DCT

1:18-cv-00775

Bial Portela & Ca SA v. SPH Shanghai Zhongxi Pharmaceutical Co Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-00775, D. Del., 05/21/2018
  • Venue Allegations: Venue is alleged to be proper as Defendant is a foreign corporation and may be sued in any district where it is subject to personal jurisdiction. The complaint asserts personal jurisdiction based on Defendant's application to the FDA for approval to market its generic products in the United States, including an alleged intent to direct sales into Delaware.
  • Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs’ anticonvulsant drug APTIOM® (eslicarbazepine acetate) constitutes an act of infringement of seven U.S. patents covering the compound, its formulation, and methods of use.
  • Technical Context: The technology relates to pharmaceutical treatments for neurological conditions, specifically anticonvulsant compounds used in the management of epilepsy.
  • Key Procedural History: The litigation was triggered by Defendant's submission of ANDA No. 211247 to the FDA, which contained a "Paragraph IV certification" alleging that Plaintiffs' patents are invalid, unenforceable, and/or not infringed by the proposed generic product. Plaintiffs state they received a notice letter regarding this certification dated April 6, 2018, and filed this complaint within the 45-day statutory window provided by the Hatch-Waxman Act, thereby triggering an automatic 30-month stay on FDA approval of the ANDA.

Case Timeline

Date Event
1995-06-30 '646' Patent Priority Date
1998-05-19 '646 Patent Issue Date
2005-07-29 '135' & '929' Patents Priority Date
2007-10-26 '431' & '244' Patents Priority Date
2011-08-26 '747' & '954' Patents Priority Date
2013-02-12 '431 Patent Issue Date
2013-11-08 FDA approves APTIOM® (NDA No. 022416) for adjunctive therapy
2015-08-27 FDA approves APTIOM® for monotherapy
2015-12-08 '135 Patent Issue Date
2017-02-14 '244 Patent Issue Date
2017-05-09 '929 Patent Issue Date
2017-09-05 '747 Patent Issue Date
2017-09-13 FDA approves APTIOM® for pediatric patients
2017-09-19 '954 Patent Issue Date
2018-04-06 Defendant's Notice of Certification letter sent to Plaintiffs
2018-05-21 Complaint Filing Date

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

U.S. Patent No. 5,753,646 - “Substituted dihydrodibenzo/b,f/azepines, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compositions containing them”

The Invention Explained

  • Problem Addressed: The patent describes existing anticonvulsant drugs, such as carbamazepine, as having significant drawbacks, including adverse central nervous system effects and the induction of hepatic enzymes (’646 Patent, col. 1:15-25). It further notes that an active metabolite of a related drug, oxcarbazepine, has low oral bioavailability, hampering its practical use (’646 Patent, col. 1:28-35).
  • The Patented Solution: The patent discloses a new class of compounds that function as prodrugs, designed to be metabolized in the body into the active antiepileptic agent, 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (’646 Patent, col. 1:36-40). This is achieved by attaching various chemical groups (defined as "R") to the 10-hydroxy position of the core molecule via an ester linkage, a modification intended to improve oral bioavailability and the overall therapeutic profile of the drug (’646 Patent, Abstract; col. 1:50-54).
  • Technical Importance: This prodrug strategy aimed to create a therapy with the benefits of oxcarbazepine's metabolic profile while overcoming the practical administration challenges posed by its active metabolite's poor bioavailability (’646 Patent, col. 1:36-40).

Key Claims at a Glance

  • The complaint asserts one or more claims of the ’646 Patent (Compl. ¶54); independent claim 1 is representative of the patented compounds.
  • Claim 1 claims:
    • A compound of a specific chemical structure (general formula I), or a stereoisomer thereof
    • Wherein the structure is a 10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide
    • Substituted at the 10-position with an acyloxy group (-O-CO-R)
    • Wherein R is selected from a group including hydrogen, alkyl, aryl, or pyridyl
  • The complaint reserves the right to assert additional claims (Compl. ¶54).

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

The Invention Explained

  • Problem Addressed: The patent specification states that the active pharmaceutical ingredient (API), eslicarbazepine acetate, has an "extremely low bulk density" and "exhibits poor flowability" (’431 Patent, col. 5:3-10). These physical properties make the compound difficult to handle on an industrial scale and challenging to compress into tablets of a reasonable size that dissolve properly (’431 Patent, col. 5:10-14).
  • The Patented Solution: The patent describes a pharmaceutical composition made via a wet granulation process that solves these formulation challenges (’431 Patent, col. 3:4-13). The invention involves mixing the API with specific excipients, including a binder (e.g., povidone) and a disintegrant (e.g., croscarmellose sodium), and processing them into granules before final compression into a tablet (’431 Patent, col. 3:1-6). This process is claimed to more than double the bulk density of the drug material, improving its flow and compressibility for large-scale manufacturing (’431 Patent, col. 5:29-33).
  • Technical Importance: This formulation technology enables the efficient, large-scale manufacturing of a drug that would otherwise be difficult to produce in a consistent, solid oral dosage form due to its poor physical characteristics (’431 Patent, col. 3:7-13).

Key Claims at a Glance

  • The complaint asserts one or more claims of the ’431 Patent (Compl. ¶69); independent claim 1 is representative of the patented composition.
  • Claim 1 claims 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 specific dissolution profile (at least 60% at 30 minutes under defined conditions)
  • The complaint reserves the right to assert additional claims (Compl. ¶69).

Multi-Patent Capsules

  • Patent Identification: U.S. Patent No. 9,206,135, entitled “Asymmetric catalytic reduction of oxcarbazepine,” issued December 8, 2015.

  • Technology Synopsis: This patent describes a process for preparing specific stereoisomers (the (S)- or (R)-enantiomer) of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide, the active metabolite of eslicarbazepine acetate (’135 Patent, Abstract). The process involves the chemical reduction of oxcarbazepine using a specific ruthenium-based catalyst and a hydride source while controlling the reaction pH to achieve high optical purity (’135 Patent, col. 4:5-10).

  • Asserted Claims: One or more claims are asserted (Compl. ¶80).

  • Accused Features: The complaint alleges that Defendant’s manufacture of its generic product will infringe the patent (Compl. ¶¶76, 80).

  • Patent Identification: U.S. Patent No. 9,566,244, entitled “Pharmaceutical composition comprising licarbazepine acetate,” issued February 14, 2017.

  • Technology Synopsis: This patent, like the ’431 Patent, relates to a pharmaceutical formulation of eslicarbazepine acetate designed to address the API's poor physical properties (’244 Patent, col. 1:13-18). It claims a tablet or capsule containing a granular phase (with the drug and a super-disintegrant) and an extragranular phase (with a lubricant and a super-disintegrant), along with specific excipients (’244 Patent, col. 16:1-20).

  • Asserted Claims: One or more claims are asserted (Compl. ¶95).

  • Accused Features: The complaint alleges that Defendant's proposed generic eslicarbazepine acetate tablets infringe the patent (Compl. ¶¶91, 93).

  • Patent Identification: U.S. Patent No. 9,643,929, entitled “Asymmetric catalytic reduction of oxcarbazepine,” issued May 9, 2017.

  • Technology Synopsis: This patent is related to the ’135 Patent and similarly describes a process for the stereoselective synthesis of the active metabolite of eslicarbazepine acetate (’929 Patent, Abstract). It discloses a method using a ruthenium catalyst and a hydride source while maintaining the reaction pH between 6.5 and 8 to produce the desired single enantiomer in high yield and purity (’929 Patent, col. 3:47-49).

  • Asserted Claims: One or more claims are asserted (Compl. ¶106).

  • Accused Features: The complaint alleges that Defendant’s manufacture of its generic product will infringe the patent (Compl. ¶¶102, 106).

  • Patent Identification: U.S. Patent No. 9,750,747, entitled “Treatments involving eslicarbazepine acetate or eslicarbazepine,” issued September 5, 2017.

  • Technology Synopsis: This patent claims methods of treating various neurological disorders, including epilepsy and neuropathic pain, by administering eslicarbazepine acetate or eslicarbazepine to a patient who is susceptible to absence seizures (’747 Patent, Abstract). The patent asserts the unexpected finding that, unlike related drugs, eslicarbazepine acetate does not aggravate absence seizures (’747 Patent, col. 2:50-55).

  • Asserted Claims: One or more claims are asserted (Compl. ¶117).

  • Accused Features: The complaint alleges that the use of Defendant’s generic product as directed by its proposed labeling will infringe the patent (Compl. ¶¶118, 120).

  • Patent Identification: U.S. Patent No. 9,763,954, entitled “Therapeutical uses of eslicarbazepine,” issued September 19, 2017.

  • Technology Synopsis: This patent claims methods of treating intractable epilepsy conditions by administering eslicarbazepine or its acetate form (’954 Patent, col. 16:63-67). The invention is based on the discovery that S-licarbazepine (the active metabolite) is not a substrate for P-glycoprotein (P-gp) or Multiple Resistant Proteins (MRPs), which are drug-efflux pumps in the brain that contribute to pharmacoresistance in some patients (’954 Patent, col. 4:8-13).

  • Asserted Claims: One or more claims are asserted (Compl. ¶132).

  • Accused Features: The complaint alleges that the use of Defendant’s generic product as directed by its proposed labeling for treating epilepsy will infringe the patent (Compl. ¶¶133, 135).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is Defendant SPH Shanghai Zhongxi’s proposed generic eslicarbazepine acetate tablets in 200, 400, 600, and 800 mg dosage forms, for which it seeks FDA approval via ANDA No. 211247 (Compl. ¶¶7, 45).

Functionality and Market Context

  • The proposed product is a generic version of Plaintiffs’ APTIOM® tablets and contains eslicarbazepine acetate as its active ingredient (Compl. ¶¶23, 45). The complaint alleges that the Defendant has represented to the FDA that its product is "pharmaceutically and therapeutically equivalent" to APTIOM® tablets, which are approved for the treatment of partial-onset seizures (Compl. ¶¶23, 52). Defendant's filing of the ANDA indicates its intent to manufacture, market, and sell this generic product in the United States prior to the expiration of the patents-in-suit (Compl. ¶50).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide detailed infringement contentions or claim charts. The infringement theory is predicated on the allegation that the Defendant's proposed generic product is pharmaceutically and therapeutically equivalent to the branded APTIOM® product, and that its manufacture, use, and sale will therefore infringe the patents covering that product (Compl. ¶¶52, 67).

'646 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of general formula I, or stereoisomer thereof... Defendant’s generic product contains eslicarbazepine acetate as its active ingredient. Eslicarbazepine acetate is the (S)-stereoisomer of 10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide, a compound alleged to fall within the scope of Formula I. ¶¶23, 45, 52-53 col. 8:51-64

'431 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition consisting of: 80-90 wt % eslicarbazepine acetate, 3-10 wt % povidone, 3-10 wt % croscarmellose sodium, and 0.1-3 wt % magnesium stearate... Defendant’s ANDA product is alleged to be a pharmaceutical composition that is therapeutically equivalent to APTIOM® and will therefore contain the claimed ingredients in the specified weight percentages. ¶¶67-68 col. 16:15-20
wherein the composition exhibits a dissolution of at least 60% at about 30 minutes at a temperature of 37±0.5° C. and a pH of about 4.5 using a paddle apparatus at a speed of about 100 rpm. Defendant's product, by virtue of its alleged bioequivalence to the branded drug, will exhibit the claimed dissolution profile required for proper drug release and absorption. ¶67 col. 16:20-24
  • Identified Points of Contention:
    • Scope Questions: A central question for the formulation patents (e.g., the ’431 Patent) will be the interpretation of the term "consisting of." Whether Defendant's product contains any additional, unlisted excipients may be dispositive of literal infringement.
    • Technical Questions: For the formulation patents, a key factual dispute will be whether the specific formulation detailed in Defendant's confidential ANDA submission falls within the precise weight percentage ranges recited in the claims. For the process patents (e.g., the ’135 Patent), the dispute will center on whether the manufacturing process Defendant intends to use is the same as, or equivalent to, the patented process.

V. Key Claim Terms for Construction

  • The Term: "consisting of" (from Claim 1 of the ’431 Patent)
  • Context and Importance: This term, known as a "closed" transition phrase, is critical for defining the scope of the composition claims. Its interpretation will determine whether the presence of any additional, unlisted ingredients in Defendant's generic product would place it outside the literal scope of the claim. Practitioners may focus on this term because even minor formulation differences could be sufficient to support a non-infringement argument.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The complaint does not provide sufficient detail for analysis of this element.
    • Evidence for a Narrower Interpretation: The specification of the ’431 Patent separately discusses aspects of the invention where the composition "does not contain any filler" or "does not include a wetting agent" (’431 Patent, col. 2:11-17). This may suggest that the use of "consisting of" in claim 1 was a deliberate choice to strictly limit the composition to the four recited components, excluding other conventional excipients.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement for all asserted patents. The factual basis is the allegation that Defendant, through its proposed product labeling and instructions, will actively encourage and instruct physicians and patients to use the generic product in a manner that directly infringes the method-of-use claims (e.g., administering the claimed compound for treating seizures) (Compl. ¶¶55-57, 81-83). It also alleges contributory infringement, stating the product is especially adapted for an infringing use and has no substantial non-infringing use (Compl. ¶¶60-61).
  • Willful Infringement: The complaint does not use the term "willful infringement." However, it alleges that Defendant had knowledge of the patents-in-suit as evidenced by its April 6, 2018 Notice Letter (Compl. ¶58). The prayer for relief requests a declaration that this is an "exceptional case" and an award of attorneys' fees, which may be predicated on allegations of litigation misconduct or infringement that is willful or otherwise culpable (Compl. p. 26, ¶F).

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

  • A central issue will be one of formulation identity: does the specific composition detailed in Defendant’s confidential ANDA submission literally meet the precise weight-percentage limitations and the restrictive "consisting of" language of the asserted formulation claims, or do differences in excipients or amounts provide a basis for non-infringement?
  • A key legal question will be one of validity: given that infringement of the compound patent (’646) and method of use patents (e.g., ’747, ’954) may be straightforward if the generic product is approved for the same indication, the litigation will likely focus heavily on Defendant's defenses that these patents are invalid, for instance, on grounds of obviousness over the prior art.
  • An evidentiary question will be one of process equivalence: for the patents claiming a specific manufacturing process (e.g., ’135), what evidence exists to show that the process used by the Defendant to synthesize its API is the same as, or equivalent to, the patented method?