DCT

1:24-cv-00718

SK Biopharma Co Ltd v. Aurobindo Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00718, D. Del., 06/18/2024
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware based on the Delaware incorporation of Defendant Aurobindo USA, Inc. and Plaintiff SK Life Science, Inc. For the foreign defendants, venue is based on provisions for foreign corporations under 28 U.S.C. §§ 1391(c)(3) and 1400(b).
  • Core Dispute: Plaintiffs allege that Defendants’ filing of Abbreviated New Drug Applications (ANDAs) to market generic versions of Plaintiffs’ epilepsy drug XCOPRI® (cenobamate) infringes patents covering the active pharmaceutical ingredient and methods of its use in combination therapy.
  • Technical Context: The dispute involves cenobamate, an antiepileptic drug (AED) used for treating partial-onset seizures, and its pharmacokinetic interactions when co-administered with other AEDs.
  • Key Procedural History: The patents-in-suit are listed in the U.S. Food and Drug Administration's (FDA) "Orange Book" for XCOPRI® (NDA No. 212839). U.S. Patent No. 7,598,279 was granted a five-year patent term extension (PTE) under 35 U.S.C. § 156 based on the regulatory review period of XCOPRI®.

Case Timeline

Date Event
2005-04-22 ’279 Patent Priority Date
2009-10-06 ’279 Patent Issue Date
2018-03-21 ’133 Patent Priority Date
2020-03-10 FDA Approval of XCOPRI®
2023-05-23 ’133 Patent Issue Date
2024-05-06 Aurobindo Notice of Paragraph IV Certification
2024-05-10 Zenara Notice of Paragraph IV Certification
2024-06-18 Complaint Filing Date

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

U.S. Patent No. 7,598,279 - “Neurotherapeutic Azole Compounds,” issued October 6, 2009 (’279 Patent)

The Invention Explained

  • Problem Addressed: The patent is situated in the field of developing neurotherapeutic agents for treating central nervous system (CNS) disorders, noting that arylalkyl azole compounds have been shown to be useful as anticonvulsants (’279 Patent, col. 1:10-14). The patent aims to provide a new class of such compounds.
  • The Patented Solution: The invention discloses novel azole compounds containing a carbamoyl group that are asserted to be effective anticonvulsants for treating disorders such as epilepsy, anxiety, and depression (’279 Patent, Abstract). The patent claims a specific chemical structure, carbamic acid (R)-(+)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester, which is the active ingredient cenobamate, as an enantiomerically pure compound (’279 Patent, col. 21:8-14).
  • Technical Importance: The patent describes a new chemical entity for the treatment of CNS disorders, which ultimately became the first approved pharmaceutical product containing cenobamate (Compl. ¶35).

Key Claims at a Glance

  • The complaint asserts dependent claim 11 against Zenara (Compl. ¶85).
  • Essential elements of claim 11 (which depends from claims 1, 8, 9, and 10):
    • An azole compound that is carbamic acid (R)-(+)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.
    • The compound is substantially free of its (S)-enantiomer.
    • The (R)-enantiomer is present to the extent of at least about 95%.

U.S. Patent No. 11,654,133 - “Use of [(1R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] Carbamate in Combination Therapy,” issued May 23, 2023 (’133 Patent)

The Invention Explained

  • Problem Addressed: The patent background notes that many epilepsy patients require treatment with multiple antiepileptic drugs (AEDs). Such combination therapies are "highly susceptible to drug interactions," which can alter the pharmacokinetics (PK) of the drugs and "result in treatment failure or safety concerns" (’133 Patent, col. 1:45-51).
  • The Patented Solution: The invention provides a method for treating epilepsy by co-administering cenobamate with other specific AEDs (phenobarbital or phenytoin). The method comprises actively "modifying the therapeutically effective amount of the antiepileptic drug" to adjust its Area Under the Curve (AUC), a measure of total drug exposure (’133 Patent, col. 2:25-39). This dose modification is intended to manage the significant pharmacokinetic interaction caused by cenobamate, which can substantially increase the AUC of the co-administered drug (’133 Patent, Fig. 2). U.S. Patent 11,654,133, Figure 2 is a graph showing that co-administration of cenobamate significantly increases the AUC of phenytoin and phenobarbital relative to other AEDs (’133 Patent, Fig. 2).
  • Technical Importance: The invention provides a specific method to manage a clinically significant drug-drug interaction, potentially improving the safety and efficacy of combination therapy for epilepsy patients.

Key Claims at a Glance

  • The complaint asserts independent claim 1 against both Aurobindo and Zenara (Compl. ¶68, ¶104).
  • Essential elements of claim 1:
    • A method for treating a patient suffering from epilepsy.
    • The method involves co-administering a therapeutically effective amount of cenobamate and one or two antiepileptic drugs selected from phenobarbital and phenytoin.
    • The method comprises modifying the therapeutically effective amount of the antiepileptic drug.
    • This modification adjusts the AUC of the antiepileptic drug by at least 5% compared to its AUC when administered without cenobamate.
    • The therapeutically effective amount of cenobamate is from about 100 mg/day to about 400 mg/day.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are the generic cenobamate tablets for which Defendants seek FDA approval via Abbreviated New Drug Application (ANDA) No. 219473 (Aurobindo) and ANDA No. 219403 (Zenara) (Compl. ¶1, ¶50, ¶56). The tablets are for dosages of 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg (Compl. ¶51, ¶57).

Functionality and Market Context

  • The Defendants' ANDA products contain cenobamate as the active pharmaceutical ingredient for the treatment of partial-onset seizures in adults (Compl. ¶31-32, ¶51, ¶57).
  • The complaint alleges that the proposed prescribing information for the generic products will be substantially the same as the FDA-approved label for XCOPRI® (Compl. ¶52, ¶58). This label allegedly instructs co-administration with other AEDs, including phenytoin and phenobarbital, and further instructs physicians to reduce the dosage of these drugs when co-administered with cenobamate to manage pharmacokinetic interactions (Compl. ¶42, ¶46, ¶70).

IV. Analysis of Infringement Allegations

’279 Patent Infringement Allegations

Claim Element (from Dependent Claim 11) Alleged Infringing Functionality Complaint Citation Patent Citation
The azole of claim 10, wherein said compound is carbamic acid (R)-(+)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester Zenara’s ANDA Products are tablets that comprise cenobamate, which is (R)-(+)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester, as the active pharmaceutical ingredient. ¶57, ¶87 col. 21:8-14
substantially free of its (S)enantiomer and said (R)-enantiomer is present to the extent of at least about 95%. Zenara’s ANDA product is a purported generic version of XCOPRI®, whose active ingredient is the (R)-enantiomer of cenobamate, and to be an approved generic, it must have the same active ingredient. ¶56, ¶86-87 col. 9:5-14

’133 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating a patient who is suffering from epilepsy with co-administering a therapeutically effective amount of (i) ... cenobamate ... and (ii) one or two antiepileptic drugs, ... selected from the group consisting of phenobarbital and phenytoin. Defendants' proposed prescribing information will instruct the administration of their cenobamate products as an adjunctive therapy for epilepsy, including with phenytoin and phenobarbital. ¶42, ¶70, ¶106 col. 2:25-39
modifying the therapeutically effective amount of the antiepileptic drug to adjust AUC of the antiepileptic drug obtained after the co-administration having at least 5% difference to the level of AUC obtained after the administration of antiepileptic drug to the patient without cenobamate... The proposed prescribing information will instruct physicians to "gradually decrease phenytoin dosage by up to 50%" and to "consider a reduction in dosage of phenobarbital" when co-administered with cenobamate, which is alleged to reduce the AUC by at least 5%. ¶46, ¶48, ¶49, ¶70 col. 4:40-50
wherein the therapeutically effective amount of cenobamate ... is from about 100 mg/day to about 400 mg/day The proposed prescribing information recommends a maintenance dosage of 200 mg/day, with a maximum dose not to exceed 400 mg/day, which falls within the claimed range. ¶41, ¶68 col. 2:50-53

Identified Points of Contention

  • Scope Questions: For the ’133 Patent, a question may arise as to whether the label's instruction to "consider a reduction in dosage of phenobarbital" constitutes an instruction to perform the claimed step of "modifying the therapeutically effective amount ... to adjust AUC."
  • Technical Questions: The infringement case for the ’133 Patent relies on the factual assertion that the dosage modifications instructed by the label will necessarily result in an AUC adjustment of "at least 5% difference." While the complaint makes this allegation (Compl. ¶48), it may become a point of factual dispute requiring expert evidence.

V. Key Claim Terms for Construction

The Term: "modifying the therapeutically effective amount of the antiepileptic drug to adjust AUC" (from ’133 Patent, claim 1)

  • Context and Importance: This term recites the central active step of the claimed method. The outcome of the case may depend on whether the instructions in the Defendants' proposed drug labels are construed as directing this specific action.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification repeatedly links the co-administration of cenobamate with the need for dose adjustments of other AEDs to manage safety and toxicity concerns arising from PK interactions (’133 Patent, col. 1:48-54). This context may support a construction where any instructed dose change made in response to a known PK interaction constitutes "modifying...to adjust AUC."
    • Evidence for a Narrower Interpretation: The claim links the "modifying" step to the purpose of "adjust[ing] AUC." A defendant might argue that for infringement, the label must explicitly instruct a modification for the purpose of adjusting AUC, rather than simply instructing a dose reduction for general safety reasons.

The Term: "substantially free of its (S)enantiomer" (from ’279 Patent, claim 11)

  • Context and Importance: This term, along with "at least about 95%," defines the required enantiomeric purity of the claimed compound. Practitioners may focus on this term if the Defendants' manufacturing process for its generic API results in a different purity profile than that of the branded product.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The word "substantially" suggests that minor, insignificant amounts of the (S)-enantiomer would not defeat a claim of infringement. The patent does not provide an explicit definition beyond the "at least about 95%" recitation in the same claim.
    • Evidence for a Narrower Interpretation: The patent emphasizes the importance of pure enantiomers, stating that the invention includes "substantially pure enantiomers such as the R and S enantiomers" (’279 Patent, col. 9:5-8). This focus on purity could be used to argue for a strict interpretation of the term.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement of both the ’279 and ’133 patents. The basis for this allegation is that Defendants, upon receiving FDA approval, will market and sell their ANDA products with proposed prescribing information that will allegedly instruct healthcare professionals and patients to administer the cenobamate compound and to perform the claimed method of treatment, including the dose modification steps (Compl. ¶70, ¶89, ¶106).
  • Willful Infringement: Willfulness is alleged based on Defendants having actual and constructive notice of the patents-in-suit prior to filing their ANDAs (Compl. ¶71, ¶90, ¶107). The complaint asserts that Defendants' certification of invalidity, unenforceability, and/or noninfringement lacked an adequate justification, rendering the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶72, ¶91, ¶108).

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

  • A core issue will be one of induced infringement: Will the instructions in the proposed generic drug label, which recommend specific dosage reductions for co-administered drugs like phenytoin, be deemed to actively encourage and instruct medical professionals to perform the patented method of "modifying" a drug amount "to adjust AUC," as claimed in the ’133 patent?
  • A central validity question for the ’133 patent will be obviousness: Given the general knowledge in pharmacology that new drugs can cause pharmacokinetic interactions, was it obvious for a skilled artisan to conduct routine studies to identify such interactions with cenobamate and, upon discovering them, to instruct standard dose adjustments to ensure patient safety?
  • For the ’279 patent, which claims the cenobamate compound itself, the dispute will likely focus on validity, particularly whether the specific (R)-enantiomer of cenobamate, at a purity of at least 95%, was obvious in light of prior art disclosing related neurotherapeutic azole compounds.