’s Counsel: Ashby & Geddes; Morris, Nichols, Arsht & Tunnell LLP; Finnegan, Henderson, Farabow, Garrett & Dunner, LLP

• Case Identification: 1:18-cv-00342, D. Del., 03/02/2018

• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Hetero USA Inc. is a Delaware corporation, and the other Hetero entities are organized under the laws of India and may be sued in any U.S. judicial district.

• Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' APTIOM® (eslicarbazepine acetate) tablets constitutes an act of infringement of six patents related to the drug's composition, manufacture, and methods of use.

• Technical Context: The technology concerns eslicarbazepine acetate, an anticonvulsant drug used for the treatment of partial-onset seizures associated with epilepsy.

• Key Procedural History: The litigation was triggered by Defendants' submission of ANDA No. 211186 to the U.S. Food and Drug Administration (FDA). This submission included a "paragraph IV certification" alleging that Plaintiffs' patents are invalid, unenforceable, or would not be infringed by the proposed generic product. Plaintiffs received notice of this filing via a letter dated January 18, 2018, and filed this complaint within the 45-day statutory window.

Case Timeline

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

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

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" (less than about 0.3 g/mL), which results in poor flowability and makes it difficult to handle and compress into tablets, particularly on an industrial scale ('431 Patent, col. 5:4-14).
• The Patented Solution: The invention claims a specific pharmaceutical composition and wet granulation process that more than doubles the bulk density of the drug preparation (e.g., to around 0.6 g/mL), thereby improving its manufacturing properties ('431 Patent, col. 3:18-31). The process involves specific formulation techniques, such as splitting the disintegrant so that part is mixed within the granules ("intragranular") and part is added after granulation ("extragranular") to optimize tablet dissolution ('431 Patent, col. 3:1-9).
• Technical Importance: This approach addresses a fundamental manufacturing challenge in pharmaceutical science: converting a physically difficult-to-handle API into a form suitable for high-speed, large-scale, and cost-effective tablet production ('431 Patent, col. 3:4-14).

Key Claims at a Glance

• The complaint does not specify which claims are asserted but makes a general allegation of infringement (Compl. ¶ 66). Claim 1 is the first independent claim.
• Essential elements of Independent Claim 1 include:
  • A pharmaceutical composition consisting of:
  • 80-90 wt % eslicarbazepine acetate
  • 3-10 wt % povidone
  • 3-10 wt % croscarmellose sodium
  • 0.1-3 wt % magnesium stearate
  • Wherein the composition exhibits a specified dissolution profile.

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

The Invention Explained

• Problem Addressed: The patent background describes prior art methods for synthesizing the active enantiomers of licarbazepine (the active metabolite of eslicarbazepine acetate) from a precursor, oxcarbazepine. These prior methods required a "high amount of catalyst" and large quantities of a hydride source, making the process expensive, potentially hazardous, and not "economically viable for large-scale manufacturing purposes" ('135 Patent, col. 2:12-32).
• The Patented Solution: The invention discloses an improved process for this chemical reduction that achieves high yields of "optically pure" product by controlling the pH of the reaction to a range between 6.5 and 8 ('135 Patent, Abstract; col. 3:48-52). This pH control allows for a "greatly reduced quantity of catalyst," which lowers costs, simplifies product purification, and makes the process suitable for industrial production ('135 Patent, col. 3:1-4).
• Technical Importance: This process provides a more efficient and economically viable method for producing a key stereoisomer of a drug metabolite, a common challenge in modern pharmaceutical manufacturing where specific enantiomers are often required for therapeutic effect and safety ('135 Patent, col. 2:61-65).

Key Claims at a Glance

• The complaint does not specify which claims are asserted (Compl. ¶ 77). Claim 1 is the first independent claim.
• Essential elements of Independent Claim 1 include:
  • A process for preparing (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide
  • by reduction of oxcarbazepine
  • in the presence of a specific type of ruthenium catalyst and a hydride source
  • wherein during the process a pH from 6.5 to 8 is maintained.

U.S. Patent No. 9,566,244 ('244 Patent)

• Patent Identification: U.S. Patent No. 9,566,244, "Pharmaceutical composition comprising licarbazepine acetate," Issued February 14, 2017.
• Technology Synopsis: This patent, like the '431 Patent, is directed to pharmaceutical compositions of licarbazepine acetate. It addresses the problem of the API's low bulk density and claims specific formulations, created through a wet granulation process, that improve manufacturability by increasing the preparation's density ('244 Patent, Abstract; col. 1:11-17).
• Asserted Claims: The complaint does not specify claims (Compl. ¶ 92).
• Accused Features: The composition of Hetero's Generic Product is alleged to infringe (Compl. ¶ 90).

U.S. Patent No. 9,643,929 ('929 Patent)

• Patent Identification: U.S. Patent No. 9,643,929, "Asymmetric catalytic reduction of oxcarbazepine," Issued May 9, 2017.
• Technology Synopsis: This patent, like the '135 Patent, discloses a process for synthesizing an enantiomer of licarbazepine from oxcarbazepine. The process uses a specific catalyst and hydride source while maintaining the reaction pH between 6.5 and 8, which improves efficiency and yield for industrial-scale production ('929 Patent, Abstract).
• Asserted Claims: The complaint does not specify claims (Compl. ¶ 103).
• Accused Features: The process by which Hetero's Generic Product is manufactured is alleged to infringe, with infringement occurring upon importation, sale, or use of the resulting product (Compl. ¶ 103).

U.S. Patent No. 9,750,747 ('747 Patent)

• Patent Identification: 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 or preventing various disorders, including epilepsy, by administering eslicarbazepine acetate or eslicarbazepine to a patient who is also suffering from or susceptible to absence seizures ('747 Patent, Abstract). The invention is based on the discovery that, unlike related compounds, eslicarbazepine does not aggravate absence seizures ('747 Patent, col. 1:50-55).
• Asserted Claims: The complaint does not specify claims (Compl. ¶ 114).
• Accused Features: Hetero's marketing of its generic product for the treatment of partial-onset seizures, as described in its proposed package insert, is alleged to induce infringement by healthcare providers (Compl. ¶ 115-117).

U.S. Patent No. 9,763,954 ('954 Patent)

• Patent Identification: U.S. Patent No. 9,763,954, "Therapeutical uses of eslicarbazepine," Issued September 19, 2017.
• Technology Synopsis: This patent claims methods for treating intractable epilepsy by administering eslicarbazepine. The invention is based on the discovery that eslicarbazepine is not a substrate for P-glycoprotein (P-gp) or Multiple Resistant Proteins (MRPs), which are drug-efflux transporters in the brain that contribute to pharmacoresistance in some epilepsy patients ('954 Patent, Abstract; col. 4:8-12).
• Asserted Claims: The complaint does not specify claims (Compl. ¶ 129).
• Accused Features: Hetero's marketing of its generic product for treating epilepsy is alleged to induce infringement by physicians prescribing it for patients with intractable epilepsy (Compl. ¶ 130-132).

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is "Hetero's Generic Product," described as Eslicarbazepine Acetate Tablets in 200, 400, 600, and 800 mg dosage forms (Compl. ¶ 14, 57).

Functionality and Market Context

• The complaint alleges that Hetero filed ANDA No. 211186 to obtain FDA approval to market this product as a generic version of Plaintiffs' APTIOM® tablets (Compl. ¶ 57). As part of the ANDA process, Hetero has represented to the FDA that its product is "pharmaceutically and therapeutically equivalent" to APTIOM®, which is approved for treating partial-onset seizures (Compl. ¶ 64, 38). The complaint alleges that upon FDA approval, Hetero intends to manufacture, market, and sell this generic product in the United States before the expiration of the patents-in-suit (Compl. ¶ 14, 67).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain a claim chart or detailed, element-by-element infringement allegations. The infringement theory is based on the nature of an ANDA filing under the Hatch-Waxman Act.

• Summary of Infringement Theory ('431 and '244 Patents): The infringement allegation for the composition patents is predicated on Hetero's representation to the FDA that its generic product is pharmaceutically and therapeutically equivalent to the branded APTIOM® product (Compl. ¶ 64, 90). The complaint's theory suggests that for the generic product to be equivalent, it must necessarily possess the composition claimed in the '431 and '244 Patents. The filing of the ANDA itself is alleged to be a statutory act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶ 65, 91).

• Identified Points of Contention ('431 and '244 Patents):

  • Factual Question: A central question will be whether Hetero's proposed generic product, as described in the confidential ANDA filing, actually meets all limitations of the asserted claims. This will involve discovery into the precise weight percentages of all ingredients and the physical structure of the formulation, such as whether the disintegrant is divided into intragranular and extragranular portions as described in the '431 Patent (col. 3:1-9).
  • Scope Question: The parties may dispute the meaning of claim terms defining the composition, such as the specific percentages of each component (e.g., "80-90 wt %"). The analysis may turn on whether Hetero's formulation falls within these claimed ranges.

• Summary of Infringement Theory ('135 and '929 Patents): For the process patents, the infringement theory is that the commercial manufacture, use, sale, or importation of Hetero's Generic Product after FDA approval will constitute infringement under 35 U.S.C. § 271(g), which makes it an act of infringement to import, offer to sell, sell, or use within the United States a product which is made by a process patented in the United States (Compl. ¶ 77, 103). The complaint alleges that the submission of the ANDA to seek approval for such a product is itself an act of infringement under § 271(e)(2)(A) (Compl. ¶ 76, 102).

• Identified Points of Contention ('135 and '929 Patents):

  • Evidentiary Question: The primary issue will be factual and evidentiary: what is the actual chemical process Hetero uses to synthesize its eslicarbazepine acetate API? The dispute will focus on whether that process includes the patented step of reducing oxcarbazepine while maintaining the pH within the claimed range of 6.5 to 8 ('135 Patent, cl. 1).
  • Technical Question: Assuming Hetero's process involves pH control, a technical question may arise as to whether its method of "maintaining" the pH and its specific reaction conditions fall within the scope of the claims as construed by the court.

V. Key Claim Terms for Construction

• The Term: "wherein at least part of the disintegrant is present in the granules (intragranular) and at least part of the disintegrant is extragranular" (representative language from '431 Patent, col. 3:1-9).

  • Context and Importance: This limitation defines a key structural feature of the claimed pharmaceutical composition. The infringement analysis for the '431 and '244 Patents may depend on whether Hetero's formulation process results in this specific distribution of the disintegrant. Practitioners may focus on this concept because it goes beyond simple ingredient percentages and relates to the physical architecture of the tablet, which is critical to its dissolution and bioavailability.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification describes this split as a preferred embodiment, which may suggest the overarching claims could be interpreted more broadly. The summary of the invention describes the composition as comprising granules "wherein at least part of the disintegrant is present... (intragranular) and at least part... is extragranular" ('431 Patent, col. 3:1-9), language which may support an interpretation covering any meaningful split.
    • Evidence for a Narrower Interpretation: The detailed examples provide specific ratios, such as "1/2 intra-/1/2 extragranular" ('431 Patent, Examples 6-9). A defendant may argue that these examples limit the term to a substantially even split, rather than any fractional distribution. The patent also notes that this split "improved dissolution," which may tie the term's construction to achieving that specific functional outcome ('431 Patent, col. 5:15-20).

• The Term: "wherein during the process a pH from 6.5 to 8 is maintained" ('135 Patent, cl. 1).

  • Context and Importance: This clause is the central novel step of the manufacturing process claimed in the '135 and '929 Patents. The infringement determination will likely turn on whether Hetero's manufacturing process includes this specific pH control step.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent abstract and summary broadly recite "a pH from 6.5 to 8 is maintained," which could be argued to cover any process that keeps the pH generally within that window for the effective duration of the reaction ('135 Patent, Abstract).
    • Evidence for a Narrower Interpretation: The detailed description and examples specify that the pH is controlled by "gradual, controlled manner, e.g. dropwise by titration" with formic acid ('135 Patent, col. 8:8-10). A defendant may argue that "maintained" requires this type of active, continuous adjustment and would not read on a process that uses buffers or simply starts within the pH range without active management throughout the reaction.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that upon approval, Hetero will actively induce infringement of the method-of-use patents ('747 and '954 Patents) and process patents ('135 and '929 patents) (Compl. ¶ 77, 103, 114, 129). The basis for inducement is the allegation that Hetero's promotional activities and proposed package insert will instruct physicians and patients to use the generic product in a manner that directly infringes the claimed methods of treatment (Compl. ¶ 79-80, 116-117, 131-132).
• Willful Infringement: The complaint does not explicitly use the term "willful infringement." However, it alleges that Hetero has had knowledge of the patents-in-suit at least since sending its January 18, 2018 Notice Letter (Compl. ¶ 81, 118, 133). This alleged knowledge is a predicate for potential enhanced damages if infringement is found. The prayer for relief also requests a declaration that this is an "exceptional case" warranting an award of attorney fees (Compl. p. 22, ¶ F).

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

• A core issue will be one of compositional identity: Will discovery into Hetero's confidential ANDA reveal that its proposed generic product meets the specific quantitative and structural limitations of the '431 and '244 Patents, particularly the claimed weight percentages and the intra/extragranular distribution of excipients?
• A central evidentiary question will be one of process replication: What evidence will emerge regarding Hetero’s proprietary API manufacturing process, and will that process be found to practice the pH-controlled catalytic reduction method required by the '135 and '929 Patents?
• A key legal and factual question will be one of induced infringement: Will Hetero's proposed product labeling, which seeks to mirror the indications of the branded drug, be found to encourage, recommend, or promote an infringing use by physicians, thereby satisfying the requirements for inducing infringement of the '747 and '954 method-of-use patents?