DCT

1:23-cv-00654

Hikma Pharma USA Inc v. Padagis Israel Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00654, D. Del., 06/14/2023
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendants conduct substantial business in the district, including the distribution of generic drugs, and because two of the defendant entities are incorporated in Delaware.
  • Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff’s Kloxxado® naloxone nasal spray infringes five patents related to liquid naloxone formulations.
  • Technical Context: The technology concerns stable, high-bioavailability liquid formulations of naloxone, an opioid antagonist used for the emergency treatment of opioid overdose, delivered as a nasal spray.
  • Key Procedural History: The action was triggered by Padagis's submission of ANDA No. 216719 to the FDA and its subsequent Paragraph IV certification notice letters to Hikma, asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by its proposed generic product.

Case Timeline

Date Event
2014-07-08 Priority Date for ’510, ’814, ’155, ’713, ’139 Patents
2020-07-28 U.S. Patent No. 10,722,510 Issues
2021-04-13 U.S. Patent No. 10,973,814 Issues
2021-10-05 U.S. Patent No. 11,135,155 Issues
2023-04-04 U.S. Patent No. 11,617,713 Issues
2023-04-18 U.S. Patent No. 11,628,139 Issues
2023-05-02 Date of Defendant's "Notice Letter" regarding ANDA filing
2023-05-31 Date of Defendant's "Amended Notice Letter"
2023-06-14 Complaint Filing Date

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

U.S. Patent No. 10,722,510 - "Liquid Naloxone Spray"

The Invention Explained

  • Problem Addressed: The patent background describes a need for safe and effective liquid naloxone formulations that are stable and possess high bioavailability, noting that existing delivery methods like oral administration suffer from low bioavailability due to metabolism, while injections can require repeat dosing and cause patient discomfort (Compl. Ex. A, ’510 Patent, col. 1:47-59).
  • The Patented Solution: The invention is a stable liquid spray formulation for intranasal or sublingual administration. It comprises an effective amount of naloxone (or a salt thereof) combined with specific co-solvents (ethanol and propylene glycol), water, and a permeation enhancer to improve stability and absorption through the nasal mucosa, thereby addressing the problems of prior art formulations (’510 Patent, Abstract; col. 2:1-12).
  • Technical Importance: This formulation approach allows for rapid, non-invasive administration of a life-saving opioid antagonist, which is critical in emergency overdose situations where speed and ease of use are paramount (’510 Patent, col. 1:21-25).

Key Claims at a Glance

  • The complaint asserts one or more claims of the ’510 patent (Compl. ¶36). Independent claim 1 is representative:
    • A stable liquid spray formulation comprising from about 8% to about 12% w/w naloxone or a pharmaceutically acceptable salt thereof,
    • from about 35% to about 85% w/w water,
    • from about 3% to about 7% w/w propylene glycol,
    • from about 20% to about 50% w/w ethanol and
    • from about 0.005% to about 0.01% w/w edetate disodium dihydrate,
    • wherein the formulation is for intranasal and/or sublingual administration.

U.S. Patent No. 10,973,814 - "Liquid Naloxone Spray"

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problem as the ’510 Patent: the need for a safe, stable, and effective liquid naloxone spray formulation that overcomes the bioavailability and administration challenges of prior art naloxone products (Compl. Ex. B, ’814 Patent, col. 2:1-9).
  • The Patented Solution: The ’814 patent claims a liquid spray formulation containing naloxone that is specifically designed for intranasal administration and does not contain an isotonicity agent or a buffer. The formulation relies on a chelating agent (edetate disodium dihydrate) and specific co-solvents to achieve stability and user comfort without traditional buffering or isotonicity agents like sodium chloride (’814 Patent, col. 2:15-21; col. 3:5-12).
  • Technical Importance: By eliminating buffers and isotonicity agents, the invention may simplify the formulation while still providing a stable and effective product suitable for rapid administration in overdose scenarios (’814 Patent, col. 3:13-17).

Key Claims at a Glance

  • The complaint asserts one or more claims of the ’814 patent (Compl. ¶45). Independent claims 1, 5, and 9 are asserted. Claim 1 is representative:
    • A liquid spray formulation comprising about 7.5% w/w naloxone, or a pharmaceutically acceptable salt thereof,
    • about 66% w/w water,
    • about 5.0% w/w propylene glycol,
    • about 20.0% w/w ethanol and
    • about 0.01% w/w edetate disodium dihydrate
    • wherein the formulation does not contain an isotonicity agent or a buffer.

U.S. Patent No. 11,135,155 - "Liquid Naloxone Spray"

  • Technology Synopsis: This patent is directed to stable, non-alcoholic liquid spray formulations of naloxone. The formulation comprises naloxone, water, a chelating agent, and optionally a co-solvent like propylene glycol, providing an alternative for patient populations for whom alcohol-containing formulations may be unsuitable (Compl. Ex. C, ’155 Patent, col. 11:7-22).
  • Asserted Claims: One or more claims of the ’155 patent (Compl. ¶54).
  • Accused Features: The entirety of Padagis's proposed generic naloxone hydrochloride nasal spray formulation is accused of infringement (Compl. ¶54).

U.S. Patent No. 11,617,713 - "Liquid Naloxone Spray"

  • Technology Synopsis: This patent claims liquid naloxone spray formulations with specific ranges of ethanol and propylene glycol as co-solvents. The claims cover formulations with varying concentrations of these components, again focused on creating a stable and effective product for intranasal delivery that does not require a buffer or isotonicity agent (Compl. Ex. D, ’713 Patent, col. 57:1-12).
  • Asserted Claims: One or more claims of the ’713 patent (Compl. ¶63).
  • Accused Features: The entirety of Padagis's proposed generic naloxone hydrochloride nasal spray formulation is accused of infringement (Compl. ¶63).

U.S. Patent No. 11,628,139 - "Liquid Naloxone Spray"

  • Technology Synopsis: This patent claims liquid naloxone spray formulations defined by specific component ratios and the absence of certain excipients. Like the related patents, the invention aims to provide a stable, effective naloxone formulation for intranasal use without conventional isotonicity agents, buffers, or preservatives like benzalkonium chloride (Compl. Ex. E, ’139 Patent, col. 55:31-41).
  • Asserted Claims: One or more claims of the ’139 patent (Compl. ¶72).
  • Accused Features: The entirety of Padagis's proposed generic naloxone hydrochloride nasal spray formulation is accused of infringement (Compl. ¶72).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Padagis’s ANDA Product," identified as a naloxone hydrochloride nasal spray, 8mg/spray, for which Padagis submitted ANDA No. 216719 to the FDA (Compl. ¶28).

Functionality and Market Context

The product is a generic version of Hikma's Kloxxado® and is intended for the emergency treatment of known or suspected opioid overdose (Compl. ¶¶26, 28). The complaint alleges that the purpose of the ANDA filing is to obtain marketing approval for commercial manufacture, use, and sale of this generic product prior to the expiration of the patents-in-suit (Compl. ¶29). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain element-by-element infringement allegations or a claim chart. The central allegation is that the proposed generic product described in ANDA No. 216719 is covered by the asserted patents (Compl. ¶¶36, 45). In an ANDA case, infringement is premised on the assertion that the proposed generic drug will have the same characteristics as the patented branded drug.

’510 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A stable liquid spray formulation comprising from about 8% to about 12% w/w naloxone or a pharmaceutically acceptable salt thereof... The Padagis ANDA Product is alleged to be a stable liquid spray formulation containing naloxone hydrochloride within the claimed concentration range. ¶36 col. 6:3-5
...from about 35% to about 85% w/w water... The Padagis ANDA Product is alleged to be a formulation containing water within the claimed concentration range. ¶36 col. 6:5-6
...from about 3% to about 7% w/w propylene glycol... The Padagis ANDA Product is alleged to contain propylene glycol within the claimed concentration range. ¶36 col. 6:6-7
...from about 20% to about 50% w/w ethanol and... The Padagis ANDA Product is alleged to contain ethanol within the claimed concentration range. ¶36 col. 6:7-8
...from about 0.005% to about 0.01% w/w edetate disodium dihydrate... The Padagis ANDA Product is alleged to contain edetate disodium dihydrate within the claimed concentration range. ¶36 col. 6:8-9

Identified Points of Contention

  • Scope Questions: A primary issue will be whether the precise formulation of the Padagis ANDA Product, particularly the weight-by-weight percentages of each component, falls literally within the ranges recited in claim 1.
  • Technical Questions: The case may raise questions about the definition of "stable" as used in the claim and whether Padagis's product meets that requirement under the conditions specified in the patent (’510 Patent, col. 11:26-29).

’814 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A liquid spray formulation comprising about 7.5% w/w naloxone, or a pharmaceutically acceptable salt thereof... The Padagis ANDA Product is alleged to be a formulation containing naloxone hydrochloride at approximately the claimed concentration. ¶45 col. 31:48-50
...about 66% w/w water... The Padagis ANDA Product is alleged to contain water at approximately the claimed concentration. ¶45 col. 31:50
...about 5.0% w/w propylene glycol... The Padagis ANDA Product is alleged to contain propylene glycol at approximately the claimed concentration. ¶45 col. 31:51
...about 20.0% w/w ethanol... The Padagis ANDA Product is alleged to contain ethanol at approximately the claimed concentration. ¶45 col. 31:52
...and about 0.01% w/w edetate disodium dihydrate wherein the formulation does not contain an isotonicity agent or a buffer. The Padagis ANDA Product is alleged to contain edetate disodium dihydrate at approximately the claimed concentration and to lack an isotonicity agent or a buffer. ¶45 col. 31:52-54

Identified Points of Contention

  • Scope Questions: The term "about" preceding each concentration value raises a question of claim scope. The dispute will likely center on how much deviation from the specified percentages is permissible while still falling within the claim.
  • Technical Questions: A key question will be whether any excipients in the Padagis ANDA Product function as an "isotonicity agent" or a "buffer" as those terms are understood in the patent, which would constitute a non-infringing design.

V. Key Claim Terms for Construction

"stable" (’510 Patent, Claim 1)

  • Context and Importance: This term is critical because stability is a primary objective of the invention. Whether the accused product is "stable" in the manner required by the patent will be a core infringement question. Practitioners may focus on this term because its definition could either broaden the claim to cover various stable formulations or narrow it to those meeting specific, measurable criteria.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term "stable" in the claims is not explicitly limited, which could support an argument for its plain and ordinary meaning of resisting chemical and physical degradation over time.
    • Evidence for a Narrower Interpretation: The specification provides a specific definition: ""stable" refers to formulations which maintain greater than 95% purity following at least four weeks at about 40° C." (’510 Patent, col. 11:26-29). This explicit definition may be used to argue for a narrower, more technical construction of the term.

"about" (’814 Patent, Claim 1)

  • Context and Importance: The term "about" modifies every numerical concentration in claim 1. Its interpretation will determine the literal scope of the claimed formulation ranges and will be central to the infringement analysis, especially if the accused product's formulation is close to but not exactly at the recited percentages.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The repeated use of "about" suggests the patentee did not intend to be limited to the exact numerical values, allowing for minor variations that do not change the fundamental character of the invention.
    • Evidence for a Narrower Interpretation: The ’814 patent does not provide an explicit definition for "about." A defendant may argue that the term should be construed narrowly in light of the precision of the examples in the specification, which list component percentages to two decimal places (e.g., ’814 Patent, col. 15, Table 1).

VI. Other Allegations

Indirect Infringement

The complaint alleges that unless enjoined, Padagis will actively induce infringement upon ANDA approval through its commercial activities, including marketing and distribution (Compl. ¶¶40, 49, 58, 67, 76). The act of filing an ANDA for a generic version of a drug with knowledge of patents covering that drug is the statutory basis for the suit under the Hatch-Waxman Act.

Willful Infringement

The complaint does not contain a separate count for willful infringement. However, it alleges that Padagis had knowledge of the patents-in-suit when it submitted its ANDA, based on the Paragraph IV certification letters it sent to Hikma (Compl. ¶¶30-31, 33). These allegations could form the basis for a later claim of willfulness.

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

  • A core issue will be one of claim scope: can the term "about," as used in the context of pharmaceutical formulations in the ’814 patent, be construed to encompass the precise weight-by-weight component percentages of the Padagis ANDA product, or will the analysis turn on functional equivalence under the doctrine of equivalents?
  • A second central issue will be one of validity: as asserted in its Paragraph IV letters (Compl. ¶¶30-31), can Padagis demonstrate by clear and convincing evidence that the specific formulation ranges claimed in the patents-in-suit would have been obvious to a person of ordinary skill in the art at the time of the invention, thereby rendering the claims invalid?
  • A key evidentiary question will be one of characterization: do any of the components in the Padagis ANDA Product, even if not explicitly labeled as such, perform the function of a "buffer" or "isotonicity agent" as prohibited by negative limitations in patents like the ’814 patent, potentially allowing Padagis to design around the claims?