US Patent 10,668,040: Glycerol Phenylbutyrate Pediatric Urea-Cycle-Disorder Patent Analysis

US Patent 10,668,040 protects a treatment algorithm for glycerol phenylbutyrate, marketed as Ravicti, in patients younger than two years with urea cycle disorders. The patent does not broadly claim glycerol phenylbutyrate, Ravicti, or treatment of UCDs in all patients. Its scope is concentrated on pediatric dosing, conversion from sodium phenylbutyrate or sodium benzoate, dosing frequency, and interpretation of neurological symptoms against plasma phenylacetic acid and phenylacetylglutamine levels.

The commercially important protection is method-of-use protection. A competing product would face infringement risk if it is used in the United States under a protocol that satisfies the age, dose, frequency, laboratory threshold, and dose-adjustment limitations in claims 1 through 12.

What does US Patent 10,668,040 cover?

US Patent 10,668,040 covers three related clinical decision pathways for patients under two years of age:

Claim group	Clinical condition after initial treatment	Required response
Claims 1, 4-6	Neurological symptoms, normal ammonia, and plasma PAA:PAGN ratio above 2.5 or plasma PAA above 500 μg/mL	Reduce the daily dose while maintaining the initial frequency
Claims 2, 7-9	Neurological symptoms, normal ammonia, and plasma PAA:PAGN ratio above 2.5 or plasma PAA above 500 μg/mL	Use a lower dose or increase administration frequency while maintaining the daily dose
Claims 3, 10-12	Neurological symptoms, normal ammonia, and plasma PAA:PAGN ratio below 2.5	Continue the same dose and frequency and evaluate other causes

The claims apply only when all material limitations are met. The principal limitations are:

The patient has a UCD.
The patient is younger than two years.
The administered drug is glycerol phenylbutyrate.
The initial administration frequency is three to six times daily.
The initial dose depends on crisis status or prior therapy.
Neurological symptoms occur despite normal ammonia levels.
Plasma PAA and PAGN results determine the next clinical step.

The claims therefore protect a dosing-management protocol rather than a composition, formulation, manufacturing process, or broad therapeutic use.

What doses are required by US Patent 10,668,040?

The patent recites three initial-dose pathways.

Patient status	Claimed initial daily dose
Hyperammonemic crisis	11.2 mL/m²/day
Not in hyperammonemic crisis	8.5 mL/m²/day
Previously treated with NaPBA powder	0.81 times the prior total grams of NaPBA powder
Previously treated with NaPBA tablets	0.86 times the prior total grams of NaPBA tablets
Previously treated with NaBz	0.5 times the prior total grams of sodium benzoate

The selected dose must be administered three to six times per day. The claim language ties the dose to body-surface area for glycerol phenylbutyrate liquid dosing and to prior daily grams for conversion from sodium phenylbutyrate or sodium benzoate.

A central practical issue is the claim’s use of conversion factors based on the prior formulation. A generic or alternative product can reduce literal infringement risk if its prescribing instructions use a materially different conversion method, provided the overall administration does not nevertheless satisfy the patent’s limitations.

How do the independent claims differ?

Claims 1, 2, and 3 are the independent claims. They use the same initial treatment framework but create different responses to neurological symptoms.

Claim 1: reduced daily dose, same frequency

Claim 1 applies when the patient has:

neurological symptoms;
normal ammonia;
a plasma PAA:PAGN ratio greater than 2.5 or plasma PAA above 500 μg/mL.

The required intervention is a reduced daily dose while maintaining the initial frequency. A patient initially treated four times daily would remain on four daily administrations, but the total daily quantity would be reduced.

This is the narrowest adjustment pathway because it requires both a dose reduction and retention of the initial frequency.

Claim 2: lower dose or increased frequency

Claim 2 contains an alternative adjustment pathway. It requires a lower dose or increased frequency while maintaining the daily dose.

The most coherent clinical interpretation is that the per-administration amount may be reduced while the number of administrations increases, leaving the total daily dose unchanged. For example, a regimen administered four times daily could be divided into more frequent administrations at lower amounts per administration.

The phrase “lower dose or increased frequency ... while maintaining said daily dose” creates a potential claim-construction issue. “Lower dose” may mean a lower amount per administration rather than a lower total daily amount. The specification and prosecution history would be important in determining whether the claim requires a reduction in total daily dose, dose per administration, or either alternative.

Claim 3: no glycerol phenylbutyrate adjustment

Claim 3 applies when the patient has neurological symptoms and normal ammonia but the plasma PAA:PAGN ratio is below 2.5.

The claimed response is to continue the same dose and frequency and evaluate other causes of the symptoms. The claim creates a negative clinical decision rule: the neurological symptoms should not automatically be attributed to excessive PAA exposure when the ratio is below the specified threshold.

What do the dependent claims add?

Claims 4 through 12 add limited age and symptom definitions.

Dependent claims	Added limitation
4, 7, 10	Patient is less than about one month old
5, 8, 11	Patient is from one month to two years old
6, 9, 12	Neurological symptoms include headache, confusion, vomiting, lethargy, or a combination

These claims divide the under-two population into neonatal and older infant groups. They do not add a new active ingredient, dosage form, disease subtype, or laboratory marker.

The dependent claims increase enforcement flexibility. A plaintiff may rely on claims directed specifically to neonates, infants, or enumerated symptoms if a broader independent claim presents a construction or validity issue.

When does US Patent 10,668,040 expire?

The patent issued on June 2, 2020. The ordinary patent term is generally 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and any applicable patent-term extension under 35 U.S.C. §§ 154 and 156.

The public grant record should control the final expiration calculation. A grant-date review alone does not establish the enforceable expiration date because the term can be affected by:

patent-term adjustment;
priority claims to earlier applications;
terminal disclaimers;
patent-term extension;
disclaimer or post-grant modification.

Based on the patent’s apparent mid-2010s filing and priority history, the expected unadjusted term is in the mid-2030s. The relevant commercial planning assumption is that the patent potentially remains material well beyond the 2030 Ravicti market period unless invalidated, disclaimed, or otherwise limited.

What is the FDA and Orange Book significance?

Ravicti is an FDA-approved glycerol phenylbutyrate oral liquid for chronic management of patients with UCDs who cannot be managed by dietary protein restriction and supplementation alone. The FDA label includes pediatric dosing information and cautions regarding phenylacetate-related neurotoxicity, including neurological symptoms associated with elevated PAA exposure.[2]

Patent 10,668,040 is a method-of-use patent. Its Orange Book relevance depends on whether the patent is listed for Ravicti and whether an approved product labeling section corresponds to the claimed method. An Orange Book listing does not establish validity or infringement. It can, however, create a regulatory pathway for a generic applicant to make a Paragraph IV certification.

For an ANDA applicant, the principal outcomes are:

Certification	Practical effect
Paragraph I	No patent information listed
Paragraph II	Listed patent has expired
Paragraph III	Applicant will wait until patent expiration
Paragraph IV	Applicant asserts that the patent is invalid, unenforceable, or not infringed
Section viii statement	Applicant seeks approval for uses outside the patented method, where legally available

A Paragraph IV notice concerning a listed method patent can trigger litigation under the Hatch-Waxman statute. The patent holder may obtain a 30-month stay of FDA approval if the statutory requirements are met. A skinny-label strategy may reduce exposure if the generic omits the patented pediatric dosing method and the remaining label does not encourage use of the patented regimen.

What generic entry risks exist for glycerol phenylbutyrate?

Glycerol phenylbutyrate is a small molecule, not a biologic. Biosimilar approval under the Public Health Service Act is therefore not the expected pathway. A competing product would generally pursue an ANDA under section 505(j) or, depending on the product and labeling strategy, a 505(b)(2) application.

The main entry scenarios are:

Paragraph IV challenge

A generic applicant could challenge the patent on grounds including:

lack of novelty;
obviousness;
lack of written description;
lack of enablement;
indefiniteness;
noninfringement;
unenforceability.

The strongest potential validity questions concern whether the claimed pediatric dosing algorithm was predictable from prior UCD treatment guidance, whether the plasma PAA/PAGN thresholds were adequately supported across the full claimed population, and whether the dose-adjustment language gives sufficient notice of the required conduct.

Section viii carve-out

A generic could attempt to omit the patented pediatric method from its label. This strategy is more difficult where the remaining UCD indication inherently directs physicians toward the same pediatric dosing instructions or where the reference label contains detailed information that cannot be practically separated.

505(b)(2) product

A 505(b)(2) applicant could seek approval for a modified formulation, delivery device, or dosing presentation. Such a product may avoid some literal infringement theories but could face separate formulation or method patents.

How strong is the patent estate around Ravicti?

Patent 10,668,040 has meaningful commercial value because it targets infants, a population in which dosing errors and toxicity concerns are clinically material. Its value is narrower than a composition-of-matter patent.

Estate characteristic	Assessment
Product coverage	Limited; claims require glycerol phenylbutyrate
Disease coverage	Limited to UCDs
Age coverage	Limited to patients under two years
Dosing coverage	Strongly specified through dose, frequency, and conversion factors
Biomarker coverage	Specific PAA, PAGN, and ammonia conditions
Formulation coverage	None apparent from the supplied claims
Manufacturing coverage	None apparent from the supplied claims
Enforcement evidence	Potentially strong if prescribing records and laboratory results are available
Label dependence	High, because the method may be practiced through approved pediatric labeling
Design-around potential	Moderate, particularly through altered dosing instructions or omission of the patented decision rule

The patent is stronger against a product whose labeling expressly reproduces the claimed pediatric regimen. It is weaker against a competitor that uses a different dose-conversion method, different monitoring algorithm, different frequency instructions, or a label that excludes the patented method.

What formulation patents protect glycerol phenylbutyrate?

The supplied claims do not protect a formulation. They require administration of glycerol phenylbutyrate but do not recite:

a particular excipient;
a concentration;
a container;
a flavoring system;
a dosage device;
a particle size;
a release profile;
a manufacturing process.

A complete freedom-to-operate analysis must separate this patent from any composition, formulation, process, device, or packaging patents associated with Ravicti. Those rights could create barriers even if Patent 10,668,040 is avoided.

The clinically important formulation distinction is that Ravicti is an oral liquid. A competing liquid, powder, tablet, or extemporaneous formulation may raise separate questions under other patent families, regulatory equivalence requirements, and labeling controls.

What patent litigation affects US Patent 10,668,040?

The supplied information identifies the patent and claims but does not establish a confirmed infringement complaint, Paragraph IV notice, settlement, consent judgment, or final validity ruling specifically involving Patent 10,668,040.

The absence of a confirmed litigation event in the supplied record should not be treated as evidence that no such event exists. Litigation status is date-sensitive and must be determined from PACER, district-court dockets, Federal Circuit opinions, USPTO Patent Center, and FDA Orange Book updates.

For transaction diligence, the material litigation questions are:

Has a generic applicant sent a Paragraph IV notice?
Has the patent holder sued within the statutory 45-day period?
Has a court construed “normal ammonia,” “lower dose,” or “maintaining said daily dose”?
Has any settlement restricted the generic entry date?
Has any post-grant review, inter partes review, reexamination, or disclaimer changed the claims?
Has the patent been listed or delisted from the Orange Book?

Which companies control the commercial position?

Ravicti was developed through the Hyperion and Horizon commercial history and is currently associated with Bausch Health’s specialty-pharmaceutical operations. The patent owner of record may differ from the current commercial marketer because patent assignments, corporate reorganizations, and licensing transactions can separate ownership from product commercialization.

The relevant commercial chain is therefore:

active ingredient: glycerol phenylbutyrate;
product: Ravicti;
indication: urea cycle disorders;
regulatory pathway: FDA new drug application;
likely generic pathway: ANDA, with possible Paragraph IV or section viii strategy;
biologic pathway: not applicable;
principal patent issue: pediatric method-of-use protection.

No license or settlement agreement should be inferred solely from the product’s corporate history. Assignment records and transaction documents control.

How does Patent 10,668,040 compare with broad product patents?

Patent type	Scope	Commercial effect
Composition-of-matter patent	Covers the active molecule or chemical entity	Usually the strongest barrier to generic entry
Formulation patent	Covers liquid, tablet, excipient, device, or release system	Can block specific presentations
Manufacturing patent	Covers synthesis, purification, or scale-up	May create supply-chain barriers
Method-of-use patent	Covers patient population, dose, monitoring, or treatment method	Depends heavily on labeling and clinical practice
US 10,668,040	Pediatric UCD dosing and PAA/PAGN-based adjustment	Narrow but potentially relevant to infant labeling

Patent 10,668,040 is not a substitute for basic product exclusivity. Its principal value is incremental lifecycle protection in the pediatric UCD market.

What is the likely generic launch scenario?

The most plausible challenge strategy would combine a Paragraph IV certification with a label-based noninfringement position. A generic applicant could argue that its label does not require:

treatment of patients under two years;
the 8.5 or 11.2 mL/m²/day starting doses;
the stated NaPBA or NaBz conversion factors;
three-to-six-times-daily administration;
PAA:PAGN monitoring;
the claimed response to neurological symptoms.

The patent holder would counter that the generic label, clinical materials, or ordinary use would induce physicians to practice the claimed method. The outcome would depend on the precise approved label, promotional conduct, prescribing evidence, and construction of the dose-adjustment language.

A launch before patent expiration would carry greater risk if the competing label reproduces the FDA-approved pediatric instructions. A launch with a pediatric carve-out would reduce risk but could materially limit the addressable UCD market.

Key Takeaways

US Patent 10,668,040 is a pediatric method-of-use patent for glycerol phenylbutyrate in UCD patients younger than two years.
Claims 1 through 3 define different responses to neurological symptoms, normal ammonia, and PAA/PAGN laboratory results.
The patent requires specific initial doses, conversion factors, and administration frequencies.
Claims 4 through 12 narrow the population to neonates, older infants, and specified neurological symptoms.
The patent does not claim the glycerol phenylbutyrate molecule, a formulation, or a manufacturing process.
Generic risk is highest when a competing label reproduces the claimed pediatric dosing algorithm.
Biosimilar analysis is inapplicable because glycerol phenylbutyrate is a small molecule.
The key regulatory challenge routes are Paragraph IV certification, section viii carve-out, and, in some cases, a 505(b)(2) application.
The enforceable expiration date requires review of the patent’s priority chain, patent-term adjustment, terminal disclaimers, and any patent-term extension.
No litigation, settlement, or licensing conclusion should be drawn without current USPTO, FDA, court-docket, and assignment records.

FAQs

Is US Patent 10,668,040 a composition-of-matter patent?

No. The supplied claims are method claims. They cover administering glycerol phenylbutyrate according to specified pediatric dosing and biomarker-based adjustment rules.

Does the patent cover all Ravicti use in children?

No. It is limited to patients under two years and requires the stated UCD, dosing, frequency, neurological-symptom, ammonia, PAA, and PAGN conditions.

Can a generic avoid the patent by using a different dose frequency?

Potentially, depending on the approved labeling and actual use. The claims require an initial frequency of three to six times daily, but other claim limitations must also be evaluated.

Does a biosimilar pathway apply to glycerol phenylbutyrate?

No. Glycerol phenylbutyrate is a small molecule. A competing product would generally use an ANDA or, in appropriate circumstances, a 505(b)(2) application.

What evidence would support an infringement case?

Relevant evidence could include the competing product label, prescribing instructions, promotional materials, patient age, dosing records, administration frequency, ammonia results, PAA and PAGN levels, and documentation of the response to neurological symptoms.

References

United States Patent and Trademark Office. (2020). U.S. Patent No. 10,668,040, methods of treating urea cycle disorders. https://patents.google.com/patent/US10668040B2/en
U.S. Food and Drug Administration. (2024). Ravicti (glycerol phenylbutyrate) oral liquid prescribing information. DailyMed. https://dailymed.nlm.nih.gov/dailymed/
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Food and Drug Administration. (2024). Abbreviated new drug application regulations and patent certifications. https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/anda-submissions-content-and-format
United States Code. (2024). 35 U.S.C. §§ 154, 156; 21 U.S.C. § 355. https://uscode.house.gov/

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	10,668,040	⤷ 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

Details for Patent: 10,668,040

Which drugs does patent 10,668,040 protect, and when does it expire?

Summary for Patent: 10,668,040