1:23-cv-00630
Hikma Pharma USA Inc v. Padagis Israel Pharma Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Hikma Pharmaceuticals USA Inc. (Delaware)
- Defendant: Padagis Israel Pharmaceuticals Limited (Israel), Padagis US LLC (Delaware), and Padagis LLC (Delaware)
- Plaintiff’s Counsel: Winston & Strawn LLP
- Case Identification: 1:23-cv-00630, W.D. Mich., 06/16/2023
- Venue Allegations: Venue is based on Defendant Padagis LLC maintaining a place of business in Allegan, Michigan, and Defendant Padagis Israel's consent to jurisdiction in the district for actions arising from its Abbreviated New Drug Application (ANDA) submission.
- Core Dispute: Plaintiff alleges that Defendants' filing of an ANDA to market a generic version of Plaintiff's Kloxxado® (naloxone hydrochloride) Nasal Spray constitutes an act of infringement of five U.S. patents.
- Technical Context: The technology relates to stable, liquid formulations of naloxone, a life-saving opioid antagonist, designed for rapid administration as a nasal spray for the emergency treatment of opioid overdose.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 216719 with a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by the proposed generic product. The patents are listed in the U.S. Food and Drug Administration's "Orange Book" for Kloxxado®. The complaint was filed within the 45-day statutory window, triggering an automatic 30-month stay on the FDA's approval of the ANDA.
Case Timeline
| Date | Event |
|---|---|
| 2014-07-08 | Earliest Priority Date for all Patents-in-Suit |
| 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 | Defendant sends Notice Letter of ANDA filing to Plaintiff |
| 2023-05-03 | Plaintiff receives Notice Letter |
| 2023-05-31 | Defendant sends Amended Notice Letter |
| 2023-06-16 | Complaint Filed |
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's background section notes that naloxone, an opioid overdose treatment, has low bioavailability when taken orally due to "hepatic first pass metabolism," and that injectable forms have a short half-life requiring repeat dosing (Compl. Ex. A, ’510 Patent, col. 2:47-52). This creates a need for a stable, safe, and effective liquid spray formulation suitable for non-oral, non-injectable administration (Compl. Ex. A, ’510 Patent, col. 2:53-59).
- The Patented Solution: The invention provides stable liquid spray formulations of naloxone designed for intranasal or sublingual delivery, which bypasses first-pass metabolism (Compl. Ex. A, ’510 Patent, col. 2:60-62). The formulations comprise naloxone, water, a co-solvent system (such as ethanol and propylene glycol), an antioxidant, a chelating agent, and a permeation enhancer to ensure chemical stability and effective absorption through the nasal mucosa (Compl. Ex. A, ’510 Patent, col. 2:1-11).
- Technical Importance: This technology offers a non-invasive, rapid-acting delivery method for a critical emergency medication, making it more accessible for administration by non-medical personnel in overdose situations (Compl. Ex. A, ’510 Patent, col. 2:20-26).
Key Claims at a Glance
- The complaint asserts infringement of one or more unspecified claims (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.
- The complaint broadly alleges infringement of "one or more claims," reserving the right to assert dependent claims (Compl. ¶36).
U.S. Patent No. 10,973,814 - “Liquid naloxone spray”
The Invention Explained
- Problem Addressed: The patent identifies a need for safe, stable, and effective liquid naloxone spray formulations, while distinguishing the invention from prior art aqueous nasal sprays that contain an isotonicity agent (e.g., sodium chloride) and/or a buffer (e.g., citric acid) (Compl. Ex. B, ’814 Patent, col. 1:39-54).
- The Patented Solution: The invention is a liquid spray formulation containing naloxone, water, a co-solvent, and a chelating agent, which is explicitly defined as not containing an isotonicity agent or a buffer (Compl. Ex. B, ’814 Patent, Abstract; col. 3:20-30). This approach aims to create a stable and effective formulation with fewer excipients (Compl. Ex. B, ’814 Patent, col. 3:12-16).
- Technical Importance: Developing a stable and user-tolerable nasal spray without conventional isotonicity or buffering agents represents a distinct formulation strategy that can reduce manufacturing complexity and potential for component interactions (Compl. Ex. B, ’814 Patent, col. 3:12-16).
Key Claims at a Glance
- The complaint asserts infringement of one or more unspecified claims (Compl. ¶45). Independent 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.
- The complaint broadly alleges infringement of "one or more claims," reserving the right to assert dependent claims (Compl. ¶45).
U.S. Patent No. 11,135,155 - “Liquid naloxone spray”
Technology Synopsis
The ’155 Patent, part of the same family, is directed at stable liquid naloxone formulations for intranasal delivery (Compl. Ex. C, ’155 Patent, col. 2:3-9). The claimed invention is a nasal spray formulation comprising naloxone, water, and a chelating agent, specifically excluding an isotonicity agent or buffer, presenting a simplified formulation approach (Compl. Ex. C, ’155 Patent, col. 2:25-30, Claim 1).
Asserted Claims
The complaint is general; independent claims 1 and 12 are asserted (Compl. ¶54).
Accused Features
The complaint alleges that "Padagis's ANDA Product" is covered by one or more claims of the ’155 Patent (Compl. ¶54).
U.S. Patent No. 11,617,713 - “Liquid naloxone spray”
Technology Synopsis
The ’713 Patent is also directed at stable liquid naloxone formulations for intranasal delivery that do not contain an isotonicity agent or a buffer (Compl. Ex. D, ’713 Patent, col. 2:3-9). The claims cover specific formulations comprising naloxone, water, co-solvents (ethanol and propylene glycol), and a chelating agent, defining the invention by the presence and concentration of these components and the absence of others (Compl. Ex. D, ’713 Patent, Claim 1).
Asserted Claims
The complaint is general; independent claims 1, 11, and 15 are asserted (Compl. ¶63).
Accused Features
The complaint alleges that "Padagis's ANDA Product" is covered by one or more claims of the ’713 Patent (Compl. ¶63).
U.S. Patent No. 11,628,139 - “Liquid naloxone spray”
Technology Synopsis
The ’139 Patent continues the theme of stable, buffer-free, and isotonicity-agent-free naloxone nasal sprays (Compl. Ex. E, ’139 Patent, col. 2:3-9). The claims define a formulation where naloxone is the sole active ingredient, combined with specific concentrations of ethanol, propylene glycol, water, and edetate disodium dihydrate (Compl. Ex. E, ’139 Patent, Claim 1).
Asserted Claims
The complaint is general; independent claims 1 and 7 are asserted (Compl. ¶72).
Accused Features
The complaint alleges that "Padagis's ANDA Product" is covered by one or more claims of the ’139 Patent (Compl. ¶72).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is "Padagis's naloxone hydrochloride nasal spray, 8mg/spray," for which Defendant submitted ANDA No. 216719 to the FDA (Compl. ¶28). The complaint refers to this as "Padagis's ANDA Product."
Functionality and Market Context
The product is identified as a generic version of Plaintiff's Kloxxado® product, which is indicated for the emergency treatment of opioid overdose (Compl. ¶28, ¶26). As this is a Hatch-Waxman action, the act of infringement alleged is the submission of the ANDA itself, which seeks FDA approval to market the generic drug before the expiration of the patents-in-suit (Compl. ¶29, ¶37). The complaint does not provide technical details on the specific formulation of the accused product, as this information is contained within the confidential ANDA filing.
IV. Analysis of Infringement Allegations
The complaint alleges that the submission of the ANDA for the accused product, which if commercially manufactured and sold would infringe, constitutes infringement under 35 U.S.C. § 271(e)(2) (Compl. ¶37, ¶46, ¶55, ¶64, ¶73). The complaint does not include a detailed claim chart. No probative visual evidence provided in complaint.
U.S. Patent No. 10,722,510 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 ANDA product is alleged to be a stable liquid spray formulation containing naloxone hydrochloride within the claimed concentration range. | ¶36 | col. 6:1-12 |
| ...from about 35% to about 85% w/w water... | The ANDA product is alleged to contain water within the claimed concentration range. | ¶36 | col. 3:37-42 |
| ...from about 3% to about 7% w/w propylene glycol... | The ANDA product is alleged to contain propylene glycol within the claimed concentration range. | ¶36 | col. 6:60-63 |
| ...from about 20% to about 50% w/w ethanol and... | The ANDA product is alleged to contain ethanol within the claimed concentration range. | ¶36 | col. 6:55-59 |
| ...from about 0.005% to about 0.01% w/w edetate disodium dihydrate... | The ANDA product is alleged to contain edetate disodium dihydrate within the claimed concentration range. | ¶36 | col. 3:60-64 |
Identified Points of Contention
- Scope Questions: A central question will be the proper construction of "about" as it applies to each claimed weight percentage. The scope afforded to this term will determine whether the precise formulation in the Padagis ANDA falls within the claimed ranges.
- Technical Questions: The primary factual dispute will be a direct comparison of the accused product's formulation, as detailed in its ANDA, against the specific concentration ranges required by Claim 1. Any deviation from one of the five recited concentration ranges may support a non-infringement argument.
U.S. Patent No. 10,973,814 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... 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... | The ANDA product is alleged to contain each of the recited components at approximately the claimed weight percentages. | ¶45 | col. 4:35-42 |
| ...wherein the formulation does not contain an isotonicity agent or a buffer... | The ANDA product is alleged to lack any component that functions as an isotonicity agent or a buffer. | ¶45 | col. 3:20-30 |
Identified Points of Contention
- Scope Questions: The interpretation of "isotonicity agent" and "buffer" will be critical. The dispute may center on whether these terms apply only to components added for the primary purpose of adjusting tonicity or pH, or if they cover any component that has such a secondary effect.
- Technical Questions: A key factual question is whether any excipient in the accused product, regardless of its primary designated function, could be characterized by a court as an "isotonicity agent or a buffer." Additionally, discovery will determine if the product's component concentrations are close enough to be considered "about" the claimed values.
V. Key Claim Terms for Construction
Term: "about" (from ’510 Patent, Claim 1 and ’814 Patent, Claim 1)
- Context and Importance: This term modifies every numerical concentration in the asserted claims. Its construction is dispositive for infringement, as it defines the permissible boundary around each claimed percentage. Practitioners may focus on this term because even small differences in the ANDA product's formulation could place it outside a narrowly construed range.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specifications disclose very broad ranges for components (e.g., water from "about 10% to about 99% w/w") which may suggest the inventors did not intend the claimed numbers to be exact and inflexible (Compl. Ex. A, ’510 Patent, col. 3:37-39).
- Evidence for a Narrower Interpretation: The patents provide numerous examples with highly specific weight percentages (e.g., "31.32% w/w water," "10.26% w/w naloxone") (Compl. Ex. A, ’510 Patent, col. 6:25-26). A party could argue that "about" should be interpreted narrowly to cover only minor variations consistent with standard measurement tolerances in the pharmaceutical arts.
Term: "isotonicity agent" and "buffer" (from ’814 Patent, Claim 1)
- Context and Importance: These are negative limitations; infringement requires their absence. The case could turn entirely on whether any substance in the accused product meets the definition of these terms.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation (favors Defendant): The patents do not explicitly define these terms, leaving them open to a broad, plain, and ordinary meaning. A defendant could argue that any component that has a measurable effect on the formulation's tonicity or pH, even if secondary to its main purpose, qualifies as an "isotonicity agent" or "buffer."
- Evidence for a Narrower Interpretation (favors Plaintiff): The background of the ’814 Patent distinguishes the invention from a prior art product (Narcan®) that contains "sodium chloride as an isotonicity agent" (Compl. Ex. B, ’814 Patent, col. 1:43-44). This context suggests the terms refer to conventional excipients added specifically for that purpose, not substances with incidental effects.
VI. Other Allegations
Indirect Infringement
The complaint alleges active inducement of infringement based on Defendants' intent for the ANDA product to be approved and marketed for infringing uses before the patents expire (Compl. ¶40, ¶49, ¶58, ¶67, ¶76). The factual basis for intent is the act of filing the ANDA with knowledge of the patents-in-suit (Compl. ¶33).
Willful Infringement
The complaint does not contain an explicit allegation of "willful infringement" or a request for enhanced damages. However, it does allege that Defendants had knowledge of the ’510, ’814, and ’155 patents when they submitted the ANDA, which is a predicate for a willfulness finding (Compl. ¶33).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: can the negative limitations "isotonicity agent" and "buffer," which are central to the ’814 patent family, be construed to exclude a formulation containing excipients that may have secondary effects on pH or tonicity? The interpretation of these terms will be a critical battleground in claim construction.
- A second key issue will be a comparison of compositions: does the precise formulation disclosed in Padagis’s confidential ANDA filing fall within the numerical boundaries of the claims, particularly given the flexibility afforded by the term "about"? The outcome of the case will depend on the factual evidence of the accused product's composition revealed during discovery.