US Patent 10,183,005: Claim Scope, Ravicti Exclusivity, Orange Book Status and Generic Entry Risk

US Patent 10,183,005 protects a specific clinical dosing and monitoring protocol for glyceryl tri[4-phenylbutyrate], also known as glycerol phenylbutyrate and marketed as Ravicti. The patent does not broadly claim the molecule, every use of Ravicti, or every method of treating a urea cycle disorder. Its coverage depends on a tightly defined sequence involving a stable, non-crisis UCD patient, a single fasting ammonia measurement, laboratory-specific normal ranges, dose escalation, adverse-event monitoring, and dose reduction.

The patent is relevant to generic Ravicti applicants because an ANDA label that instructs physicians to follow the claimed protocol could create induced-infringement exposure. A product-only generic launch would not inherently practice the method, but labeling, promotional material, prescribing instructions, or clinical support programs could determine risk.

What does US Patent 10,183,005 cover?

US Patent 10,183,005 covers a method of treating a subject with a urea cycle disorder using glyceryl tri[4-phenylbutyrate]. The patent was assigned to Hyperion Therapeutics, the original developer of Ravicti. Commercial rights later moved through Horizon Therapeutics, which Amgen acquired in 2023.[1,2]

Element	Required limitation in claim 1
Patient population	Subject has a urea cycle disorder
Baseline condition	Fasting plasma ammonia is below the upper limit of normal
Crisis status	Patient is not experiencing a hyperammonemic crisis
Drug	Orally administered glyceryl tri[4-phenylbutyrate]
Initial step	Initial dosage is administered
Stabilization	Drug reaches steady state before testing
Testing	One fasting plasma ammonia measurement
Excluded testing approach	No serial blood draws
Comparator	Ammonia is compared with the laboratory’s upper limit of normal
Escalation trigger	Ammonia greater than one-half of the upper limit of normal
Dose adjustment	Adjusted dose is greater than the initial dose when the trigger is met
Safety monitoring	Monitoring for headache, somnolence, nausea, and/or vomiting
Toxicity response	Reduced dose if one or more listed symptoms occur
Outcome limitation	0 to 0.5 ULN ammonia corresponds to a greater than 80% likelihood of average daily ammonia within normal range

The claim is a combination claim. Every material limitation must be present for literal infringement. A method that uses glyceryl tri[4-phenylbutyrate] but omits the fasting measurement, uses serial blood draws, treats a patient in crisis, or does not include the specified adverse-event dose reduction may fall outside the literal scope of claim 1.

How should claim 1 of US Patent 10,183,005 be construed?

Patient and disease limitations

The claim applies only to a subject with a UCD. UCDs include disorders affecting the urea cycle, such as ornithine transcarbamylase deficiency, carbamoyl phosphate synthetase I deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, arginase deficiency, and ornithine translocase deficiency.

The patient must have a fasting plasma ammonia level below the applicable upper limit of normal and must not be in a hyperammonemic crisis. This excludes acute rescue treatment during a crisis. The method is directed to maintenance treatment and outpatient or stable-care titration.

Single-measurement limitation

The protocol requires a single fasting plasma ammonia measurement after steady state. The express phrase "not serial blood draws" narrows the claim and creates a potential distinction from protocols requiring repeated or multiple ammonia measurements.

The claim does not require a particular analytical platform. The relevant reference point is the laboratory’s own upper limit of normal. Claim 7 narrows that limit to 35 micromoles per liter.

Dose-escalation limitation

When fasting ammonia exceeds 0.5 ULN, the adjusted glyceryl tri[4-phenylbutyrate] dosage must be greater than the initial dosage. This is a dose-escalation rule, not merely a general instruction to adjust treatment.

The claim does not expressly state the adjustment amount. A small increase could satisfy the "greater than" requirement if the other limitations are met. The claim also does not specify a particular milliliter-per-square-meter dose, patient weight, age group, or dosing frequency.

Adverse-event limitation

The method requires monitoring for headache, somnolence, nausea, and/or vomiting. If the subject experiences one or more of those symptoms, the protocol requires oral administration of a reduced dosage.

This limitation creates two separate infringement questions:

Whether the accused method actually monitors for at least one listed symptom.
Whether the dose is reduced when the symptom occurs.

A label that merely lists nausea or vomiting as a possible adverse event may not necessarily instruct the claimed monitoring-and-reduction sequence. The wording and clinical instructions would matter.

Probability limitation

The claim ends with the statement that a subject with fasting ammonia in the range of 0 to 0.5 ULN has a greater than 80% likelihood of having an average daily ammonia level within a normal range.

This limitation may be litigated as an inherent-result limitation or as a statement describing the clinical relationship underlying the protocol. Its practical effect depends on whether the limitation is interpreted as requiring the claimed statistical relationship to be present in the treated population, demonstrated in clinical evidence, or used as a treatment-selection criterion.

What do dependent claims 2 through 8 add?

Claims 2 through 8 narrow claim 1 rather than creating independent treatment methods.

Claim	Added limitation
2	Steady-state period is 48 hours
3	Steady-state period is 48 to 72 hours
4	Steady-state period is 72 hours to one week
5	Steady-state period is one week to two weeks
6	Steady-state period is greater than two weeks
7	Upper limit of normal is 35 micromoles per liter
8	Fasting period is overnight

Claims 2 through 6 collectively cover multiple timing windows. They overlap at the boundaries. For example, 48 hours falls within both claim 2 and claim 3, while 72 hours falls within claims 3 and 4 depending on how the endpoints are construed.

The timing claims create prosecution and litigation value because a competing protocol could avoid one timing claim while remaining exposed under another. Claim 7 is narrower because it fixes ULN at 35 micromoles per liter. Claim 8 is directed to a conventional overnight fasting procedure.

When does US Patent 10,183,005 expire?

The patent has a 2030 patent-term endpoint based on its underlying priority and filing history. Public patent records identify the relevant family as directed to methods of treating UCDs with glycerol phenylbutyrate.[3] The exact enforceable date should be determined from the USPTO patent record, including any patent-term adjustment and terminal-disclaimer information.

The practical exclusivity timeline is:

Event	Date or period
Ravicti FDA approval	February 1, 2013
Orphan-drug exclusivity	Initially seven years from approval, subject to statutory exceptions
Patent family endpoint	Approximately November 2030
US Patent 10,183,005 grant	January 22, 2019
Likely commercial relevance	Generic or label-driven method risk through the 2030 patent term

Ravicti’s orphan exclusivity is separate from patent protection. Orphan exclusivity does not prevent all generic activity after the exclusivity period ends, while an active patent can continue to restrict commercial activity if the product or proposed labeling practices the patented method.

What is the FDA regulatory status of Ravicti?

Ravicti is FDA-approved under NDA 203284 for chronic management of patients with UCDs who cannot be adequately managed by dietary protein restriction and amino-acid supplementation alone.[1]

The approved product is an oral liquid containing glycerol phenylbutyrate. The FDA label provides dosing and administration instructions, ammonia monitoring, conversion guidance from sodium phenylbutyrate, and safety information. Those instructions overlap technically with portions of the patented protocol, particularly oral administration, ammonia monitoring, dose adjustment, and adverse-event management.

Regulatory overlap does not automatically establish patent infringement. The FDA label must be compared limitation by limitation with the issued claims and with the actual conduct induced by the proposed generic labeling.

What patents protect Ravicti and glyceryl phenylbutyrate?

Ravicti’s patent estate has included several families addressing the active ingredient, pharmaceutical compositions, dosing, and treatment methods. The scope is broader than US Patent 10,183,005 because it includes product and formulation subject matter as well as clinical-use claims.

Patent category	Subject matter	Relevance to generic entry
Active-ingredient patents	Glyceryl phenylbutyrate and related chemical subject matter	May restrict manufacture or use of the active ingredient
Composition patents	Oral liquid formulations and pharmaceutical compositions	May affect formulation design and ANDA product selection
Method-of-use patents	Treatment of UCDs and ammonia control	May create label-based induced-infringement risk
Dosing patents	Patient selection, titration, monitoring, and steady-state protocols	May affect prescribing instructions and clinical support
Manufacturing patents	Synthesis, purification, and formulation processes	May restrict API or finished-dose supply chains
Regulatory listings	Patents listed in the FDA Orange Book for the approved product	Drive Paragraph IV certification and patent litigation risk

Public patent records associate the principal Ravicti development program with Hyperion Therapeutics. The relevant commercial successor is Amgen through its acquisition of Horizon Therapeutics.[2,3]

What is the Orange Book status of US Patent 10,183,005?

Orange Book status must be evaluated through the patent listing for the relevant Ravicti NDA, not solely through the patent document. A patent can be valid and enforceable without being listed in the Orange Book, and a listed patent can still be challenged for validity, enforceability, or scope.

For Ravicti, the Orange Book analysis should address:

Whether US Patent 10,183,005 is listed against NDA 203284.
Whether the listing is categorized as a drug-substance, drug-product, or method-of-use patent.
Whether the listed use code corresponds to the claimed stable-patient ammonia-monitoring method.
Whether the patent has been delisted, expired, or subject to a statutory correction.
Whether FDA records identify additional unexpired Ravicti patents.

The patent’s method-of-use character is significant. An ANDA applicant may certify that it will not market for the patented use, submit a Paragraph IV certification challenging validity or enforceability, or use a section viii statement to carve out the patented indication where the remaining label permits a noninfringing market.

Are there Paragraph IV challenges to Ravicti patents?

The supplied claim text does not establish a Paragraph IV filing, a named generic challenger, or a settlement agreement. A definitive challenge analysis requires the FDA Orange Book, FDA patent-certification records, and federal district court dockets.

The principal Paragraph IV risk would arise if an applicant:

Certifies that the listed patent is invalid, unenforceable, or will not be infringed;
Submits a notice letter to the NDA holder and patent owner;
Triggers a patent suit within the statutory period; and
Seeks approval after the applicable litigation stay.

A section viii carve-out would be commercially important because it could permit approval for non-patented UCD uses while avoiding express instructions for the patented protocol. The strength of that strategy would depend on whether ordinary prescribing behavior still induces the claimed method.

How strong is the patent estate for Ravicti?

US Patent 10,183,005 has strong formal claim specificity but narrower practical coverage than a composition or product-by-process patent.

Strengths

It targets a clinically defined population.
It captures dose escalation based on a quantitative ammonia threshold.
It expressly covers laboratory-specific ULN values.
It includes symptom monitoring and dose reduction.
The FDA label may provide evidence that physicians are instructed to monitor ammonia and adjust treatment.
The patent reaches treatment conduct, even if the generic product itself is chemically identical.

Weaknesses

Every limitation must be proven.
The "single fasting measurement" and "not serial blood draws" language creates an avoidance path.
The crisis exclusion removes acute-care use from the claim.
The claim does not broadly cover all glyceryl tri[4-phenylbutyrate treatment.
The probability statement may present claim-construction and proof issues.
A generic applicant may attempt a label carve-out or omit the specific monitoring sequence.

The patent is strongest against a label that reproduces the full titration algorithm. It is weaker against a generic label that provides the drug for UCD treatment but omits the patented single-draw, half-ULN escalation, and symptom-triggered reduction instructions.

What generic launch scenarios exist for glyceryl phenylbutyrate?

Scenario 1: Paragraph III certification

The applicant accepts the listed patent and delays approval until expiration. For the relevant family, that would place the commercial launch window near the 2030 patent endpoint.

Scenario 2: Paragraph IV challenge

The applicant challenges validity, enforceability, or infringement. Litigation could delay approval through the statutory stay and could produce an earlier launch through settlement, judgment, or license.

Scenario 3: Section viii carve-out

The applicant removes the patented method from its labeling. This strategy is more credible if the non-patented uses are commercially meaningful and the remaining label does not direct physicians toward the claimed protocol.

Scenario 4: Noninfringing clinical protocol

A manufacturer could design instructions using serial ammonia measurements, a different timing scheme, a non-overnight fasting protocol, or a different threshold. Avoiding one dependent claim would not avoid claim 1 unless the entire independent claim is avoided.

Scenario 5: Formulation or supply-chain challenge

A generic may use a formulation or manufacturing route outside a separate formulation or process patent. This avoids one patent category but does not resolve method-of-use exposure.

Does Ravicti face biosimilar competition?

No. Ravicti is a small-molecule drug, not a biologic. The relevant pathway is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a biosimilar application under the Biologics Price Competition and Innovation Act.

The competitive threat is therefore generic glyceryl phenylbutyrate, formulation competition, or alternative nitrogen-scavenging therapy. Sodium phenylbutyrate products are clinically related but are not automatically substitutable for Ravicti because they differ in formulation, dosing burden, tolerability, and administration requirements.

How does US Patent 10,183,005 compare with formulation patents?

A formulation patent generally focuses on the composition, excipients, concentration, stability, impurity profile, or delivery format. It can present a direct product infringement risk because the generic drug may use the claimed formulation.

US Patent 10,183,005 is different:

Issue	US Patent 10,183,005	Formulation patent
Primary target	Treatment conduct	Drug product
Infringement evidence	Label, prescribing, clinical use	Product composition and manufacturing records
Avoidance strategy	Carve out or redesign treatment instructions	Use a different formulation
FDA relevance	Method-of-use listing and label language	Product patent listing
Main commercial risk	Induced infringement	Direct infringement

The patent should therefore be analyzed alongside Ravicti composition and formulation patents, not as a substitute for them.

What licensing and litigation issues affect the patent?

The underlying commercial rights were developed by Hyperion and later held by Horizon Therapeutics, now part of Amgen.[2] The claim text alone does not establish a license to a generic manufacturer, a patent settlement, or an active district-court dispute involving US Patent 10,183,005.

A transaction review should distinguish:

Patent ownership;
NDA sponsorship;
Commercialization rights;
Manufacturing licenses;
Patent settlements;
Authorized-generic arrangements; and
Covenants not to sue.

A license covering the molecule would not necessarily authorize the patented dosing method. Conversely, a method-of-use license would not necessarily resolve formulation or manufacturing patents.

What geographic coverage does US Patent 10,183,005 provide?

The patent provides US protection only. Parallel protection may exist in foreign family members, but foreign claim scope, prosecution history, term, and validity must be assessed separately.

The principal geographic risks are:

United States: Orange Book and ANDA-driven litigation;
Europe: national validation and separate national enforcement;
Japan and Canada: separate patent and regulatory systems;
Emerging markets: manufacturing, export, and local-registration issues.

A US patent does not block manufacture entirely outside the United States. It can, however, restrict importing, offering for sale, selling, or using the patented method in the United States, subject to statutory defenses and claim-specific facts.

Key Takeaways

US Patent 10,183,005 is a narrow method-of-treatment patent for stable UCD patients receiving glyceryl tri[4-phenylbutyrate.
Claim 1 requires a single fasting ammonia test after steady state and excludes serial blood draws.
The key escalation threshold is greater than 0.5 times the laboratory’s ULN.
The claim also requires monitoring for specified symptoms and dose reduction if they occur.
Claims 2 through 6 cover different steady-state periods from 48 hours through more than two weeks.
Claim 7 specifies a 35 micromole-per-liter ULN; claim 8 requires overnight fasting.
Ravicti was FDA-approved in 2013 under NDA 203284 for chronic UCD management.
The relevant patent family has a commercial endpoint near November 2030, subject to the USPTO-calculated term.
Generic risk is label-driven and depends on whether an ANDA label instructs the full patented protocol.
Ravicti is a small molecule, so biosimilar competition is not the applicable pathway.
The claim text alone does not establish a Paragraph IV challenger, settlement, license, or active litigation outcome.

FAQs About US Patent 10,183,005 and Ravicti

Can a generic glyceryl phenylbutyrate product launch before 2030?

It could seek approval through a Paragraph IV challenge or a section viii carve-out. Commercial launch would depend on patent litigation, claim scope, FDA approval, and any settlement or injunction.

Does using Ravicti for a UCD automatically infringe US Patent 10,183,005?

No. The accused method would need to satisfy the limitations of claim 1 or a dependent claim. The patient status, fasting measurement, steady-state timing, threshold, symptom monitoring, and dose reduction requirements all matter.

Is the 35 micromole-per-liter threshold required in every case?

No. It is required only by claim 7. Claim 1 uses the upper limit of normal established by the laboratory, without fixing that value at 35 micromoles per liter.

Does the patent cover treatment during a hyperammonemic crisis?

No. Claim 1 expressly requires that the subject not be experiencing a hyperammonemic crisis.

What is the main design-around opportunity for a generic applicant?

The most direct opportunities are to avoid directing a single fasting measurement, use serial testing, omit the specific greater-than-0.5-ULN escalation rule, or avoid instructions requiring dose reduction after the listed symptoms. The entire claim must be assessed, not only one limitation.

References

U.S. Food and Drug Administration. (2013). Ravicti (glycerol phenylbutyrate) prescribing information. NDA 203284.
Amgen Inc. (2023). Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934. U.S. Securities and Exchange Commission.
United States Patent and Trademark Office. (2019). U.S. Patent No. 10,183,005, Methods of treating urea cycle disorders. Patent Center and Patent Full-Text and Image Database.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
United States Code. (2024). 35 U.S.C. §§ 154, 271(e), and 282. Cornell Law School Legal Information Institute.

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
China	104039358	⤷ Start Trial
China	107271696	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 10,183,005