Exela Pharma Sciences LLC v. Avadel Legacy Pharma LLC

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Exela Pharma Sciences, LLC (Delaware)
  • Defendant: Avadel Legacy Pharmaceuticals, LLC; and Avadel US Holdings, Inc. (Delaware)
  • Plaintiff’s Counsel: Fish & Richardson P.C.
• Case Identification: 1:20-cv-00024, D. Del., 01/07/2020
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because both Defendant entities are incorporated in Delaware.
• Core Dispute: Plaintiff alleges that Defendant’s recently FDA-approved NOURESSTM injectable solution, an L-cysteine formulation, will infringe a patent covering stable, highly pure L-cysteine compositions with low levels of aluminum contamination.
• Technical Context: The technology relates to pharmaceutical compositions for total parenteral nutrition (TPN), a form of intravenous feeding for high-risk patients, such as premature infants, who cannot obtain nutrition orally.
• Key Procedural History: Plaintiff’s own L-cysteine product, ELCYS®, received FDA approval in April 2019 and is covered by the patent-in-suit, which is listed in the FDA’s Orange Book. Defendant’s competing product, NOURESSTM, received FDA approval in December 2019, prompting this declaratory judgment action filed before the accused product’s anticipated commercial launch.

Case Timeline

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

U.S. Patent No. 10,478,453 - "Stable, Highly Pure L-Cysteine Compositions for Injection and Methods of Use"

The Invention Explained

• Problem Addressed: The patent’s background section notes that L-cysteine, an amino acid, is conditionally essential for certain patients, like preterm infants, who require intravenous supplementation (’453 Patent, col. 1:20-31). The complaint elaborates that prior L-cysteine products contained high levels of aluminum, which can be toxic and cause serious health problems, particularly in neonates with immature kidney function (Compl. ¶¶13-14).
• The Patented Solution: The invention is a stable, injectable L-cysteine composition characterized by very low levels of specific impurities, including aluminum (e.g., below 250 ppb), L-cystine (an oxidation product), and pyruvic acid (’453 Patent, Abstract). To achieve this stability, the patent teaches controlling oxygen levels throughout the manufacturing process, specifying low concentrations of both dissolved oxygen in the liquid carrier and oxygen in the container’s headspace, which minimizes the oxidation of L-cysteine to L-cystine (’453 Patent, col. 4:38-43, col. 4:63-67). Patent Figure 3 provides a schematic of the manufacturing setup, indicating points for dissolved oxygen (DO) testing during compounding, filling, and after capping to ensure oxygen levels remain low throughout the process (’453 Patent, Fig. 3).
• Technical Importance: By strictly controlling impurity and oxygen levels, the invention enables an L-cysteine formulation stable enough and pure enough to meet FDA safety standards for administration to vulnerable patient populations (Compl. ¶16).

Key Claims at a Glance

• The complaint asserts independent claims 1 (a composition) and 22 (a method of preparation), and reserves the right to assert dependent claims (Compl. ¶¶33, 92). Dependent claims 4-7 narrow the aluminum concentration of claim 1 (Compl. ¶¶28-31).
• Independent Claim 1 (Composition): The essential elements are:
  • A stable L-cysteine composition for parenteral administration.
  • L-cysteine (or a salt/hydrate thereof) in a concentration of about 10 mg/mL to about 100 mg/mL.
  • Aluminum in an amount from about 1.0 ppb to about 250 ppb.
  • L-cystine and pyruvic acid each in an amount from about 0.001 wt % to about 2.0 wt % relative to L-cysteine.
  • A water-based carrier.
  • Low levels of headspace oxygen (about 0.5% to 4.0% v/v) and dissolved oxygen (about 0.1 to 5 ppm) for at least one month post-manufacture.
  • Enclosure in a single-use container (10 mL to 100 mL).
• Independent Claim 22 (Method): The essential elements are:
  • A method of preparing a reduced Aluminum composition for a TPN regimen.
  • The method comprises mixing a first composition (containing L-cysteine with specified low levels of Al, L-cystine, and pyruvic acid).
  • With a second composition containing one or more other amino acids.
  • To form a final infusion composition (about 100 mL to 1000 mL).
  • Wherein the total aluminum provided by the regimen is from about 1-2 to about 4-5 micrograms/kg/day.

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendant's NOURESSTM brand cysteine hydrochloride injection USP, 50 mg/mL (the "Accused Product") (Compl. ¶34).

Functionality and Market Context

• The Accused Product is a sterile, injectable solution for intravenous use, supplied in a 10 mL single-dose vial (Compl. ¶47). Its FDA-approved labeling indicates it is for use "as an additive to amino acid solutions to meet nutritional requirements of neonates" in TPN regimens (Compl. ¶74). The label states the product contains 50 mg/mL of cysteine hydrochloride and "no more than 145 mcg/L [145 ppb] of aluminum" (Compl. ¶¶47-48).
• The complaint alleges, based on a press release from the Defendant, that the U.S. market for cysteine hydrochloride injections could exceed $50 million annually and that the launch of the Accused Product is "imminent" (Compl. ¶¶43-44).

IV. Analysis of Infringement Allegations

'453 Patent Infringement Allegations (Claim 1)

'453 Patent Infringement Allegations (Claim 22)

Identified Points of Contention

• Factual Questions: A primary point of contention will be factual. The complaint's allegations regarding the specific concentrations of L-cystine, pyruvic acid, dissolved oxygen, and headspace oxygen are made "on information and belief" (Compl. ¶¶53, 56, 72, 68). The infringement case for composition claim 1 will depend heavily on whether discovery and testing confirm that the Accused Product meets these specific technical limitations.
• Scope Questions: For both claims, a potential dispute may arise over the term "about" as it modifies every numerical range. The scope of literal infringement hinges on how much variance this term permits, particularly for the lower bound of the aluminum range ("about 1.0 ppb").

V. Key Claim Terms for Construction

• The Term: "stable"

• Context and Importance: This term appears in the preamble of independent claim 1 ("A stable L-cysteine composition..."). Its construction is critical because it may impose temporal and compositional requirements on the accused product beyond the specific limitations enumerated in the claim body. Practitioners may focus on this term because the patent's entire objective is to create a stable product.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification provides a definition, stating "the term 'stable' refers to a composition that has the component profiles described herein... for the amount of time identified... In general, products are considered stable if the period of time is three months, or three to six months..." (’453 Patent, col. 15:40-52). A party could argue this defines stability in commercially practical terms.
  • Evidence for a Narrower Interpretation: Another party could argue that the claim itself provides a more specific definition of stability by requiring the oxygen limitations to be met for a period of "about 1 month from manufacture" (’453 Patent, col. 35:19-25). This suggests that "stable" for the purpose of claim 1 is tied to this specific one-month window, not a longer commercial shelf-life.

• The Term: "about"

• Context and Importance: This term is ubiquitous, modifying every quantitative limitation in the asserted claims (e.g., "about 1.0 ppb to about 250 ppb"). Its construction will directly impact the scope of infringement, as it determines the permissible deviation from the recited numerical values.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: A party may argue that the term should be given its ordinary meaning in the context of pharmaceutical chemistry, allowing for standard measurement tolerances and minor variations that do not affect the invention's function.
  • Evidence for a Narrower Interpretation: The specification states that "support for actual numerical values is provided even when the term 'about' is used" and that "the range encompassed by 'about' will include all discrete values within that range" (’453 Patent, col. 57:27-36). A party could use this language to argue that "about" provides little to no leeway beyond the explicitly recited endpoints.

VI. Other Allegations

Indirect Infringement

The complaint alleges that Defendant will induce infringement of method claim 22 because the NOURESS™ product label instructs healthcare providers to perform the patented method of mixing the L-cysteine solution with other amino acid solutions to prepare a TPN regimen (Compl. ¶¶93, 95). It further alleges contributory infringement, stating that NOURESS™ is a material part of the patented method, is not a staple article of commerce suitable for substantial non-infringing use, and was especially adapted for this infringing use (Compl. ¶¶99-101).

Willful Infringement

The complaint alleges that Defendant had pre-suit knowledge of the '453 patent, at least as of its publication in the FDA's Orange Book and by its own acknowledgement in a December 16, 2019 press release (Compl. ¶¶90-91). These allegations form the basis for a claim of willful infringement (Compl. ¶104).

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

• A central issue will be one of evidentiary proof: will discovery and testing confirm that the accused NOURESSTM product meets the specific quantitative limits for L-cystine, pyruvic acid, and dissolved/headspace oxygen recited in the patent, which are currently alleged only on "information and belief"?
• A key question of claim construction will be the interpretation of "about." The breadth given to this term will define the literal scope of every numerical limitation and could be determinative of infringement, especially concerning the lower bound of the aluminum concentration.
• A final question will be one of induced infringement: does the product labeling for NOURESSTM provide instructions with sufficient specificity to establish that Defendant possessed the affirmative intent for end-users to perform every step of the patented method, including the final step of delivering a total daily aluminum dosage within the narrow range claimed?