Jazz Pharma Ireland Ltd v. Alkem Laboratories Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Jazz Pharmaceuticals Ireland Limited (Ireland)
  • Defendant: Alkem Laboratories Ltd. (India)
  • Plaintiff’s Counsel: Saul Ewing LLP
• Case Identification: 2:23-cv-03182, D.N.J., 06/09/2023
• Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey based on Defendant's systematic and continuous contacts with the state, purposeful conduct of business in the district, and because the district is a likely destination for the accused generic drug product. The complaint also asserts that Defendant, as a foreign corporation, is subject to venue in any judicial district and has previously consented to jurisdiction in the D.N.J. in other patent cases.
• Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's Xyrem® (sodium oxybate) oral solution constitutes an act of infringement of seven U.S. patents directed to methods of safely administering the drug in combination with other medications.
• Technical Context: The technology concerns pharmaceutical methods for managing drug-drug interactions between gamma hydroxybutyrate (GHB), the active ingredient in Xyrem®, and a class of drugs known as monocarboxylate transporter (MCT) inhibitors, which includes common medications like valproate.
• Key Procedural History: The complaint certifies that this case is related to prior and pending litigation involving the same plaintiff and some of the same patents-in-suit against other generic drug manufacturers, including Roxane Labs, Amneal Pharmaceuticals, Lupin Inc., and Teva Pharmaceuticals. This history of serial litigation against different ANDA filers for the same drug product is common in Hatch-Waxman cases and suggests the patents are of significant commercial importance to the plaintiff.

Case Timeline

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

U.S. Patent No. 8,772,306 - "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters"

• Patent Identification: U.S. Patent No. 8772306, "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters," issued July 8, 2014 (Compl. ¶3; ’306 Patent, cover).

The Invention Explained

• Problem Addressed: The patent addresses the safety and efficacy risks that arise when administering gamma hydroxybutyrate (GHB) to patients who are also taking other common drugs that inhibit monocarboxylate transporters (MCTs) ('306 Patent, col. 1:16-22). The patent's abstract notes that co-administration with valproate can dangerously increase the effect of GHB, while co-administration with diclofenac can lower its effect, potentially causing an unsafe loss of efficacy ('306 Patent, Abstract).
• The Patented Solution: The invention provides a method for safely managing these drug-drug interactions by adjusting the dosage of GHB. The method involves reducing the GHB dose when co-administered with valproate to avoid additive toxic effects, and increasing the GHB dose when co-administered with diclofenac to ensure the patient receives a therapeutic benefit ('306 Patent, col. 2:1-40).
• Technical Importance: This dosing method allows for the continued, safe use of GHB—an important treatment for narcolepsy—in patients who may also require treatment with other commonly prescribed drugs that would otherwise create unpredictable and potentially harmful interactions (Compl. ¶11-12).

Key Claims at a Glance

• The complaint does not identify specific asserted claims, alleging infringement of "one or more claims" of the patent (Compl. ¶29). Independent claim 1 is representative of the invention.
• Essential elements of Independent Claim 1 include:
  • A method for treating a patient suffering from a condition (such as excessive daytime sleepiness or cataplexy) with GHB or a salt thereof.
  • The method comprises orally administering an adjusted dosage amount of GHB when the patient is also receiving a concomitant administration of an MCT inhibitor.
  • The adjusted amount is at least 5% decreased if the MCT inhibitor is valproate.
  • The adjusted amount is at least 5% increased if the MCT inhibitor is diclofenac.
• The complaint does not explicitly reserve the right to assert dependent claims but makes broad allegations covering the patent generally.

U.S. Patent No. 9,050,302 - "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters"

• Patent Identification: U.S. Patent No. 9050302, "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters," issued June 9, 2015 (Compl. ¶4; ’302 Patent, cover).

The Invention Explained

• Problem Addressed: The ’302 Patent, which shares a specification with the ’306 Patent, addresses the same technical problem of managing the drug-drug interaction between GHB and MCT inhibitors like valproate (’302 Patent, col. 1:12-18).
• The Patented Solution: The patent claims a more specific method for managing the interaction between GHB and divalproex sodium (a form of valproate). It requires reducing the daily dosage of GHB by a specific minimum percentage for patients whose normal, unadjusted dose falls within a specified therapeutic range (’302 Patent, col. 23:29-43). This represents a refinement of the broader dose-adjustment concept disclosed in the ’306 patent.
• Technical Importance: This patent provides more precise dosing guidance for the specific and common clinical scenario of patients taking both GHB and divalproex sodium, aiming to enhance safety and predictability of the treatment regimen (Compl. ¶12).

Key Claims at a Glance

• The complaint alleges infringement of "one or more claims" of the patent (Compl. ¶38). Independent claim 1 is representative.
• Essential elements of Independent Claim 1 include:
  • A method for the treatment of cataplexy or excessive daytime sleepiness in narcolepsy in a patient currently taking GHB.
  • The method comprises administering a concomitant dose of divalproex sodium.
  • The method further comprises reducing the daily dosage amount of GHB administered to the patient by at least 20%.
  • This reduction is relative to a baseline daily dosage of GHB between 4.5 g to 9 g that would be used in the absence of divalproex sodium.

Multi-Patent Capsules

• U.S. Patent No. 9,486,426

  • Patent Identification: U.S. Patent No. 9486426, "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters," issued November 8, 2016 (Compl. ¶5).
  • Technology Synopsis: Continuing the same inventive concept, this patent claims methods for treating narcolepsy or cataplexy by reducing the daily dosage of GHB when co-administered with divalproex sodium. The claims specify a reduction of between about 20% and about 50% relative to a baseline daily dosage.
  • Asserted Claims: "one or more claims" (Compl. ¶47).
  • Accused Features: The submission of ANDA No. 218315 for a generic sodium oxybate product whose proposed labeling allegedly instructs users to perform the claimed dosing adjustments when co-administered with divalproex sodium (Compl. ¶12-13, ¶45).

• U.S. Patent No. 10,213,400

  • Patent Identification: U.S. Patent No. 10213400, "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters," issued February 26, 2019 (Compl. ¶6).
  • Technology Synopsis: This patent further refines the dosing method, claiming a reduction in the daily GHB dosage of between about 5% and about 35% for patients also taking divalproex sodium, relative to a manufacturer's recommended starting daily dosage.
  • Asserted Claims: "one or more claims" (Compl. ¶56).
  • Accused Features: The submission of ANDA No. 218315 for a generic sodium oxybate product whose proposed labeling allegedly instructs users to perform the claimed dosing adjustments when co-administered with divalproex sodium (Compl. ¶12-13, ¶54).

• U.S. Patent No. 10,864,181

  • Patent Identification: U.S. Patent No. 10864181, "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters," issued December 15, 2020 (Compl. ¶7).
  • Technology Synopsis: This patent claims the method in more functional terms, reciting a method of treatment that involves administering a reduced daily dose of GHB to a patient concomitantly taking divalproex sodium, where the reduction "compensates for pharmacokinetic (PK) and/or pharmacodynamic (PD) changes caused by the divalproex sodium."
  • Asserted Claims: "one or more claims" (Compl. ¶65).
  • Accused Features: The submission of ANDA No. 218315 for a generic sodium oxybate product whose proposed labeling allegedly instructs users to perform the claimed dosing adjustments when co-administered with divalproex sodium (Compl. ¶12-13, ¶63).

• U.S. Patent No. 11,253,494

  • Patent Identification: U.S. Patent No. 11253494, "Method of administration of gamma hydroxybutyrate with monocarboxylate transporters," issued February 22, 2022 (Compl. ¶8).
  • Technology Synopsis: This patent claims another specific range for the method, requiring a reduction in the daily GHB dosage of about 15% to about 35% for patients also taking divalproex sodium, as compared to the recommended daily dosage.
  • Asserted Claims: "one or more claims" (Compl. ¶74).
  • Accused Features: The submission of ANDA No. 218315 for a generic sodium oxybate product whose proposed labeling allegedly instructs users to perform the claimed dosing adjustments when co-administered with divalproex sodium (Compl. ¶12-13, ¶72).

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is "Alkem’s Proposed Product," which is a generic sodium oxybate oral solution for which Defendant Alkem seeks FDA approval via Abbreviated New Drug Application (ANDA) No. 218315 (Compl. ¶1, ¶22).

Functionality and Market Context

• The complaint alleges that Alkem's Proposed Product is a generic version of Plaintiff's Xyrem® drug product (Compl. ¶1). The core of the infringement allegation centers on the proposed labeling for Alkem's product. The complaint asserts that this labeling will instruct and encourage physicians and patients to administer the generic product for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy (Compl. ¶11). Crucially, the complaint alleges the labeling will also instruct users "to modify the dose" of the product for patients who are concomitantly receiving divalproex sodium (valproate), thereby instructing users to perform the methods claimed in the patents-in-suit (Compl. ¶12-13).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain or reference a claim chart. The infringement theory is one of induced infringement under 35 U.S.C. § 271(b), based on the argument that the label for Alkem’s Proposed Product will instruct medical professionals and patients to perform the patented methods. The following tables summarize this implied infringement theory.

’306 Patent Infringement Allegations

’302 Patent Infringement Allegations

• Identified Points of Contention:
  • Evidentiary Question: A primary point of contention will be the specific language of Alkem's proposed product label. The complaint alleges the label will induce infringement, but it does not quote the label's text. The case will depend on whether the label’s instructions for dose modification in the presence of valproate meet the specific quantitative limitations of the asserted claims (e.g., "at least 20%" reduction).
  • Scope Question: The analysis will raise the question of whether a general instruction to "modify the dose" is sufficient to meet a claim limitation requiring a specific, quantified reduction (e.g., "by at least 20%"). The degree of specificity required by the claims versus that provided in the accused label will be a central issue.

V. Key Claim Terms for Construction

• The Term: "reducing the daily dosage amount... by at least 20%" ('302 Patent, Claim 1)

• Context and Importance: This term is critical because it quantifies the core inventive step of dose adjustment. The infringement analysis will turn on whether the instructions on Alkem's proposed product label direct a reduction that meets this specific numerical threshold. Practitioners may focus on this term because a label that instructs a non-specific "dose modification" or a reduction of less than 20% may fall outside the scope of the claim.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patent specification discloses a wide spectrum of possible dosage reductions, including embodiments where the dose is reduced by "at least about 1%, 5%, 10%, 15%, 20%..." ('302 Patent, col. 1:29-34). An argument could be made that the invention broadly covers the concept of dose reduction, with the specific percentages being exemplary.
  • Evidence for a Narrower Interpretation: The plain language of Claim 1 explicitly recites a floor of "at least 20%." The doctrine of claim differentiation may suggest that broader claims covering any reduction would render this specific limitation superfluous. Furthermore, the patent's detailed examples from clinical studies focus on specific, quantified adjustments, which may support a narrower construction requiring a clear, quantitative instruction ('302 Patent, Examples 1-2).

• The Term: "concomitant administration" ('306 Patent, Claim 1)

• Context and Importance: This term defines the timeframe and relationship between the administration of GHB and the MCT inhibitor that triggers the claimed dose adjustment. A dispute could arise over whether the co-administration scenario described on Alkem's label falls within the patent's definition of "concomitant."

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The term itself could be argued to have a plain and ordinary meaning of simply being taken during the same overall period of treatment, without a strict temporal limit.
  • Evidence for a Narrower Interpretation: The specification provides an explicit definition, stating that "concomitant" refers to administration "either subsequently, simultaneously, or consequently within a time period during which the effects of the first administered drug are still operative in the patient" (’306 Patent, col. 8:36-41). It further provides examples of this time period as "within two weeks, preferably within one week or even three days" ('306 Patent, col. 8:42-45), which could be used to argue for a more temporally limited construction.

VI. Other Allegations

• Indirect Infringement: The complaint's central theory is induced infringement. It alleges that Alkem, upon approval of its ANDA, will intentionally encourage direct infringement by physicians and patients by providing a product with a label that instructs users to perform the patented methods of dose adjustment (Compl. ¶30, ¶39, ¶48, ¶57, ¶66, ¶75). Knowledge of the patents is alleged based on Alkem's Paragraph IV certification letter (Compl. ¶25).
• Willful Infringement: The complaint does not explicitly allege "willful infringement" but does state for each count that the case is "an exceptional one" and requests an award of attorneys' fees under 35 U.S.C. § 285 (Compl. ¶34, ¶43, ¶52, ¶61, ¶70, ¶79). The basis for this allegation is not detailed but is predicated on Alkem's filing of an ANDA with a Paragraph IV certification challenging the validity and/or infringement of the patents-in-suit.

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

• A core issue will be one of evidentiary proof: What are the precise instructions contained within Alkem’s proposed product label? The disposition of the case will likely hinge on a direct comparison of the label's language against the specific numerical and directional limitations recited in the patent claims.
• A key legal question will be one of claim scope and inducement: Can a product label that contains a general warning or instruction to "modify the dose" of GHB when taken with valproate be construed as actively inducing infringement of claims that require a specific, quantitative reduction (e.g., "by at least 20%")? The court's construction of the claim language will be critical in determining whether Alkem's proposed label contains the requisite instruction to encourage the infringing acts.