US Patent 9,962,359: Claim Scope, Patent Landscape, and Generic Entry Risk for Ravicti

US Patent 9,962,359 protects a clinical dosing-and-monitoring protocol for glyceryl tri-[4-phenylbutyrate], also known as glycerol phenylbutyrate and marketed as Ravicti. The patent does not claim the active ingredient itself, the Ravicti formulation generally, or treatment of every urea cycle disorder. Its core limitation is narrower: treating specified UCD patients who are clinically stable, measuring one fasting morning ammonia value after the drug reaches steady state, and increasing the dose when ammonia exceeds one-half of the laboratory-specific upper limit of normal.[1]

The principal commercial risk is a method-of-use infringement theory against a generic or alternative product whose labeling instructs physicians to titrate glycerol phenylbutyrate using the claimed fasting-ammonia protocol. A product with the same active ingredient could avoid literal infringement if its labeling and actual use omit one or more required limitations, particularly the single fasting measurement, the steady-state interval, or the threshold-based dose increase.

What does US Patent 9,962,359 protect?

The patent protects a treatment algorithm rather than a chemical compound. Independent claims 1 and 11 require the following elements:

Claim element	Required limitation
Patient population	Subject has a UCD
Covered disorders	OTC, CPS1, ASS, or ASL deficiency
Clinical status	Fasting morning or fasting plasma ammonia is below the laboratory ULN
Crisis status	Subject is not experiencing a hyperammonemic crisis
Product	Orally administered glyceryl tri-[4-phenylbutyrate]
Initiation	An initial dosage is administered
Pharmacokinetic timing	Ammonia is measured after the product reaches steady state
Testing protocol	One fasting plasma ammonia measurement, not serial blood draws
Comparator	Result is compared with the laboratory-specific ULN
Dose adjustment	Dose is increased when ammonia is greater than 0.5 ULN
Outcome relationship	A 0-0.5 ULN fasting result is associated with a greater than 80% likelihood of normal average daily ammonia
Repetition	Dependent claim 7 requires repeating the process until ammonia is at or below 0.5 ULN

The patent therefore covers a defined titration workflow. It does not require a particular milligram dose, a particular body-weight calculation, a specific commercial bottle or device, or a particular nitrogen-scavenger combination.

How broad are the independent claims?

Claim 1 is a “comprising” claim. That transition generally permits additional treatment or monitoring steps, provided the accused method includes every recited limitation. Claim 11 uses “consisting of,” creating a materially narrower claim construction issue because the claimed method is closed to additional method steps that materially alter the claimed combination.

The practical distinction is significant:

Claim 1 can potentially cover a protocol that includes other routine clinical acts, such as nutritional counseling, amino-acid supplementation, or additional safety monitoring.
Claim 11 is more vulnerable to arguments that an accused protocol contains unclaimed method steps inconsistent with the closed transition.
Both claims require the same central patient-selection, testing, comparison, and dose-adjustment sequence.

The claims do not cover patients with arginase deficiency, even though arginase deficiency is a recognized UCD. They expressly identify OTC deficiency, CPS1 deficiency, ASS deficiency, and ASL deficiency. A method used exclusively for arginase deficiency would not meet the specified disease limitation.

What are the key limitations in US Patent 9,962,359?

Fasting ammonia below the upper limit of normal

The patient must begin with a fasting plasma ammonia level below the ULN. The patent defines the comparator by reference to the normal range used by the laboratory performing the test. Claim 8 narrows the ULN to 35 μmol/L.

This laboratory-specific language has two effects. It accommodates differences in laboratory reference ranges, but it also creates claim-construction questions. An accused party may argue that the protocol does not use a laboratory-specific reference range if it applies a fixed clinical threshold without consulting the laboratory’s reported ULN.

No hyperammonemic crisis

The claims exclude subjects experiencing a hyperammonemic crisis. This limitation separates chronic maintenance treatment from emergency management. A protocol used during acute inpatient treatment, emergency rescue, or crisis stabilization would not necessarily meet the claimed patient-status limitation.

The exclusion also creates factual exposure. In a litigation setting, patient records, diagnosis codes, ammonia values, hospitalization records, and prescribing instructions could be used to determine whether the treated population included subjects in crisis.

Single fasting measurement rather than serial blood draws

The claims specifically require measuring a single fasting plasma ammonia level and not serial blood draws. This limitation is central to the patent’s distinction from intensive ammonia monitoring.

A protocol requiring several ammonia measurements during the same dose-adjustment cycle may create a non-infringement position if the claim requires one measurement only. The strength of that position would depend on whether the serial testing occurs in place of the claimed single measurement or is performed in addition to it. Claim 1’s “comprising” language makes this issue more difficult than it would be under a closed claim.

Steady-state timing

Claims 2 through 6 cover a series of alternative time periods:

Dependent claim	Claimed interval
Claim 2	48 hours
Claim 3	48 to 72 hours
Claim 4	72 hours to one week
Claim 5	One week to two weeks
Claim 6	More than two weeks

The dependent claims collectively create substantial timing coverage. A protocol that waits beyond 48 hours may still fall within claims 3 through 6. A protocol that uses a time period described as sufficient to reach steady state, but does not specify a fixed duration, may still implicate claim 1.

The word “steady state” is likely to generate expert testimony concerning glyceryl phenylbutyrate pharmacokinetics, metabolite formation, dose changes, patient adherence, food intake, and the clinical meaning of the interval. The patent’s timing claims are more commercially relevant than the 48-hour limitation alone because the dependent claims extend across the full range from two days to more than two weeks.

Threshold-based dose increase

The protocol requires increasing the dose when fasting ammonia is greater than one-half of the ULN. A method that maintains the dose, decreases the dose, or uses a different threshold may avoid this limitation.

A labeling strategy that grants physicians unrestricted discretion may reduce literal infringement exposure. The risk increases if the label directs dose escalation at a result above 0.5 ULN or instructs prescribers to repeat testing until the patient reaches that threshold.

What do claims 7 through 10 add?

Claim 7 requires repeating the measurement, comparison, and adjustment steps until ammonia is at or below one-half of the ULN. This claim reaches iterative dose titration protocols. It is narrower than claim 1 because a single adjustment is insufficient.

Claim 8 specifies a ULN of 35 μmol/L. The half-ULN threshold is therefore 17.5 μmol/L when that laboratory value is used.

Claim 9 requires a fasting morning blood draw. Claim 10 specifies an overnight fasting period. These limitations make the dependent claims easier to assess operationally because medical records may show the timing of the draw and the patient’s fasting instructions.

How does US Patent 9,962,359 compare with Ravicti composition and formulation patents?

US Patent 9,962,359 should be separated from patents directed to the active ingredient, pharmaceutical composition, dosage form, or manufacturing process.

IP category	Relevance to Ravicti
Active-ingredient protection	Would cover glyceryl phenylbutyrate or a related chemical entity itself
Formulation protection	May cover the oral liquid composition, excipients, concentration, stability, or packaging
Manufacturing protection	May cover synthesis, purification, impurity control, or production processes
Method-of-use protection	Covers a clinical indication, dosing regimen, patient population, or monitoring protocol
Patent 9,962,359	Covers ammonia-guided dose adjustment after steady-state exposure

Ravicti received FDA approval in 2013 for chronic management of patients with UCDs who cannot be adequately managed by dietary protein restriction and amino-acid supplementation alone.[2] The FDA-approved product is an oral liquid containing glycerol phenylbutyrate. The approval does not by itself establish infringement of every Ravicti-related patent. Each patent must be analyzed against the product, labeling, and use instructions.

A generic or follow-on product may face multiple independent barriers. A formulation patent may remain relevant even if a generic avoids the dosing protocol in US Patent 9,962,359. Conversely, a generic that designs around formulation claims could still face method-of-use exposure if its labeling reproduces the patented ammonia-guided titration method.

What is the Orange Book status of US Patent 9,962,359?

The Orange Book is the controlling FDA source for patents submitted by an NDA holder for an approved drug product. Patent listing, use codes, expiration dates, and any pediatric extensions must be reviewed in the current Orange Book record for Ravicti.[3]

The relevant regulatory question is not whether US Patent 9,962,359 concerns Ravicti generally. It is whether the patent is listed against the Ravicti NDA with a use code that corresponds to the claimed ammonia-monitoring and dose-adjustment method.

A method patent may be listed only for a specific approved use. If the use code is narrower than the full patent claims, an applicant may use a section viii statement to carve out the protected method while pursuing approval for non-infringing uses. If the applicant seeks approval for the listed method, it may need to submit a Paragraph IV certification and provide notice to the patent owner or NDA holder.[4]

The listed patent expiration date must be distinguished from the statutory patent term. Patent term adjustment, patent term extension, pediatric exclusivity, terminal disclaimers, and Orange Book corrections can affect the effective barrier to approval.

When does US Patent 9,962,359 lose exclusivity?

The patent’s effective expiration date must be taken from the USPTO patent record and the FDA Orange Book listing, if applicable. The patent was issued on May 8, 2018.[1] A precise enforceable expiration date cannot be inferred from the issue date alone because US patent term is generally measured from the earliest relevant nonprovisional filing date and may be modified by patent-term adjustment or other statutory provisions.[5]

For commercial planning, the relevant timeline has four separate components:

Barrier	Business significance
Patent term	Determines when infringement liability ends
Orange Book listing	Determines whether an ANDA applicant must address the patent
Regulatory exclusivity	May delay approval independently of patent expiry
Litigation or settlement	May delay commercial launch beyond statutory expiry

The patent is a method-of-use asset. Its value depends on whether the FDA-approved labeling, generic labeling, physician practice, or payer protocols direct use of the claimed method.

Which companies are challenging the Ravicti patent estate?

A patent-number-only review does not establish a current Paragraph IV challenger, litigation defendant, or settlement agreement. Those facts must be tied to an FDA Paragraph IV notice, a Hatch-Waxman complaint, a district-court docket, or a publicly disclosed settlement.

The principal potential challengers are generic applicants seeking approval for glyceryl phenylbutyrate. Relevant entities may include the NDA holder, authorized generic partners, ANDA applicants, and manufacturers of alternative nitrogen-scavenging products. A company does not need to challenge US Patent 9,962,359 directly if it can:

omit the patented method from its proposed labeling;
submit a section viii statement for a carved-out use;
certify that the patent is not listed or is not a valid barrier;
market a product for a non-covered patient population; or
rely on a different dosing and monitoring protocol.

What Paragraph IV challenges and litigation risks apply?

A Paragraph IV certification would typically raise one or more of four issues:

non-infringement because the proposed labeling omits the fasting single-draw protocol;
invalidity for anticipation or obviousness;
lack of written description or enablement for the full range of steady-state intervals and laboratory-specific ULNs;
indefiniteness concerning terms such as “sufficient” time, “initial dosage,” and “adjusted dosage.”

The strongest infringement theory would likely arise from a label that instructs prescribers to initiate glycerol phenylbutyrate, wait for steady state, obtain a fasting morning ammonia level, compare the result with the laboratory ULN, and increase the dose above 0.5 ULN. The strongest design-around would remove or alter at least one of those instructions.

Induced infringement would require proof that a manufacturer knew of the patent and encouraged acts constituting direct infringement. A generic label that merely permits a physician to perform the patented method may present a different risk from a label that expressly recommends the method.[6]

How strong is the patent estate for glyceryl phenylbutyrate?

US Patent 9,962,359 has meaningful but narrow scope.

Strengths

It covers a clinically specific titration algorithm.
The claims include multiple UCD subtypes.
The steady-state timing limitations span from 48 hours to more than two weeks.
The claims use laboratory-specific ULN language, which may capture different reference ranges.
The method is tied to an objective ammonia threshold.
Claim 7 reaches repeated dose adjustment.

Weaknesses

The patent does not claim the active ingredient or the product composition.
The method requires a specific monitoring sequence.
“Greater than half the upper limit” may permit straightforward threshold design-arounds.
The “greater than 80% likelihood” limitation may create proof and claim-construction questions.
Patient-status limitations may be difficult to prove across a broad commercial population.
A generic applicant may avoid the method through labeling carve-outs or alternative titration instructions.

The estate is therefore more likely to delay a fully labeled generic Ravicti product than to block every glycerol phenylbutyrate product.

How does Ravicti compare with alternative UCD treatments?

Ravicti competes with sodium phenylbutyrate products, including Buphenyl, and with dietary management, amino-acid supplementation, and emergency ammonia-lowering therapies.[2,7]

Product or approach	Active therapy	Primary patent risk relative to US 9,962,359
Ravicti	Glycerol phenylbutyrate	Direct method-of-use relevance
Sodium phenylbutyrate products	Sodium phenylbutyrate	Generally outside the claimed active-ingredient limitation
Dietary therapy	Protein restriction and supplementation	Outside the claimed drug method
Emergency rescue therapy	Acute hyperammonemia management	Potentially outside the “not in crisis” limitation
Glycerol phenylbutyrate alternative	Same active ingredient	Highest risk if label reproduces the titration algorithm

The closest competitive threat is a glycerol phenylbutyrate product with a different dose-adjustment label. Sodium phenylbutyrate products do not ordinarily satisfy the requirement to administer glyceryl tri-[4-phenylbutyrate].

What generic launch scenarios exist?

Early launch after a successful Paragraph IV challenge

A generic applicant may obtain approval and launch before patent expiry if it prevails in litigation, obtains a favorable settlement, or establishes that its proposed use does not infringe.

Carved-out launch

A section viii carve-out may remove the patented ammonia-guided titration method from the label. This approach can preserve approval for uses that remain outside the listed method, although actual promotional conduct and physician instructions remain relevant.

At-risk launch

A company may launch before final resolution, accepting potential damages and injunctive exposure. The commercial attractiveness depends on Ravicti sales, market share, remaining patent term, and the probability of a preliminary injunction.

Post-expiry launch

A fully labeled generic can launch after the patent and any applicable exclusivity expire. This is the lowest litigation-risk pathway but may leave substantial value on the table if the patent expires later than competing formulation or product patents.

What manufacturing and geographic barriers remain?

US Patent 9,962,359 does not appear, from the supplied claims, to impose a manufacturing restriction. It is a US method patent. A manufacturer located outside the United States may still face liability for importing the product, selling it in the United States, or inducing US performance of the claimed method.[5,6]

Manufacturing barriers may arise from separate composition, process, impurity, stability, or packaging patents. Those rights must be analyzed independently. The supplied claims do not establish protection in Europe, Japan, China, Canada, or other jurisdictions. Foreign family members may differ materially in claim scope, prosecution history, validity, and expiration.

Key Takeaways

US Patent 9,962,359 is a method-of-use patent for ammonia-guided Ravicti titration.
Its core requirement is one fasting ammonia measurement after steady state, followed by dose escalation when ammonia exceeds 0.5 ULN.
The patent covers OTC, CPS1, ASS, and ASL deficiencies, but not every UCD.
It excludes patients in hyperammonemic crisis.
Claims 2 through 6 provide broad timing coverage from 48 hours to more than two weeks.
The patent does not claim glycerol phenylbutyrate composition, formulation, or manufacture.
A generic product faces the greatest risk if its labeling directs the claimed titration sequence.
Section viii labeling carve-outs and alternative thresholds are potential design-around strategies.
Orange Book listing, use code, current expiration date, Paragraph IV activity, and settlement status must be determined from current FDA, USPTO, and court records.
The patent is commercially important as a labeling and treatment-protocol barrier, but it is unlikely by itself to block every glycerol phenylbutyrate product.

FAQs

Does US Patent 9,962,359 cover all uses of Ravicti?

No. It covers a specific treatment and monitoring protocol for selected UCD patients. It does not claim every use of Ravicti or every dose of glycerol phenylbutyrate.

Can a generic use a different ammonia threshold?

Potentially. A protocol that does not increase the dose when fasting ammonia is greater than 0.5 ULN may avoid a central limitation, subject to the full claim language and the generic’s actual labeling and conduct.

Does the patent cover sodium phenylbutyrate?

No. The claims require glyceryl tri-[4-phenylbutyrate], not sodium phenylbutyrate.

Can serial ammonia testing avoid infringement?

It may support a non-infringement argument, but the answer depends on whether the accused method also includes the claimed single fasting measurement and whether additional testing is compatible with the claim’s “comprising” language.

Is the 35 μmol/L threshold required in every case?

No. Claim 8 specifies 35 μmol/L as a narrower embodiment. The independent claims use the upper limit of normal reported by the laboratory.

References

United States Patent and Trademark Office. (2018). U.S. Patent No. 9,962,359, Methods for treating urea cycle disorders.
U.S. Food and Drug Administration. (2013). Ravicti prescribing information. Horizon Therapeutics USA, Inc.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2023). Abbreviated new drug application submissions: Refuse-to-receive standards.
United States Code, 35 U.S.C. §§ 154, 271, 281.
United States Code, 35 U.S.C. § 271(e).
U.S. Food and Drug Administration. (n.d.). Urea cycle disorder treatments and approved nitrogen-scavenging products.

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

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
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,962,359

Which drugs does patent 9,962,359 protect, and when does it expire?

Summary for Patent: 9,962,359