1:23-cv-01157
Hikma Pharma USA Inc v. Cipla USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Hikma Pharmaceuticals USA Inc. (Delaware)
- Defendant: Cipla USA, Inc. (Delaware) and Cipla Limited (India)
- Plaintiff’s Counsel: Heyman Enerio Gattuso & Hirzel LLP; Winston & Strawn LLP
- Case Identification: 1:23-cv-01157, D. Del., 10/13/2023
- Venue Allegations: Venue is alleged to be proper based on Defendant Cipla USA, Inc. being a Delaware corporation and Defendant Cipla Limited having previously availed itself of the forum by filing counterclaims in other actions in the district.
- Core Dispute: Plaintiff alleges that Defendants' Abbreviated New Drug Application (ANDA) to market a generic naloxone hydrochloride nasal spray constitutes an act of infringement of five patents related to Plaintiff's Kloxxado® branded product.
- Technical Context: The technology concerns stable, liquid nasal spray formulations of naloxone, an opioid antagonist used for the emergency treatment of known or suspected opioid overdose.
- Key Procedural History: This lawsuit was filed under the Hatch-Waxman Act, triggered by Cipla's submission of ANDA No. 218239, which contained a "Paragraph IV certification." This certification asserts that the patents-in-suit are invalid, unenforceable, or will not be infringed by Cipla's proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 2014-07-08 | Earliest Priority Date ('510', '814', '155', '713', '139' Patents) |
| 2020-07-28 | U.S. Patent No. 10,722,510 Issued |
| 2021-04-13 | U.S. Patent No. 10,973,814 Issued |
| 2021-10-05 | U.S. Patent No. 11,135,155 Issued |
| 2023-04-04 | U.S. Patent No. 11,617,713 Issued |
| 2023-04-18 | U.S. Patent No. 11,628,139 Issued |
| 2023-08-29 | Date of Cipla's Notice Letter regarding ANDA submission |
| 2023-10-13 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,722,510 - "Liquid naloxone spray"
- Patent Identification: U.S. Patent No. 10,722,510, "Liquid naloxone spray", Issued July 28, 2020.
The Invention Explained
- Problem Addressed: The patent addresses the low bioavailability of orally administered naloxone due to "hepatic first pass metabolism," which necessitates alternative delivery methods. Existing non-oral methods may require repeat dosing or cause patient discomfort, creating a need for a stable and effective liquid spray formulation. (’510 Patent, col. 1:50-59).
- The Patented Solution: The invention provides a stable liquid spray formulation for intranasal or sublingual administration, comprising an effective amount of naloxone, water, a co-solvent system (such as ethanol and propylene glycol), and other excipients like antioxidants and chelating agents. This combination is designed to be physically and chemically stable while enabling effective drug delivery. (’510 Patent, col. 2:1-10, Abstract).
- Technical Importance: The formulation aims to provide a reliable, non-invasive, and rapid-acting emergency treatment for opioid overdose that overcomes the metabolic limitations of oral delivery. (’510 Patent, col. 1:21-25).
Key Claims at a Glance
- The complaint asserts infringement of one or more claims of the ’510 Patent (Compl. ¶35). Independent claim 1 is representative of the formulation claims.
- Independent Claim 1 requires:
- 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 does not explicitly reserve the right to assert dependent claims but makes a general allegation covering "one or more claims" (Compl. ¶35).
U.S. Patent No. 10,973,814 - "Liquid naloxone spray"
- Patent Identification: U.S. Patent No. 10,973,814, "Liquid naloxone spray", Issued April 13, 2021.
The Invention Explained
- Problem Addressed: The patent background notes the existence of other naloxone nasal sprays that contain components such as an isotonicity agent (e.g., sodium chloride) or a buffer (e.g., citric acid). The invention seeks to provide a stable and effective formulation that does not require these specific components. (’814 Patent, col. 1:40-56).
- The Patented Solution: The invention is a liquid spray formulation containing naloxone, water, and a chelating agent, but which "does not contain an isotonicity agent or a buffer." This formulation is described as stable, comfortable for the user, and suitable for intranasal administration, providing improved pharmacokinetic parameters compared to intramuscular injection. (’814 Patent, col. 2:16-21, 63-65).
- Technical Importance: By creating a stable formulation without common excipients like buffers and isotonicity agents, the invention offers an alternative formulation design that may reduce complexity or potential patient sensitivity. (’814 Patent, col. 3:12-14).
Key Claims at a Glance
- The complaint asserts infringement of one or more claims of the ’814 Patent (Compl. ¶44). Independent claims 1, 5, and 9 are the independent claims.
- Independent Claim 1 requires:
- 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 does not explicitly reserve the right to assert dependent claims but makes a general allegation covering "one or more claims" (Compl. ¶44).
U.S. Patent No. 11,135,155 - "Liquid naloxone spray"
- Patent Identification: U.S. Patent No. 11,135,155, "Liquid naloxone spray", Issued October 5, 2021.
Technology Synopsis
This patent also describes stable liquid naloxone formulations for intranasal administration. A key aspect is the creation of a formulation that is stable and effective without common excipients, specifically claiming formulations that do not contain an isotonicity agent, a buffer, or an anti-microbial agent. (’155 Patent, Abstract; col. 4:51-54).
Asserted Claims
The complaint asserts infringement of "one or more claims" (Compl. ¶53). The patent contains multiple independent claims directed to specific formulations and methods of use.
Accused Features
The accused instrumentality is Cipla's ANDA Product, a naloxone hydrochloride nasal spray alleged to be a generic version of Kloxxado® (Compl. ¶27, ¶53).
U.S. Patent No. 11,617,713 - "Liquid naloxone spray"
- Patent Identification: U.S. Patent No. 11,617,713, "Liquid naloxone spray", Issued April 4, 2023.
Technology Synopsis
The patent relates to stable liquid naloxone formulations for intranasal delivery. The claims are directed to specific formulations defined by the weight percentages of naloxone, water, ethanol, propylene glycol, and edetate disodium dihydrate, while also requiring the formulation to not contain an isotonicity agent or a buffer. (’713 Patent, Abstract; col. 8:1-12).
Asserted Claims
The complaint asserts infringement of "one or more claims" (Compl. ¶62). The patent contains multiple independent claims directed to specific formulations.
Accused Features
The accused instrumentality is Cipla's ANDA Product, a naloxone hydrochloride nasal spray alleged to be a generic version of Kloxxado® (Compl. ¶27, ¶62).
U.S. Patent No. 11,628,139 - "Liquid naloxone spray"
- Patent Identification: U.S. Patent No. 11,628,139, "Liquid naloxone spray", Issued April 18, 2023.
Technology Synopsis
This patent also covers stable liquid formulations of naloxone. The claims define formulations by the specific weight percentages of naloxone, ethanol, propylene glycol, water, and a chelating agent, and specify that the formulation does not contain an anti-microbial agent. (’139 Patent, Abstract; col. 8:1-11).
Asserted Claims
The complaint asserts infringement of "one or more claims" (Compl. ¶71). The patent contains multiple independent claims directed to specific formulations.
Accused Features
The accused instrumentality is Cipla's ANDA Product, a naloxone hydrochloride nasal spray alleged to be a generic version of Kloxxado® (Compl. ¶27, ¶71).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is "Cipla's naloxone hydrochloride nasal spray, 8mg/spray," for which Cipla submitted ANDA No. 218239 to the FDA ("Cipla's ANDA Product") (Compl. ¶27).
Functionality and Market Context
- The complaint alleges that Cipla's ANDA Product is a generic version of Hikma's Kloxxado® product (Compl. ¶27). Kloxxado® is indicated for the emergency treatment of known or suspected opioid overdose in adult and pediatric patients (Compl. ¶25). The complaint alleges Cipla seeks to commercially manufacture, use, and sell its generic version prior to the expiration of the patents-in-suit (Compl. ¶28).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint does not provide a detailed claim chart or specific factual allegations mapping claim elements to the accused product's features. The infringement theory is predicated on the allegation that Cipla's ANDA Product is a generic version of Hikma's Kloxxado®, and therefore embodies the claimed inventions (Compl. ¶27, ¶30).
'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 complaint alleges Cipla's ANDA Product is a stable liquid spray formulation containing naloxone hydrochloride within the claimed concentration range. | ¶27, ¶35 | col. 22:37-41 |
| from about 35% to about 85% w/w water, | The complaint alleges Cipla's ANDA Product is a formulation containing water within the claimed concentration range. | ¶27, ¶35 | col. 22:41-42 |
| from about 3% to about 7% w/w propylene glycol, | The complaint alleges Cipla's ANDA Product is a formulation containing propylene glycol within the claimed concentration range. | ¶27, ¶35 | col. 22:42-43 |
| from about 20% to about 50% w/w ethanol and | The complaint alleges Cipla's ANDA Product is a formulation containing ethanol within the claimed concentration range. | ¶27, ¶35 | col. 22:43-44 |
| from about 0.005% to about 0.01% w/w edetate disodium dihydrate | The complaint alleges Cipla's ANDA Product is a formulation containing edetate disodium dihydrate within the claimed concentration range. | ¶27, ¶35 | col. 22:44-46 |
'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 complaint alleges Cipla's ANDA Product is a liquid spray formulation containing naloxone hydrochloride at the claimed concentration. | ¶27, ¶44 | col. 32:56-58 |
| 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 complaint alleges Cipla's ANDA Product contains these excipients at the claimed concentrations. | ¶27, ¶44 | col. 32:58-62 |
| wherein the formulation does not contain an isotonicity agent or a buffer | The complaint alleges Cipla's ANDA Product is a formulation that does not contain an isotonicity agent or a buffer. | ¶27, ¶44 | col. 32:62-64 |
- Identified Points of Contention:
- Scope Questions: A primary point of contention will likely involve the scope of the term "about" as used in the concentration ranges of the asserted claims. The analysis will question whether Cipla's formulation, if not identical, falls within a range that could be considered equivalent to the claimed concentrations.
- Technical Questions: For the ’814 Patent and others with similar limitations, a key question will be whether any component in Cipla's ANDA Product functions as an "isotonicity agent" or "buffer," even if not explicitly identified as such in the ANDA filing. The evidence will need to show not only the presence or absence of certain ingredients but also their technical function within the formulation.
V. Key Claim Terms for Construction
The Term: "from about 8% to about 12% w/w naloxone" (’510 Patent, Claim 1)
Context and Importance: This term, and similar concentration ranges in other asserted patents, is central because infringement under the Hatch-Waxman Act often turns on whether the generic formulation's composition is identical or equivalent to the claimed formulation. Practitioners may focus on the term "about" to determine the permissible degree of variation from the stated numerical ranges.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specification uses "about" consistently when describing component concentrations, which may suggest the inventors did not intend for the ranges to be strictly limited to the recited numbers (’510 Patent, col. 5:7-13). The patent's definition section states that "about" means "plus or minus 10%" of the value, which could provide a specific numerical boundary for the term (’510 Patent, col. 11:8-12).
- Evidence for a Narrower Interpretation: The patent provides numerous examples with highly specific concentrations (e.g., 10.1% w/w naloxone), which could be argued to suggest the importance of precision and limit the scope of "about" to values very close to those explicitly tested and disclosed (’510 Patent, Table 1).
The Term: "wherein the formulation does not contain an isotonicity agent or a buffer" (’814 Patent, Claim 1)
Context and Importance: This negative limitation is a critical part of the claim's scope, distinguishing the invention from prior art that included such components. The dispute will likely focus on the definitions of "isotonicity agent" and "buffer" and whether any excipient in Cipla's formulation performs these functions.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent explicitly distinguishes itself from prior art containing sodium chloride as an isotonicity agent and citric acid as a buffer, potentially limiting the scope of these excluded components to those specific examples or close analogues (’814 Patent, col. 1:40-56).
- Evidence for a Narrower Interpretation: The patent does not provide explicit definitions for "isotonicity agent" or "buffer," which may invite a construction based on their plain and ordinary meaning to one of skill in the art of pharmaceutical formulation. This could encompass any substance that performs the function of regulating osmotic pressure or resisting changes in pH, regardless of its primary purpose in the formulation.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Cipla intends to, and will, actively induce infringement of the patents-in-suit once its ANDA is approved (Compl. ¶39, ¶48, ¶57, ¶66, ¶75). This allegation is based on the premise that Cipla's product labeling will instruct end-users to administer the generic naloxone spray in an infringing manner.
- Willful Infringement: The complaint does not explicitly use the word "willful." However, it alleges that "Cipla had knowledge of the '510, '814, '155, '713, and '139 patents when it submitted its ANDA" (Compl. ¶31). This allegation of pre-suit knowledge could form the basis for a later claim for enhanced damages under 35 U.S.C. § 284.
VII. Analyst’s Conclusion: Key Questions for the Case
The resolution of this case will likely depend on the answers to two central questions:
- A core issue will be one of compositional identity: does the formulation detailed in Cipla's confidential ANDA filing fall squarely within the specific weight-by-weight concentration ranges recited in the asserted claims, and what is the proper scope of the term "about" in this technical context?
- A key evidentiary question will be one of functional exclusion: for claims containing negative limitations, does any component within Cipla's proposed generic product perform the technical function of an "isotonicity agent" or "buffer," thereby placing the product outside the scope of those claims?