Details for Patent: 10,045,958
Which drugs does patent 10,045,958 protect, and when does it expire?
Patent 10,045,958 protects RAVICTI and is included in one NDA.
This patent has thirty-four patent family members in twenty-four countries.
Summary for Patent: 10,045,958
| Title: | Methods of therapeutic monitoring of nitrogen scavenging drugs | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abstract: | The present disclosure provides methods for evaluating daily ammonia exposure based on a single fasting ammonia blood level measurement, as well as methods that utilize this technique to adjust the dosage of a nitrogen scavenging drug, determine whether to administer a nitrogen scavenging drug, and treat nitrogen retention disorders. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inventor(s): | Bruce SCHARSCHMIDT, Masoud Mokhtarani | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee: | Horizon Therapeutics US Holding LLC | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Application Number: | US15/944,398 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent Litigation and PTAB cases: | See patent lawsuits and PTAB cases for patent 10,045,958 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Patent Claim Types: see list of patent claims | Use; | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent landscape, scope, and claims: | United States Patent 10,045,958: Scope, Claim Construction, Expiration Risk, and Ravicti Patent LandscapeUS Patent 10,045,958 covers a patient-specific titration method for glyceryl tri[4-phenylbutyrate], marketed as Ravicti. The patent does not broadly claim the drug, its chemical structure, or every treatment of a urea cycle disorder. Its principal claim requires a defined sequence: treating a non-crisis UCD patient, waiting for steady state, obtaining one fasting ammonia measurement, comparing that value with the laboratory’s upper limit of normal, and increasing the dose when ammonia exceeds 50% of that limit. The patent is most relevant to Ravicti prescribing protocols, product labeling, clinical decision support, and generic substitution strategies. Its commercial value depends on whether a competing label, physician protocol, or automated titration system performs the claimed single-measurement, threshold-based dose adjustment. What patent is US 10,045,958 and who owns it?US 10,045,958 is titled “Methods of treating urea cycle disorders.” It issued on August 14, 2018, from a patent family associated with Hyperion Therapeutics, the original developer of Ravicti. Hyperion was acquired by Horizon Pharma in 2015; Horizon was later acquired by Amgen in 2023. Ownership and enforcement rights should be assessed through the current assignment record rather than the original grant record.
The patent should be distinguished from composition, formulation, manufacturing, and broad treatment patents covering glycerol phenylbutyrate. US 10,045,958 is a clinical-use patent centered on how the drug is titrated. What does claim 1 of US 10,045,958 require?Claim 1 contains multiple cumulative limitations. A practice must satisfy all material elements for literal infringement. Patient populationThe treated patient must:
The claim therefore excludes patients already above the upper limit of normal at baseline and patients undergoing acute crisis management. It is directed to maintenance treatment and dose optimization. The express disease list may limit literal infringement for patients with other UCDs, including arginase 1 deficiency or lysineuric protein intolerance, unless those conditions are shown to fall within the claim through an equivalent theory. The patent’s specification and prosecution history would be important in assessing that issue. Initial administrationThe method begins with oral administration of an initial dosage of glyceryl tri[4-phenylbutyrate]. The claim does not specify a particular initial amount, body-surface-area calculation, age band, or formulation concentration. This limitation distinguishes the claim from a purely diagnostic method. The protected sequence must include administration of the drug. Steady-state intervalAfter administration, the method requires a period sufficient for glyceryl tri[4-phenylbutyrate] to reach steady state. The dependent claims define several alternative intervals:
These ranges overlap at 48 and 72 hours. Claim 2 is narrower than claim 3 because it specifies 48 hours rather than a range. Claim 6 is open-ended and can cover monitoring after any period exceeding two weeks, provided the other claim elements are met. The use of “sufficient” makes the scientific question clinically important. A party could dispute whether the selected interval actually permits steady state under the patient’s dose, adherence, metabolism, feeding pattern, and renal or hepatic condition. The dependent time ranges reduce, but do not eliminate, that dispute. Single fasting ammonia measurementThe method requires measuring “a single fasting plasma ammonia level” after steady state. The claim expressly states “and not serial blood draws.” This is one of the patent’s strongest narrowing limitations. A protocol based on repeated ammonia draws, continuous monitoring, or a series of measurements may avoid literal infringement if the measurement sequence does not include the claimed single-draw step. The issue would turn on whether the protocol also includes a qualifying single fasting measurement before later serial testing. The claim does not require a particular analyzer, blood collection tube, laboratory, or turnaround time. It does require that the measurement be fasting, plasma-based, and obtained after the relevant drug exposure period. Upper-limit comparison and dose increaseThe fasting ammonia value must be compared with the upper limit of normal used by the laboratory where the ammonia was measured. Claim 8 fixes the upper limit at 35 micromoles per liter for its narrower version. Under claim 1:
For a laboratory with a 35 micromoles/L upper limit, the relevant threshold is greater than 17.5 micromoles/L. Claim 8 requires use of 35 micromoles/L as the upper-limit value, regardless of whether another laboratory uses a different range.
The claim’s use of the laboratory-specific reference range creates a potential evidentiary issue. Medical records, laboratory reports, and electronic prescribing rules could show whether the relevant ULN and threshold were actually used. What do dependent claims 2 through 8 add?Claims 2 through 8 narrow claim 1 in different ways. Claims 2 through 6 define the time between initial dosing and ammonia measurement. They do not change the disease population, fasting requirement, or dose-adjustment threshold. Claim 7 requires repeating the measurement and adjustment steps until fasting ammonia is at or below half the upper limit of normal. This creates an iterative titration regimen. A one-time increase may infringe claim 1 but not claim 7. Claim 8 fixes the upper limit of normal at 35 micromoles/L. It is potentially important for protocols using a standardized 35 micromoles/L reference rather than each laboratory’s reported range. The statement that a patient with fasting ammonia from 0 to 0.5 ULN has a greater than 80% likelihood of having an average daily ammonia level within the normal range is unusual as a claim limitation. It may operate as a result or relationship limitation rather than a required treatment action. Its enforceability would depend on claim construction, written-description support, enablement, and whether the limitation requires proof of the statistical relationship in the accused population. What FDA product does US 10,045,958 relate to?The patent relates to Ravicti oral liquid, whose active ingredient is glycerol phenylbutyrate. The FDA approved Ravicti in 2013 for chronic management of patients with urea cycle disorders who cannot be adequately managed by dietary protein restriction and amino acid supplementation, with or without phenylbutyrate, including patients with deficiencies involving the urea cycle enzymes covered by the product labeling. FDA labeling addresses chronic treatment rather than emergency correction of acute hyperammonemic crisis. (U.S. Food and Drug Administration, 2023a) Ravicti dosing is generally individualized based on body surface area, age, prior nitrogen-scavenger exposure, dietary protein intake, and biochemical control. The patent adds a particular ammonia-monitoring and titration sequence to that broader clinical framework. The product label and the patent are not coextensive. FDA approval authorizes use under the approved indication. Patent infringement depends on whether the prescribed or implemented method satisfies the patent claims. What is the Orange Book status of US 10,045,958?Ravicti is listed in the FDA Orange Book, which identifies approved drug products and patent or exclusivity information submitted by the NDA holder. The relevant Orange Book analysis should distinguish:
US 10,045,958 is a method-of-use patent associated with the Ravicti product rather than a patent on the glycerol phenylbutyrate molecule itself. A method-of-use listing can require an ANDA applicant to make a Paragraph IV certification if the applicant seeks approval for a use covered by the listed patent, or a section viii statement if it seeks approval with the patented use carved out. The Orange Book does not establish infringement or validity. It records the sponsor’s patent listing and the FDA’s regulatory treatment of that listing. The patent’s legal enforceability remains subject to ordinary validity, claim-construction, and infringement analysis. (U.S. Food and Drug Administration, 2023b) When does US 10,045,958 lose exclusivity?The patent’s exact expiration date cannot be determined from the issued claims alone. It depends on the earliest effective nonprovisional filing or priority date, patent-term adjustment, terminal disclaimers, and any applicable patent-term extension. The issue date, August 14, 2018, is not the expiration date. The patent belongs to a Ravicti family developed in the early 2010s. Its nominal term is expected to extend into the 2030s, subject to the USPTO term calculation. Patent-term adjustment must be checked in the USPTO Patent Center record and the front page or official term calculation for US 10,045,958. A patent-term extension under 35 U.S.C. §156 would require a qualifying regulatory basis and cannot be assumed from FDA approval alone. (United States Patent and Trademark Office, 2024) Regulatory exclusivity is separate:
The practical loss-of-exclusivity date for Ravicti may therefore be later than the expiration of any single patent because multiple listed patents can create separate barriers. What Paragraph IV challenges and litigation risks apply?A generic applicant seeking approval for glycerol phenylbutyrate could challenge US 10,045,958 under Paragraph IV by alleging that the patent is invalid, unenforceable, or not infringed. The principal generic defenses would likely focus on the following issues:
The strongest noninfringement position would omit at least one mandatory limitation: use a non-covered UCD, treat a patient in crisis, use serial rather than single blood draws, measure before steady state, or avoid an automatic dose increase when ammonia exceeds 0.5 ULN. How strong is the patent estate for Ravicti?US 10,045,958 is narrow in subject matter but potentially strong in operational relevance. Its value is higher if the approved label, standard clinical practice, or payer-mandated dosing tools direct clinicians to perform the exact sequence.
The patent is therefore a targeted method-of-use barrier, not a complete Ravicti monopoly. Commercial protection depends on the rest of the Orange Book estate, regulatory exclusivity, product formulation know-how, supply arrangements, and the ability to enforce clinical-use claims. What generic launch scenarios exist for Ravicti?A generic applicant has several potential pathways: Full-label launchThe applicant includes the chronic UCD indication and dosing information. This creates the greatest exposure to method-of-use patents and Paragraph IV litigation. Carved-out launchThe applicant removes the patented ammonia-guided titration method under a section viii statement. This may reduce infringement exposure but can create regulatory and commercial limits if the omitted information is integrated into standard dosing instructions. At-risk launchThe applicant launches after receiving an unfavorable district-court decision or before final resolution of all patent appeals. This creates potential damages and injunction risk. Noninfringing clinical protocolA payer, provider, or generic sponsor may use a protocol that does not perform the claimed single fasting draw, does not use the 0.5 ULN threshold, or does not require dose escalation. Such a protocol may reduce literal infringement risk but must remain medically and regulatorily acceptable. Does US 10,045,958 create biosimilar risk?No. Biosimilar procedures under the Public Health Service Act apply to biological products. Ravicti is a chemically synthesized small-molecule drug approved under the Federal Food, Drug, and Cosmetic Act. Competitive entry would proceed through the ANDA framework, not the biosimilar pathway. The relevant competitors are generic glycerol phenylbutyrate products, alternative nitrogen scavengers such as sodium phenylbutyrate, and non-drug dietary management approaches. Sodium phenylbutyrate is not an automatic therapeutic substitute because it has different formulation, palatability, dosing, and tolerability characteristics. What licensing and commercial issues affect the patent landscape?Hyperion commercialized Ravicti before its acquisition by Horizon. The later Horizon-Amgen transaction transferred the commercial franchise and associated intellectual-property interests through the acquisition structure. No separate third-party license is required to analyze the basic scope of US 10,045,958 unless the patent has been assigned, licensed, or encumbered in a later transaction. The principal commercial exposure is the U.S. Ravicti franchise, particularly patients requiring chronic nitrogen-scavenger therapy. Patent value is concentrated in the United States because the claim is a U.S. method claim. Foreign family members, if granted, must be analyzed separately for claim scope, prosecution history, term, and national regulatory status. Key Takeaways
FAQsDoes US 10,045,958 cover all Ravicti dosing?No. It covers a specific ammonia-guided dose-adjustment method. It does not independently claim every Ravicti dose, every UCD treatment, or the glycerol phenylbutyrate molecule. Is a fasting ammonia value of exactly one-half ULN enough to require dose escalation?No. Claim 1 requires an adjusted dose greater than the initial dose when the fasting ammonia level is greater than half the ULN. Exactly one-half is outside that express threshold, although other claims, protocols, or clinical instructions may differ. Can a physician avoid the patent by measuring ammonia before steady state?That may avoid literal infringement of the steady-state limitation, but the complete clinical and promotional conduct must be assessed. A court would examine the actual protocol, instructions, and any equivalent-performance theory. Does claim 8 apply when a laboratory reports a ULN other than 35 micromoles/L?Claim 8 specifically recites 35 micromoles/L. Claim 1 instead refers to the reference range at the laboratory where the measurement occurred. The two claims should be analyzed separately. What is the main invalidity vulnerability of the patent?The principal vulnerabilities are obviousness based on prior ammonia-monitoring and nitrogen-scavenger dosing practices, indefiniteness of the steady-state and single-draw limitations, and written-description or enablement challenges to the statistical relationship in claim 1. References
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Drugs Protected by US Patent 10,045,958
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | TE | Type | RLD | RS | Patent No. | Patent Expiration | Product | Substance | Delist Req. | Patented / Exclusive Use | Submissiondate |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Horizon Therap Us | RAVICTI | glycerol phenylbutyrate | LIQUID;ORAL | 203284-001 | Feb 1, 2013 | AA | RX | Yes | Yes | ⤷ Start Trial | ⤷ Start Trial | TREATMENT OF A UREA CYCLE DISORDER | ⤷ 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 |
International Family Members for US Patent 10,045,958
| Country | Patent Number | Estimated Expiration | Supplementary Protection Certificate | SPC Country | SPC Expiration |
|---|---|---|---|---|---|
| Australia | 2012316750 | ⤷ Start Trial | |||
| Australia | 2017251691 | ⤷ Start Trial | |||
| Brazil | 112014007357 | ⤷ Start Trial | |||
| Canada | 2850391 | ⤷ Start Trial | |||
| Chile | 2014000783 | ⤷ Start Trial | |||
| China | 104039358 | ⤷ Start Trial | |||
| >Country | >Patent Number | >Estimated Expiration | >Supplementary Protection Certificate | >SPC Country | >SPC Expiration |
