Details for Patent: 10,478,453
Summary for Patent: 10,478,453
| Title: | Stable, highly pure L-cysteine compositions for injection and methods of use | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | The subject matter described herein is directed to stable L-cysteine compositions for injection, comprising: L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in an amount from about 10 mg/mL to about 100 mg/mL; Aluminum in an amount from about 1.0 parts per billion (ppb) to about 250 ppb; cystine in an amount from about 0.01 wt % to about 2 wt % relative to L-cysteine; pyruvic acid in an amount from about 0.01 wt % to about 2 wt % relative to L-cysteine; a pharmaceutically acceptable carrier, comprising water; headspace O2 that is less than 1.0%; dissolved oxygen present in the carrier in an amount from about 0.01 parts per million (ppm) to about 1 ppm, wherein the composition is enclosed in a single-use container having a volume of from 10 mL to 100 mL. Also described are compositions for a total parenteral nutrition regimen and methods for their use. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | John Maloney, Aruna Koganti, Phanesh Koneru | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | NEC Laboratories America Inc , Exela Pharma Sciences LLC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US16/248,460 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent Litigation and PTAB cases: | See patent lawsuits and PTAB cases for patent 10,478,453 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; Composition; Dosage form; | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | United States Patent 10,478,453: L-Cysteine Injection Claims, Patent Scope, Exclusivity and Competitive LandscapeUS Patent 10,478,453 protects specified low-aluminum, oxygen-controlled L-cysteine compositions for parenteral use, amino-acid total parenteral nutrition, and manufacturing processes. The patent is composition-focused but extends to container headspace, dissolved oxygen, impurity profiles, formulation ratios, and nitrogen or argon-controlled processing. Its strongest practical coverage targets single-use L-cysteine hydrochloride products used as additives to parenteral nutrition. The patent has four independent claims:
The central technical limitation is the combination of L-cysteine concentration, aluminum concentration, L-cystine and pyruvic-acid impurity ranges, and controlled oxygen exposure. What does US Patent 10,478,453 protect?The patent protects a narrow combination of formulation and manufacturing parameters rather than L-cysteine injection generally.
A competing product must satisfy every limitation of an asserted claim to face literal infringement exposure. A formulation outside one required range may still present doctrine-of-equivalents issues, but the claim structure gives manufacturers several potential design-around paths. The patent does not claim every L-cysteine formulation, every cysteine-containing nutrition product, or every low-aluminum parenteral formulation. How broad is independent claim 1?Claim 1 is the principal product claim. Its scope depends on six connected technical variables:
The claim also requires a single-use container of 10 to 100 mL. A bulk container, multi-dose container, or formulation supplied without the specified container characteristics may fall outside the literal claim. The oxygen limitations create an important evidentiary issue. The claim requires headspace oxygen and dissolved oxygen to remain within defined ranges from manufacture through approximately one month at room temperature. Infringement analysis would therefore require manufacturing records, oxygen measurements, stability data, container-closure information, and storage conditions. A product that meets the formulation specifications at release but exceeds the oxygen limits during storage may not satisfy the claim throughout the claimed period. What dependent claims add to the patent scope?Claims 2 through 14 narrow claim 1 and provide fallback positions.
The dependent claims are particularly relevant to products containing approximately 37.5 mg/mL L-cysteine, an aluminum level below 100 ppb, and a controlled oxygen headspace between 3% and 4%. Claim 8 is unusual because it attributes aluminum to separate sources. It recites 1 to 100 ppb from the container, 1 to 100 ppb from the cap, 1 to 100 ppm from L-cysteine, and 1 to 20 ppb from water, with a total of 4 to 250 ppb. The reference to 100 ppm from L-cysteine is materially different from the other source ranges and may create claim-construction and enablement questions. What does claim 15 protect in total parenteral nutrition?Claim 15 covers an admixture containing:
The amino-acid composition may contain standard parenteral nutrition amino acids, including leucine, isoleucine, lysine, valine, phenylalanine, histidine, threonine, methionine, tryptophan, alanine, arginine, glycine, proline, serine, and tyrosine. Claims 16 through 20 narrow this coverage:
Claims 17 through 19 are commercially important because they target the concentration of L-cysteine relative to total amino acids, rather than only the concentration in the original cysteine vial. The supplied claim text contains apparent typographical errors in claim 15, where “0.0.1 wt %” appears instead of “0.001 wt %.” Claim construction would ordinarily rely on the issued patent, specification, prosecution history, and any certificate of correction rather than the reproduced text alone. What manufacturing methods are protected?Claim 21 covers a specific oxygen-controlled manufacturing sequence:
This claim is narrower than the product claims because it requires a particular process sequence and operating conditions. A manufacturer using nitrogen instead of argon, adding cysteine before deoxygenating the water, or using a different pH-adjustment sequence may have a noninfringement position, subject to equivalents analysis. The process claim also creates potential trade-secret overlap. A manufacturer may avoid practicing the claimed process while using a commercially similar formulation, but the resulting product could still implicate claims 1 or 15. What does claim 22 cover in parenteral nutrition?Claim 22 covers preparation of a reduced-aluminum total parenteral nutrition regimen. It requires:
Claim 22 is broader than claim 21 in process terms because it does not recite argon, a 60°C maximum, a pH of 1.8, or a specific container. Its focus is the aluminum exposure delivered through the nutrition regimen. The dose range is relevant to neonatal and pediatric parenteral nutrition, where aluminum exposure is regulated because of potential accumulation and toxicity concerns. FDA regulations establish limits and labeling requirements for aluminum in large-volume parenteral products and small-volume parenteral products used in total parenteral nutrition. [2] How strong is the patent estate for L-cysteine injection?The estate is strongest where a product combines the following characteristics:
The estate is weaker against products that use:
The patent does not rely solely on a conventional active-ingredient claim. It uses quality attributes that can be measured analytically, which may improve infringement proof but also creates opportunities for invalidity challenges based on anticipation, obviousness, written description, enablement, indefiniteness, and lack of measurable reproducibility. When does US Patent 10,478,453 lose exclusivity?The patent issued on November 19, 2019. Its nominal patent term is generally measured from the applicable nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and any patent-term extension. The underlying application priority and filing records, rather than the claim text, control the exact expiration date. [1] Based on the public patent numbering and the reported 2017 filing chronology for the patent family, the ordinary term is expected to run into 2037, subject to any adjustment recorded by the USPTO. A definitive expiration calculation requires the USPTO continuity data, patent-term-adjustment determination, and terminal-disclaimer record. [1] The claims do not themselves establish FDA exclusivity. Patent exclusivity and FDA regulatory exclusivity are separate rights. What is the Orange Book status of the patent?The Orange Book lists patents submitted by NDA sponsors for approved drug products. A patent is not automatically Orange Book listed because it claims a formulation or manufacturing method. The sponsor must submit the patent and identify the relevant drug product and claim category under FDA rules. [3] For this patent, the relevant possible listing categories would include:
The claim text alone does not establish whether US 10,478,453 is currently listed in the Orange Book against a particular cysteine hydrochloride NDA. A listing determination must be made from the FDA’s current patent-listing data and the product’s NDA record. [3] If listed, the patent could support a Paragraph IV certification by an ANDA applicant and a potential 30-month stay if the NDA holder or patent owner files a timely infringement action. [4] What Paragraph IV challenges and generic entry risks exist?A generic applicant seeking approval for an equivalent L-cysteine injection could pursue several strategies:
A Paragraph IV challenge would likely focus on whether the claimed impurity and oxygen ranges were disclosed or rendered obvious by earlier cysteine formulations, oxygen-controlled compounding, parenteral nutrition literature, and aluminum-control requirements. The patent owner would likely emphasize the claimed combination, especially the relationship among oxygen, aluminum, cystine, pyruvic acid, and stability. The challenger would likely argue that each variable was known and that routine optimization could produce the claimed ranges. What FDA regulatory status affects commercial competition?L-cysteine hydrochloride injection is used as an additive to amino-acid solutions in parenteral nutrition. The regulatory product may be approved through an NDA or a 505(b)(2) pathway rather than a conventional ANDA, depending on the reference product and product history. FDA labeling determines whether the product is approved for adult, pediatric, or neonatal use and whether it is intended for direct administration or admixture before infusion. [5] Regulatory competition is shaped by:
A technically noninfringing product may still face regulatory barriers if it requires new stability data, a different container system, or a different labeling basis. Which companies are challenging the patent or licensing the technology?The supplied patent claims do not identify any Paragraph IV challenger, litigation defendant, settlement agreement, or licensee. Patent ownership, assignment history, litigation, and licensing must be established through USPTO assignment records, PACER, district-court dockets, ANDA litigation records, and transaction disclosures. [1, 6] No such commercial relationship can be inferred from the claim language. The competitive field likely includes:
What geographic coverage does the patent provide?US Patent 10,478,453 provides rights only in the United States. It can support infringement claims involving US manufacture, sale, offers for sale, importation, or use of a patented process or composition under 35 U.S.C. §§ 271 and 281. [7] Foreign protection requires corresponding patents in jurisdictions such as Europe, Canada, Japan, China, and Australia. The US patent number does not establish the existence, scope, status, or expiration of foreign counterparts. International manufacturers supplying the US market face importation and sale risks even if manufacturing occurs outside the United States. Separate process claims may also create liability for importing products made by a patented process under 35 U.S.C. § 271(g). [7] What manufacturing barriers remain after patent expiry?Patent expiry would not eliminate all barriers to entry. Commercial manufacturers would still need:
These requirements create regulatory and technical barriers independent of patent rights. They are most significant for injectable products supplied to neonatal and pediatric nutrition programs. How does this patent compare with conventional L-cysteine products?
The patent’s differentiation is the integration of product quality attributes with oxygen management and aluminum exposure. A product can compete clinically while avoiding infringement if it falls outside the claimed combination. Key Takeaways
Frequently Asked QuestionsDoes US Patent 10,478,453 cover all cysteine hydrochloride injections?No. It covers formulations meeting the recited concentration, aluminum, impurity, oxygen, carrier, and container limitations, plus the applicable claim-specific requirements. Can a manufacturer avoid the patent by using nitrogen instead of argon?Possibly for process claim 21, because that claim expressly recites argon. The product claims may still apply if the resulting formulation satisfies their composition and oxygen limitations. Does the patent cover a 250 mL L-cysteine container?Claim 1 requires a single-use container of about 10 to 100 mL. A 250 mL container would have a potential noninfringement position under that claim, although other claims and equivalents analysis would remain relevant. Is an aluminum level below 1 ppb outside the patent?It would be outside the literal aluminum range of claim 1, which begins at about 1 ppb, assuming the measured value and claim construction treat the lower boundary as limiting. Can a generic applicant file an ANDA before the patent expires?Yes, if the regulatory pathway is available and the applicant submits an appropriate patent certification. A Paragraph IV certification can create patent litigation exposure and may trigger the statutory 30-month stay if the statutory conditions are met. Does patent expiration eliminate FDA exclusivity?No. Patent expiration and FDA regulatory exclusivity are separate. Any applicable new-drug, pediatric, orphan, or other exclusivity period must be evaluated independently from the patent term. References
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Drugs Protected by US Patent 10,478,453
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | TE | Type | RLD | RS | Patent No. | Patent Expiration | Product | Substance | Delist Req. | Patented / Exclusive Use | Submissiondate |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Exela Pharma | ELCYS | cysteine hydrochloride | SOLUTION;INTRAVENOUS | 210660-001 | Apr 16, 2019 | RX | Yes | Yes | 10,478,453 | ⤷ Start Trial | Y | METHOD OF USING L-CYSTEINE IN AN ADMIXTURE FOR TREATING PATIENTS NEEDING PARENTERAL NUTRITION | ⤷ Start Trial | |||
| Baxter Hlthcare Corp | NOURESS | cysteine hydrochloride | SOLUTION;INTRAVENOUS | 212535-001 | Dec 13, 2019 | RX | Yes | Yes | 10,478,453 | ⤷ Start Trial | Y | METHOD OF USING L-CYSTEINE IN AN ADMIXTURE FOR TREATING PATIENTS NEEDING PARENTERAL NUTRITION | ⤷ Start Trial | |||
| >Applicant | >Tradename | >Generic Name | >Dosage | >NDA | >Approval Date | >TE | >Type | >RLD | >RS | >Patent No. | >Patent Expiration | >Product | >Substance | >Delist Req. | >Patented / Exclusive Use | >Submissiondate |
