US Patent 9,561,197: Scope, Claims, Exclusivity and Ravicti Patent Landscape

US Patent 9,561,197 protects a biomarker-guided dosing method for glyceryl phenylbutyrate, marketed as Ravicti. The patent does not broadly claim glyceryl phenylbutyrate, treatment of urea cycle disorders, or every Ravicti dosing regimen. Its central limitation is the use of the patient’s plasma phenylacetic acid-to-phenylacetylglutamine ratio, or PAA:PAGN ratio, to adjust dosing until the ratio falls within a defined range.

The two independent claims cover target ranges of 1 to 2 and 1 to 2.5. The patent is therefore most relevant to method-of-use infringement, label-driven generic entry, and clinical dosing instructions that expressly use the PAA:PAGN ratio.

What does US Patent 9,561,197 claim?

The patent contains two independent method claims:

Claim	Patient condition	Drug	Required intervention	Required endpoint
1	Plasma PAA:PAGN ratio outside 1 to 2	Glyceryl tri-[4-phenylbutyrate], also called HPN-100 or glycerol phenylbutyrate	Administer a dosage effective to change the ratio	Ratio within 1 to 2
2	Plasma PAA:PAGN ratio outside 1 to 2.5	Glyceryl tri-[4-phenylbutyrate]	Administer a dosage effective to change the ratio	Ratio within 1 to 2.5

The claims are method-of-treatment claims. They require more than administration of Ravicti to a patient with a urea cycle disorder. The claimed method requires:

A subject with a urea cycle disorder.
Measurement or knowledge that the subject’s plasma PAA:PAGN ratio is outside the specified range.
Administration of glyceryl phenylbutyrate.
A dosage effective to bring the ratio inside the claimed range.

The claim language supplied for Claim 1 requires a ratio outside 1 to 2 before treatment and a ratio within 1 to 2 after treatment. Claim 2 uses the broader numerical interval of 1 to 2.5.

What is the inventive concept?

The patent’s practical contribution is dose individualization based on exposure to PAA relative to PAGN formation. Phenylbutyrate is metabolized to phenylacetate, which conjugates with glutamine to form phenylacetylglutamine. PAGN provides an alternative nitrogen-excretion pathway in patients with urea cycle disorders. Excessive PAA exposure can create tolerability and safety concerns, while insufficient exposure may reduce nitrogen removal.

The claims use the PAA:PAGN relationship as a pharmacokinetic and pharmacodynamic control parameter. The method is not limited to a fixed milliliter dose, a fixed body-weight dose, or a particular age group unless those limitations appear in dependent claims or the specification.

How broad is the scope of US 9,561,197?

The patent has meaningful commercial scope but narrow technical architecture. Its scope is strongest against a dosing protocol that uses PAA:PAGN testing and expressly targets one of the claimed ranges.

Claim construction issues

Several terms are likely to determine infringement:

Claim element	Main legal issue
“Subject having a plasma PAA to PAGN ratio outside”	Whether a ratio must be measured before administration or may be inferred from clinical data
“Administering ... a dosage”	Whether one administration is sufficient or whether dose titration is required
“Effective to achieve”	Whether actual achievement of the target range is required or whether a prescribed dose expected to achieve it is sufficient
“Within the target range”	Whether the endpoints are inclusive
“Glyceryl tri-[4-phenylbutyrate]”	Whether the claim covers the active pharmaceutical ingredient regardless of formulation, concentration, or brand
“Treating a urea cycle disorder”	Whether treatment must improve the disorder or merely address the nitrogen-disposal defect

The claims do not expressly require Ravicti by brand name. They identify the active ingredient by chemical description and the development code HPN-100. A generic product containing the same active ingredient could fall within the product limitation if the remaining method steps are practiced.

Does the patent cover every Ravicti prescription?

No. A routine prescription of Ravicti does not necessarily practice the claims. A potential infringement theory would be stronger where the prescribing, monitoring, or product labeling instructs clinicians to:

Measure PAA and PAGN;
Calculate the ratio;
Identify a ratio outside 1 to 2 or 1 to 2.5;
Adjust glyceryl phenylbutyrate dosing; and
Continue treatment to achieve the claimed range.

A prescription based only on body surface area, age, prior sodium phenylbutyrate exposure, or total daily dose may not satisfy the ratio limitations.

What patent protects the PAA:PAGN dosing method?

US 9,561,197 is the key patent identified by the supplied claims for PAA:PAGN-ratio-guided treatment. The patent was granted on February 7, 2017, and is assigned in the public patent record to the Hyperion-related Ravicti patent estate. Hyperion developed HPN-100 and commercialized it as Ravicti before its acquisition by Horizon Pharma. Horizon was later acquired by Amgen. The chain of commercial ownership does not change the claim scope, but it affects enforcement and licensing rights. (U.S. Patent No. 9,561,197, 2017; U.S. Food and Drug Administration [FDA], 2024.)

Patent data

Field	Information
Patent	US 9,561,197
Grant date	February 7, 2017
Technology	PAA:PAGN-ratio-guided glyceryl phenylbutyrate dosing
Product association	Ravicti
Active ingredient	Glycerol phenylbutyrate
Development code	HPN-100
Claim category	Method of treatment
Primary disease area	Urea cycle disorders
Principal enforcement issue	Whether a generic label or clinical practice directs the claimed ratio-based dosing
Nominal term	Patent term extends into the early 2030s, subject to the actual priority chain, patent-term adjustment, terminal disclaimers, and any applicable extension

The precise expiration date must be taken from the current USPTO Patent Center record and the FDA Orange Book listing because the grant date alone does not establish the operative expiration date.

What is the Orange Book status of US 9,561,197?

Ravicti is an FDA-approved prescription drug for chronic management of patients with urea cycle disorders who cannot be adequately managed by dietary protein restriction and supplementation with amino acids. The FDA-approved labeling identifies glycerol phenylbutyrate as the active ingredient and provides weight- or body-surface-area-based dosing instructions. (FDA, 2023.)

US 9,561,197 is relevant to Ravicti’s Orange Book patent position as a method-of-use patent. Orange Book relevance depends on whether the patent is listed against the approved drug and whether the approved labeling describes the patented method. A method patent can affect an ANDA through a Paragraph IV certification even when the generic applicant does not challenge the composition, manufacturing, or formulation claims.

The commercial effect is narrower than a composition patent. A generic applicant may attempt to avoid infringement by using a label that omits the patented ratio-guided dosing method, subject to FDA’s requirements for a lawful section viii carve-out and the remaining approved uses.

When does US 9,561,197 lose exclusivity?

The patent’s ordinary term is determined principally by the earliest effective nonprovisional or international filing date in its priority chain, not by the 2017 grant date. The patent therefore should not be analyzed as expiring 20 years after February 7, 2017.

For business planning, the patent should be treated as an early-2030s asset unless the USPTO record shows a different terminal date. The operative date may be affected by:

Patent-term adjustment;
A terminal disclaimer;
Continuation or divisional relationships;
The earliest effective priority filing;
Patent-term extension under 35 U.S.C. § 156; and
Any post-grant correction affecting the term.

FDA’s regulatory exclusivity for Ravicti is separate from patent exclusivity. Ravicti received new chemical entity exclusivity after its 2013 approval, but that period expired before the expected patent term. FDA exclusivity does not extend the life of US 9,561,197. (FDA, 2023; FDA, 2024.)

What formulations are protected by the patent?

The supplied claims do not require a particular formulation. They identify glyceryl tri-[4-phenylbutyrate] as the administered drug. The claims therefore may reach:

Ravicti oral liquid;
A generic oral liquid containing glycerol phenylbutyrate;
A reformulated liquid containing the same active ingredient; and
Potentially another dosage form, if it delivers the claimed active ingredient and the method limitations are satisfied.

The patent is not, based on the supplied claims alone, a formulation patent. It does not expressly require a particular excipient, concentration, container, flavoring system, dosing syringe, or release profile.

That distinction matters in ANDA litigation. A generic applicant could avoid a formulation patent by changing excipients or concentration, but those changes may not avoid a method patent if the product is still used according to a ratio-guided dosing protocol.

What generic entry risks exist for Ravicti?

Generic entry risk has at least four separate components.

Label risk

The highest risk arises if an ANDA label directs clinicians to measure PAA and PAGN and adjust dosing to a claimed ratio. A full label containing that instruction could support an induced-infringement theory against the generic manufacturer.

A narrow label that removes the PAA:PAGN ratio method could reduce risk. The manufacturer would still face exposure if the remaining label, promotional material, training, or patient-support services encourage the claimed method.

Prescriber and patient-use risk

Method patents can be difficult to enforce against individual medical practice. The commercial defendant is more likely to be the manufacturer, distributor, or sponsor accused of inducing or contributing to infringement.

The patent holder would need evidence connecting the generic label or commercial conduct to the claimed steps. Mere sale of glycerol phenylbutyrate is not necessarily enough.

Certification risk

If US 9,561,197 is listed in the Orange Book for Ravicti, an ANDA applicant may be required to submit a Paragraph IV certification asserting that the patent is invalid, unenforceable, or not infringed. A Paragraph IV notice can trigger patent litigation under the Hatch-Waxman framework and a potential 30-month stay of approval under applicable statutory conditions. (21 U.S.C. § 355; FDA, 2024.)

Carve-out risk

A section viii statement may be possible if the generic label omits the patented use. The viability of that strategy depends on whether the PAA:PAGN method is an approved use reflected in the reference-listed drug labeling and whether the remaining label still practices the patented method.

Which companies are relevant to the patent landscape?

The relevant commercial entities are:

Company	Role
Hyperion Therapeutics	Original developer and commercial sponsor associated with HPN-100
Horizon Pharma	Later commercial owner of Ravicti-related assets
Amgen	Acquired Horizon and became the broader corporate owner
Generic applicants	Potential ANDA sponsors subject to Orange Book certifications and label design
FDA	Regulator responsible for approval, labeling, Orange Book listings, and exclusivity data
USPTO	Authority for patent prosecution, term adjustment, and patent-status records

The patent landscape should distinguish ownership of the patent from ownership of the approved product. A company may acquire Ravicti marketing rights without owning every related patent, and a patent assignment may occur separately from an NDA transfer.

How strong is the patent estate?

US 9,561,197 is stronger as a method-of-use barrier than as a universal block on generic glycerol phenylbutyrate.

Risk category	Relative assessment	Reason
Broad active-ingredient protection	Limited	The claims supplied do not claim glycerol phenylbutyrate as a composition
Fixed-dose protection	Limited	The claims do not require a particular dose
Ratio-guided dosing	Stronger	The PAA:PAGN ratio is a specific clinical limitation
Formulation protection	Limited under supplied claims	No formulation limitation appears in the independent claims
Label-induced infringement	Material	A generic label directing ratio-based titration could create exposure
Noninfringing prescribing	Plausible	Prescribing without PAA:PAGN targeting may avoid one or more claim elements
Invalidity exposure	Depends on prior art	Biomarker-guided dosing claims may face anticipation, obviousness, enablement, and written-description challenges

Potential validity attacks would focus on prior disclosure of:

Phenylbutyrate metabolism to PAA and PAGN;
Monitoring PAA concentrations in urea cycle disorder patients;
Dose adjustment based on PAA exposure;
Target PAA or PAGN levels;
Pharmacokinetic relationships between PAA and PAGN; and
Clinical protocols using laboratory measurements to manage nitrogen scavenger therapy.

The numerical ranges may provide a material distinction from earlier art, but their strength depends on whether the prior art disclosed the same ratio, an overlapping range, or a routine optimization pathway.

What patent litigation affects Ravicti?

The principal litigation question is not whether a generic can manufacture glycerol phenylbutyrate. It is whether the generic can obtain approval and market the product without practicing the ratio-based dosing method or inducing others to practice it.

A complete litigation assessment requires the current docket, Orange Book listing, assignment record, and any Paragraph IV notice. Patent status should be verified across:

USPTO Patent Center;
FDA Orange Book;
PACER and district court docket records;
Federal Circuit opinions;
FDA labeling history; and
Patent assignment databases.

The relevant dispute theories would include infringement, claim construction, written description, enablement, anticipation, obviousness, prosecution history estoppel, and the availability of a label carve-out.

How does US 9,561,197 compare with other Ravicti protections?

Protection type	What it protects	Commercial effect
Active-ingredient patent	Glycerol phenylbutyrate or related chemical subject matter	Broadest generic barrier if unexpired and valid
Formulation patent	Liquid composition, excipients, concentration, or stability	Can block or complicate an ANDA formulation
Method-of-use patent	Ratio-guided treatment and dose adjustment	Depends heavily on labeling and actual clinical conduct
Manufacturing patent	Production, purification, or crystallization process	Can be avoided through a different process
FDA exclusivity	Regulatory approval period	Separate from patent term
Trademark	Ravicti brand identity	Does not independently prevent generic approval

US 9,561,197 should therefore be modeled as one layer of the Ravicti exclusivity stack, not as a complete substitute for composition, formulation, manufacturing, or other method patents.

Key Takeaways

US 9,561,197 covers treating urea cycle disorders by administering glycerol phenylbutyrate to bring the plasma PAA:PAGN ratio within 1 to 2 or 1 to 2.5.
The patent is a biomarker-guided dosing patent, not a broad composition patent based on the supplied claims.
The critical infringement issue is whether a label, prescriber, or manufacturer uses PAA:PAGN testing and ratio-based dose adjustment.
A generic Ravicti applicant may evaluate a Paragraph IV certification, a section viii label carve-out, or both.
FDA regulatory exclusivity and patent exclusivity are separate. Ravicti’s regulatory exclusivity does not determine the patent’s expiration date.
The patent’s ordinary term extends into the early 2030s based on the public patent chronology, subject to the operative USPTO term calculation.
Patent strength is highest against a generic label that expressly directs clinicians to target the claimed PAA:PAGN ranges.
The broader Ravicti patent estate must be analyzed separately for active ingredient, formulation, manufacturing, and additional method-of-use claims.

FAQs

Does US 9,561,197 cover sodium phenylbutyrate?

No. The supplied claims specifically require glyceryl tri-[4-phenylbutyrate], also known as glycerol phenylbutyrate or HPN-100. Sodium phenylbutyrate is a different active pharmaceutical ingredient.

Can a generic launch before the patent expires?

Possibly. A generic sponsor could pursue a Paragraph IV challenge, a section viii carve-out, or a label that does not direct the patented ratio-guided method. Launch risk depends on the Orange Book listing, litigation outcome, claim construction, and final approved labeling.

Is US 9,561,197 a formulation patent?

No, not based on the supplied independent claims. The claims do not require a particular excipient, concentration, container, or liquid formulation.

What clinical test is central to the patent?

The central measurement is the plasma ratio of phenylacetic acid, or PAA, to phenylacetylglutamine, or PAGN. The claimed method uses that ratio to guide glycerol phenylbutyrate dosing.

Does a physician infringe by prescribing Ravicti?

Only if the prescribed treatment satisfies all claim limitations, including the out-of-range PAA:PAGN condition, administration of glycerol phenylbutyrate, and dosing effective to bring the ratio within the claimed range. Manufacturer liability would more likely involve inducement or contributory infringement based on labeling and commercial conduct.

References

Food and Drug Administration. (2023). Ravicti (glycerol phenylbutyrate) oral liquid prescribing information. U.S. Department of Health and Human Services.
Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.
U.S. Patent No. 9,561,197. (2017). Methods for treating urea cycle disorders. United States Patent and Trademark Office.
United States Code, 21 U.S.C. § 355. (2024). New drugs.
United States Patent and Trademark Office. (2024). Patent Center: Patent term adjustment, assignment, and prosecution records. U.S. Department of Commerce.

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	9,561,197	⤷ Start Trial				DOSAGE ADJUSTMENT OF A NITROGEN SCAVENGING DRUG IN THE 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	2012377389	⤷ Start Trial
Australia	2018200163	⤷ Start Trial
Australia	2019201811	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,561,197

Which drugs does patent 9,561,197 protect, and when does it expire?

Summary for Patent: 9,561,197