DCT
1:25-cv-00018
Nexus Pharma LLC v. Hikma Pharma USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Nexus Pharmaceuticals, LLC (Illinois)
- Defendant: Hikma Pharmaceuticals USA Inc. (Delaware) and Hikma Pharmaceuticals PLC (United Kingdom)
- Plaintiff’s Counsel: Richards, Layton & Finger, P.A.
- Case Identification: 1:25-cv-00018, D. Del., 01/06/2025
- Venue Allegations: Venue is alleged to be proper as to Hikma USA because it is a Delaware corporation. Venue is alleged as to Hikma PLC, a foreign entity, on the basis that it is not a resident of the United States.
- Core Dispute: Plaintiff alleges that Defendant’s generic ephedrine sulfate prefilled-syringe product infringes three patents related to ready-to-use, shelf-stable pharmaceutical compositions, methods of making them, and methods of administering them.
- Technical Context: The technology concerns ready-to-use injectable drug formulations designed to eliminate the need for bedside dilution by clinicians, a practice known to be a source of dosage errors and microbial contamination.
- Key Procedural History: The complaint alleges that Defendant was aware of and tracked the patent applications that matured into the patents-in-suit during their prosecution before the U.S. Patent and Trademark Office, which may be relevant to the allegations of willful infringement.
Case Timeline
| Date | Event |
|---|---|
| 2019-05-16 | Earliest Priority Date for '752, '369, and '398 Patents |
| 2022-08-30 | U.S. Patent No. 11,426,369 ('369 Patent) Issues |
| 2022-10-11 | U.S. Patent No. 11,464,752 ('752 Patent) Issues |
| 2023-02-07 | U.S. Patent No. 11,571,398 ('398 Patent) Issues |
| 2024-12-20 | Accused Product Commercial Marketing Allegedly Begins |
| 2025-01-06 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 11,464,752 - "Compositions Comprising Ephedrine Or An Ephedrine Salt And Methods Of Making And Using Same"
- Patent Identification: U.S. Patent No. 11,464,752, “Compositions Comprising Ephedrine Or An Ephedrine Salt And Methods Of Making And Using Same,” issued October 11, 2022.
The Invention Explained
- Problem Addressed: The patent describes that FDA-approved formulations of ephedrine sulfate must be diluted before administration to a patient, a step that is inconvenient, delays administration, and creates a significant risk of contamination or dosing errors in a clinical setting (e.g., ’369 Patent, col. 1:30-40, attached as Compl. Ex. B). Furthermore, ephedrine sulfate compositions are known to be unstable, susceptible to degradation from light, pH changes, and humidity, with short shelf lives (e.g., ’369 Patent, col. 2:1-5).
- The Patented Solution: The invention is a sterile, "ready-to-use" pharmaceutical product containing ephedrine sulfate at a specific concentration (5 mg/mL) with sodium chloride and water, formulated at an initial pH level between 4.5 and 7. This composition is designed to remain stable—maintaining its pH and active ingredient concentration within specified narrow limits—after prolonged storage under defined temperature and humidity conditions, thereby providing a safe and convenient alternative to formulations requiring dilution (’752 Patent, Abstract; col. 13:57-14:21).
- Technical Importance: The invention provides clinicians with a pre-mixed, shelf-stable ephedrine sulfate product, intended to increase patient safety by removing the risks associated with manual, point-of-care dilution (’369 Patent, col. 1:30-33).
Key Claims at a Glance
- The complaint asserts independent claim 1 (Compl. ¶56).
- Essential elements of independent claim 1 include:
- A pharmaceutical product comprising a packaged syringe.
- The syringe contains a sterilized ready-to-use ephedrine composition.
- The composition comprises specific concentrations of ephedrine sulfate (5 mg/mL), sodium chloride (9 mg/mL), no preservative, water, and an initial pH of about 4.5 to 7.
- The composition has specific stability characteristics after storage for defined times and conditions (e.g., 12 months at 25° C./60% humidity): a pH level within 0.5 units of the initial pH, an ephedrine sulfate concentration of at least 95% of the packaged concentration, and a bacterial endotoxin level not more than 7 EU/mg.
- The complaint does not explicitly reserve the right to assert dependent claims for the ’752 Patent.
U.S. Patent No. 11,426,369 - "Compositions Comprising Ephedrine Or An Ephedrine Salt And Methods Of Making And Using Same"
- Patent Identification: U.S. Patent No. 11,426,369, “Compositions Comprising Ephedrine Or An Ephedrine Salt And Methods Of Making And Using Same,” issued August 30, 2022.
The Invention Explained
- Problem Addressed: As with the ’752 Patent, the technology addresses the clinical need for a stable, ready-to-use ephedrine sulfate formulation that avoids the risks of contamination and error associated with bedside dilution (’369 Patent, col. 1:30-40).
- The Patented Solution: The patent claims a specific multi-step method for making a shelf-stable, ready-to-use ephedrine sulfate composition. The method involves combining the ingredients to form a batch solution with specific initial concentrations, optionally adjusting the pH, filtering the solution, sanitizing containers, placing a specific volume into the containers, and sealing them. A key step is maintaining the pH level of the final composition within 0.5 pH units of the initial level during prolonged storage under specified conditions (’369 Patent, Abstract; col. 16:1-33).
- Technical Importance: This patent purports to protect a reproducible manufacturing process that results in a clinically safe, stable, and ready-to-use ephedrine sulfate product, which was previously unavailable (’369 Patent, col. 2:1-5).
Key Claims at a Glance
- The complaint asserts independent claim 1 (Compl. ¶110).
- Essential elements of independent claim 1 include:
- A method of making a shelf-stable, ready-to-use ephedrine sulfate composition.
- A step of combining ephedrine sulfate, sodium chloride or dextrose, and water to form a batch solution with specific initial concentrations and no preservative.
- An optional step of contacting the solution with an acid or base to obtain an initial pH of 4.5 to 7.
- Steps of filtering the batch solution, sanitizing containers, and placing not more than 20 mL of the solution into the sanitized containers.
- A step of sealing each filled container.
- A final step of maintaining a pH level within 0.5 pH units of the initial pH during storage under specified conditions (e.g., 12 months at 25° C./60% humidity).
- The complaint does not explicitly reserve the right to assert dependent claims for the ’369 Patent.
U.S. Patent No. 11,571,398 - "Compositions Comprising Ephedrine Or An Ephedrine Salt And Methods Of Making And Using Same"
- Patent Identification: U.S. Patent No. 11,571,398, “Compositions Comprising Ephedrine Or An Ephedrine Salt And Methods Of Making And Using Same,” issued February 7, 2023.
Technology Synopsis
This patent is directed to a method of administering ephedrine to treat or prevent hypotension. The claimed method involves using a pre-packaged, sterilized, ready-to-use ephedrine composition that does not require dilution before injection, thereby addressing the clinical risks of manual preparation (Compl. ¶159). The composition itself is defined by the same specific ingredients, concentrations, and stability parameters as recited in the ’752 Patent (’398 Patent, col. 45:7-46:21).
Asserted Claims
The complaint asserts independent claim 1 (Compl. ¶160).
Accused Features
The complaint alleges infringement by healthcare providers who administer the accused product according to its FDA-approved label and instructions, which allegedly direct users to perform the claimed steps (Compl. ¶157, 161, 163-164).
III. The Accused Instrumentality
Product Identification
- Defendant’s Ephedrine Sulfate Injection, 25 mg/5 mL (5 mg/mL), supplied in a prefilled syringe and approved under Abbreviated New Drug Application (ANDA) No. 217721 (Compl. ¶36).
Functionality and Market Context
- The accused product is alleged to be a premixed, ready-to-use, sterile formulation of ephedrine sulfate that does not require dilution prior to use (Compl. ¶59, 113). The product label allegedly states that each mL contains 5 mg of ephedrine sulfate and 8.6 mg of sodium chloride in water for injection, with a pH range of 4.5 to 6.5 (Compl. ¶63, 114). The product is supplied in a "single-dose 5mL prefilled syringe" (Compl. ¶59, 113). The complaint alleges that Defendant began commercial marketing of the product on or about December 20, 2024 (Compl. ¶40).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
U.S. Patent No. 11,464,752 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical product comprising: a packaged syringe containing a sterilized ready-to-use ephedrine composition comprising: | Defendant's product is described as "Ephedrine sulfate injection, 25mg/5ml (5 mg/mL) in a pre-filled syringe," which is a "premixed formulation" that is "ready to use." The solution is described as sterile. | ¶59, ¶61 | col. 14:1-3 |
| a packaged concentration of ephedrine sulfate of 5 mg/mL, | The product's label allegedly states it is an "ephedrine sulfate injection, 25mg/5ml (5 mg/mL)." | ¶59 | col. 14:15-18 |
| 9 mg/mL sodium chloride, no preservative, water, and an initial pH level of about 4.5 to about 7; | The product's label allegedly states it contains 8.6 mg Sodium Chloride (approximating 9 mg/mL), water for injection, makes no mention of a preservative, and has a pH range of 4.5 to 6.5. | ¶63 | col. 14:1-9 |
| having, after storage...a pH level within 0.5 pH units of the initial pH level, | On information and belief, the product meets this requirement to gain FDA approval, as ephedrine sulfate is pH-sensitive and product stability requires maintaining pH within a tight range. | ¶64, ¶66, ¶67 | col. 14:10-14 |
| an ephedrine sulfate concentration of at least 95% of the packaged concentration, and | On information and belief, the product meets this requirement to comply with FDA standards for maintaining product potency of 95%-105% throughout its shelf life. | ¶66, ¶67 | col. 14:15-18 |
| a bacterial endotoxin level not more than 7 EU/mg. | On information and belief, the product has an endotoxin level not more than 7 EU/mg, as the FDA sets standards limiting endotoxins and Defendant would have conducted testing. | ¶68 | col. 13:3-8 |
U.S. Patent No. 11,426,369 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of making a shelf-stable, ready-to-use ephedrine sulfate composition, the method comprising: combining ephedrine sulfate, sodium chloride...to form a batch solution comprising an initial ephedrine sulfate level of 5 mg/mL...and no preservative; | On information and belief, Defendant uses a general manufacturing process of creating large batches of solution with the specified concentrations, as this is the standard, efficient method for an FDA-approved process. | ¶114, ¶115, ¶116 | col. 16:1-9 |
| optionally contacting the batch solution with an acid or a base to obtain an initial pH level of the solution of 4.5 to 7; | The product label states that the pH is "adjusted with Sodium Hydrochloride, NF" and that the final pH range is 4.5 to 6.5, which falls within the claimed range. | ¶119 | col. 16:10-12 |
| filtering the batch solution through a membrane filter to obtain a filtered batch solution; | On information and belief, Defendant filters its product or performs an equivalent sterilization step to meet stringent FDA standards regarding impurities. | ¶121 | col. 16:13-15 |
| sanitizing one or more containers; | On information and belief, Defendant sanitizes its syringe containers to meet stringent FDA standards required for an approved product. | ¶123 | col. 16:16 |
| placing not more than 20 mL of the filtered batch solution into one of the one or more sanitized containers...; | The approved labeling for the product is a "5 mL single-dose prefilled syringe." Since 5 mL is less than 20 mL, this limitation is allegedly met. | ¶124 | col. 16:17-20 |
| sealing each filled container to obtain sealed containers...; and | The product is sold in individual single-dose prefilled syringes intended for one patient, indicating each container is individually sealed. | ¶125 | col. 16:21-24 |
| maintaining a pH level...that is within 0.5 pH units of the initial pH level during storage at 25° C. and 60% relative humidity for at least 12 months... | On information and belief, Defendant's product meets this requirement, as it would be necessary to demonstrate such stability to the FDA to gain approval for a pH-sensitive drug like ephedrine sulfate. | ¶128, ¶129, ¶130 | col. 16:25-33 |
Identified Points of Contention
- Evidentiary Questions: The allegations for several key limitations—particularly those related to stability over time (pH and concentration maintenance) and specific manufacturing steps (filtering, sanitizing)—rely on "information and belief" and inferences drawn from the requirements of the FDA approval process. A primary point of contention may be what factual evidence discovery reveals about the accused product's actual stability data under the claimed conditions and Defendant's specific manufacturing process, as opposed to what can be inferred from general regulatory compliance.
- Scope Questions: The complaint alleges that the accused product's 8.6 mg/mL of Sodium Chloride meets the "9 mg/mL sodium chloride" limitation of claim 1 of the ’752 Patent (Compl. ¶63). This raises the question of whether this concentration, which is approximately 4.4% lower than the recited value, meets the claim limitation either literally or under the doctrine of equivalents.
V. Key Claim Terms for Construction
The Term: "ready-to-use"
- Context and Importance: This term is central to the invention's purpose of avoiding bedside dilution. The dispute may turn on whether the accused "premixed formulation" is "ready-to-use" as understood in the context of the patent.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification consistently frames the invention in contrast to prior art that requires dilution. Language such as "Requiring dilution steps is inconvenient, delays administration...and introduces a significant and dangerous source of potential error" could support a construction where any formulation not requiring such dilution is "ready-to-use" (’369 Patent, col. 1:30-33).
- Evidence for a Narrower Interpretation: Practitioners may argue that the term should be limited to the specific concentrations and stability profiles disclosed in the embodiments. The patent states that "all FDA-approved formulations must be diluted ten-fold before administration" (’752 Patent, col. 1:20-22), suggesting "ready-to-use" is defined primarily by its contrast with that specific requirement.
The Term: "shelf-stable"
- Context and Importance: This term appears in the method claims of the ’369 Patent. The claims themselves provide functional definitions for stability (e.g., maintaining pH within 0.5 units over 12 months). The construction of "shelf-stable" will likely be coterminous with meeting these explicit functional requirements.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term could be given its plain and ordinary meaning in the pharmaceutical arts, referring generally to a product that remains chemically and physically stable for a specified period. The specification notes that "FDA-approved formulations have short shelf lives" (’369 Patent, col. 2:2-3), suggesting the invention provides an improvement on this general characteristic.
- Evidence for a Narrower Interpretation: The claims themselves arguably define the term by reciting specific, objective stability criteria (e.g., "maintaining a pH level...that is within 0.5 pH units of the initial pH level during storage...") (’369 Patent, col. 16:25-33). A court may find that these limitations provide the exclusive definition of "shelf-stable" for the purposes of the patent.
VI. Other Allegations
Indirect Infringement
- The complaint alleges inducement of infringement of the ’398 method-of-use patent, asserting that Defendant’s FDA-approved package insert instructs and encourages healthcare providers to administer the product in a manner that performs the claimed steps (Compl. ¶156, 158). The complaint also makes general allegations of inducement concerning the ’752 and ’369 patents, potentially implicating contract manufacturers (Compl. ¶57, 111).
Willful Infringement
- Willfulness is alleged based on Defendant’s alleged pre-suit knowledge of the patents and the underlying applications. The complaint asserts that Defendant tracked the prosecution of the applications leading to the patents-in-suit and has been aware of the issued patents since their respective issue dates (Compl. ¶46, 47, 70, 133, 179).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of evidentiary proof: will discovery substantiate the complaint’s "information and belief" allegations that the accused product meets the specific, quantitative stability parameters recited in the claims (i.e., maintaining pH and concentration within narrow limits after 12 months of storage), or will the Defendant's internal data show a material deviation from these requirements?
- A key question will be one of process verification: for the method claims of the ’369 Patent, what evidence will emerge regarding the Defendant’s actual manufacturing process? The case may turn on whether the process, as practiced, includes each claimed step, such as forming a batch solution and filtering through a membrane, beyond what is merely inferred from the final product's approved status.
- The dispute may also involve a question of definitional scope: does the claim term "9 mg/mL sodium chloride" read on a product containing 8.6 mg/mL, either literally or under the doctrine of equivalents, or is this difference technically significant enough to place the accused product outside the scope of the claims?