DCT
1:23-cv-00137
Exela Pharma Sciences LLC v. Hikma Pharma USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Exela Pharma Sciences, LLC (Delaware)
- Defendant: Nivagen Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Fish & Richardson P.C.
- Case Identification: 1:23-cv-00137, D. Del., 02/06/2023
- Venue Allegations: Venue is based on Defendant's incorporation in the State of Delaware, establishing residency in the district.
- Core Dispute: Plaintiff alleges that Defendant’s generic injectable L-cysteine product, intended for use in parenteral nutrition, will infringe patents related to stable, low-aluminum L-cysteine formulations and their methods of use.
- Technical Context: The technology concerns injectable L-cysteine, an amino acid supplement critical for high-risk patients like neonates, with a focus on formulations that minimize toxic aluminum contamination and degradation products.
- Key Procedural History: The complaint notes that in prior litigation against a different party, Claim 27 of the '155 patent was found not invalid after a bench trial, which may inform arguments regarding the validity of that claim in this case.
Case Timeline
| Date | Event |
|---|---|
| 2019-01-15 | Earliest Priority Date for ’155 and ’941 Patents |
| 2020-03-10 | U.S. Patent No. 10,583,155 Issues |
| 2022-08-08 | Court finds Claim 27 of ’155 Patent not invalid in Exela v. Eton |
| 2022-11-29 | U.S. Patent No. 11,510,941 Issues |
| 2023-01-26 | FDA approves Defendant's ANDA for generic L-cysteine product |
| 2023-02-06 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,583,155 - "Stable, Highly Pure L-Cysteine Compositions for Injection and Methods of Use"
- Issued: March 10, 2020.
The Invention Explained
- Problem Addressed: The patent's background section describes that L-cysteine is a critical amino acid supplement for patients like preterm infants but that existing injectable formulations were known to contain high levels of aluminum, a toxic contaminant, and were prone to degradation into impurities (’155 Patent, col. 1:21-42; Compl. ¶¶9-10).
- The Patented Solution: The invention is a stable, highly pure L-cysteine composition for injection that solves this problem by strictly limiting the concentration of aluminum (e.g., to less than 250 parts per billion) as well as the concentration of degradation products like cystine and pyruvic acid (’155 Patent, Abstract; col. 2:1-16). This control over impurities is intended to provide a safer product for parenteral administration.
- Technical Importance: This approach directly addresses regulatory and clinical concerns about aluminum toxicity from parenteral nutrition products, particularly for vulnerable neonatal patient populations (Compl. ¶¶11-12).
Key Claims at a Glance
- The complaint asserts independent claims 1 and 27 (Compl. ¶¶29, 30).
- Independent Claim 1: A method of treating a subject by parenterally administering a composition that includes a "stable L-cysteine composition," which is defined by:
- a therapeutically effective amount of L-cysteine;
- from about 1.0 mcg to about 250 mcg of Aluminum per Liter;
- not more than about 2.0 wt % of cystine relative to L-cysteine; and
- not more than about 2.0 wt % of pyruvic acid relative to L-cysteine.
- Independent Claim 27: A method of treating a subject by parenterally administering a composition including a "stable L-cysteine composition" with a narrower aluminum limitation, defined by:
- a therapeutically effective amount of L-cysteine;
- not more than about 150 mcg of Aluminum per Liter;
- cystine relative to L-cysteine not more than about 2.0 wt%; and
- pyruvic acid relative to L-cysteine not more than about 2.0 wt%.
U.S. Patent No. 11,510,941 - "Stable, Highly Pure L-Cysteine Compositions for Injection and Methods of Use"
- Issued: November 29, 2022.
The Invention Explained
- Problem Addressed: Like its related ’155 patent, the ’941 patent addresses the need for L-cysteine compositions that are stable and have desirable safety attributes, particularly low levels of impurities like aluminum (’941 Patent, col. 1:21-45).
- The Patented Solution: The invention is a specific L-cysteine solution defined by a combination of physical and chemical parameters. The solution comprises L-cysteine at a specific concentration range, a low level of aluminum (<200 ppb) maintained for at least six months, limited L-cystine, a specific low pH range (1.0-2.5), and substantial freedom from visible particulates (’941 Patent, Abstract; col. 5:14-19).
- Technical Importance: This combination of features defines a ready-to-use or concentrated product with a specific formulation designed for stability and safety, providing a clear chemical profile for a drug product intended for a sensitive patient population (Compl. ¶¶11-12).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claim 6 (Compl. ¶¶35, 36).
- Independent Claim 1: A solution of L-cysteine with a specific combination of properties:
- L-cysteine concentration from about 10 mg/mL to about 100 mg/mL;
- not more than 200 ppb of aluminum for at least 6 months from manufacture;
- not more than 2.0% L-cystine relative to L-cysteine;
- a pharmaceutically acceptable carrier;
- a pH from about 1.0 to about 2.5;
- is substantially free of visually detectable particulate matter; and
- is suitable for use as an additive in a parenteral nutrition composition.
- The complaint also asserts dependent claim 6, which further narrows the aluminum limitation to "not more than 150 ppb of aluminum for at least 12 months" (Compl. ¶36).
III. The Accused Instrumentality
Product Identification
- Defendant's injectable Generic Cysteine Hydrochloride product, having a cysteine hydrochloride concentration of 7.25% (Compl. ¶38). The product was approved by the FDA via Abbreviated New Drug Application (ANDA) No. 213073 (Compl. ¶38).
Functionality and Market Context
- The accused product is a generic drug intended for use as an additive to amino acid solutions to meet the nutritional requirements of patients requiring total parenteral nutrition (TPN), including newborn infants and patients with severe liver disease (Compl. ¶43).
- As an ANDA product, its labeling and conditions of use must be the same as the Reference Listed Drug, which the complaint alleges makes its indication identical to that of Plaintiff's ELCYS® product (Compl. ¶43).
- The complaint alleges that the launch of the accused product is imminent and that Defendant has contacted potential customers with offers to sell the product at a significant discount to Plaintiff's ELCYS® (Compl. ¶39).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
10,583,155 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating a subject... comprising: parenterally administering to said subject a parenteral composition... | Defendant’s product label allegedly instructs healthcare providers to dilute the product and administer it as an admixture in parenteral nutrition solutions via intravenous infusion. | ¶60, ¶65 | col. 3:9-16 |
| wherein said stable L-cysteine composition contributes to said parenteral composition: a therapeutically effective amount of L-cysteine... | The product label allegedly contains recommended dosage and volume information for pediatric patients, which constitutes a therapeutically effective amount. | ¶47, ¶63 | col. 3:5-8 |
| per Liter of said stable L-cysteine composition, from about 1.0 mcg to about 250 mcg of Aluminum; | The complaint alleges on information and belief that Defendant's product contains no more than 500 mcg/L of aluminum, which falls within the claimed range of 1.0 to 250 mcg/L. | ¶54, ¶56 | col. 2:8-10 |
| not more than about 2.0 wt % of cystine relative to L-cysteine; | On information and belief, Defendant’s product specification limits total impurities to 2.0%, which necessarily limits cystine to not more than 2.0%. | ¶58 | col. 2:10-12 |
| and, not more than about 2.0 wt % of pyruvic acid relative to L-cysteine. | On information and belief, Defendant’s product specification limits total impurities to 2.0%, which necessarily limits pyruvic acid to not more than 2.0%. | ¶58 | col. 2:12-14 |
- Identified Points of Contention: The primary infringement theory for the ’155 Patent is indirect infringement, based on Defendant’s product label instructing users to perform the patented method (Compl. ¶74). A potential area of dispute may be whether the instructions on the label, which must conform to the Reference Listed Drug, direct users to perform every step of the claimed method and whether Defendant possessed the requisite intent to induce infringement.
11,510,941 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A solution of L-cysteine comprising, L-cysteine... in an amount from about 10 mg/mL to about 100 mg/mL; | Defendant’s product is alleged to contain 72.5 mg/mL of L-cysteine hydrochloride monohydrate. | ¶48 | col. 2:5-7 |
| not more than 200 ppb of aluminum for at least 6 months from the time of manufacture of the solution; | The complaint alleges Defendant's product contains no more than 500 mcg/L (500 ppb) of aluminum and has a shelf life of at least twelve months, and that by seeking approval, Defendant sought to market a product containing aluminum in the amounts recited by the claims. | ¶54, ¶56, ¶57 | col. 2:8-10 |
| not more than 2.0% L-cystine relative to L-cysteine; | Defendant's product allegedly has a specification limiting total impurities to no more than 2.0%, thereby limiting L-cystine to that amount. | ¶58 | col. 2:10-12 |
| wherein the solution: has a pH from about 1.0 to about 2.5; | On information and belief, Defendant's product has a pH range from about 1.0 to about 2.5, consistent with the RLD and Plaintiff's product. | ¶51 | col. 5:14-16 |
| is substantially free of visually detectable particulate matter; | The complaint alleges this is evidenced by the FDA's approval of Defendant's ANDA No. 213073. | ¶53 | col. 5:17-19 |
- Identified Points of Contention:
- Scope Questions: A central dispute may arise over the aluminum limitation. The claim requires "not more than 200 ppb," whereas the complaint alleges the accused product contains "no more than 500 mcg/L" (500 ppb) (Compl. ¶54). This raises the question of whether there is literal infringement or if Plaintiff will need to rely on the doctrine of equivalents.
- Technical Questions: The infringement analysis will depend on the actual, tested characteristics of Defendant's product. A key question will be what evidence demonstrates that the accused product meets the limitations regarding aluminum content, L-cystine percentage, and pH throughout its shelf-life as required by the claims.
V. Key Claim Terms for Construction
The Term: "stable L-cysteine composition" (’155 Patent, Claim 1)
- Context and Importance: This term appears in the preamble of the method claims and is central to defining what is being administered. The dispute will likely focus on whether "stable" is a simple descriptor or if it is implicitly defined by the specific impurity limitations recited in the body of the claim (low aluminum, cystine, and pyruvic acid).
- Evidence for a Broader Interpretation: The specification discusses stability in general terms, such as compositions having "desirable safety attributes for extended periods of time" (’155 Patent, col. 1:16-18), which a party could argue is not strictly limited to the recited impurity levels.
- Evidence for a Narrower Interpretation: The patent’s "Brief Summary" and "Detailed Description" repeatedly link the invention's stability and safety profile directly to the "exceptionally low levels" of aluminum and other impurities, suggesting the term is defined by these characteristics (’155 Patent, col. 1:38-42; col. 4:30-38).
The Term: "substantially free of visually detectable particulate matter" (’941 Patent, Claim 1)
- Context and Importance: Practitioners may focus on this term because it is a qualitative, rather than quantitative, limitation. Its construction will determine the standard of proof required to show infringement or non-infringement.
- Evidence for a Broader Interpretation: A party could argue this term should be construed to mean compliance with the general standard for parenteral drug products set by the U.S. Pharmacopeia (USP), a standard an FDA-approved product would necessarily meet.
- Evidence for a Narrower Interpretation: The specification emphasizes that "Particulates are dangerous in injectable compositions and create a safety concern" (’941 Patent, col. 5:17-19), which a party could argue imbues the term with a specific meaning tied to the particular safety objectives of the invention, potentially requiring a standard stricter than the general regulatory baseline.
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement on the basis that Defendant's product label will instruct healthcare providers to perform the patented methods of administration, thus providing evidence of an affirmative intent to induce (Compl. ¶74). It further alleges contributory infringement, stating that the accused product is a material part of the patented method and is not a staple article of commerce suitable for substantial non-infringing use (Compl. ¶77).
- Willful Infringement: The complaint alleges willfulness based on Defendant's alleged actual knowledge of the patents-in-suit. This knowledge is alleged to stem from the patents' listing in the FDA's Orange Book and from Defendant having followed prior litigation involving the '155 patent (Compl. ¶¶70, 75, 111, 116).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of quantitative scope: can the ’941 patent’s limitation of “not more than 200 ppb of aluminum” be met, either literally or under the doctrine of equivalents, by an accused product alleged to contain “no more than 500 [ppb] of aluminum”? The resolution will depend on the evidence presented regarding the actual composition of Defendant's product and the technical significance of the difference in aluminum levels.
- A second key question will be one of induced infringement: does the product labeling for Defendant's generic drug, which is constrained by the labeling of the Reference Listed Drug, contain sufficient instructional language to demonstrate a specific intent to encourage direct infringement of the asserted method claims of the ’155 patent?
- Finally, a central question for the court will be validity resilience: in light of the previous judicial finding that Claim 27 of the ’155 patent is not invalid, what new evidence or legal arguments can Defendant present to challenge the validity of the asserted claims in this case, and will those arguments be sufficient to overcome the patent’s presumption of validity?