Details for Patent: 4,284,647

Summary for Patent: 4,284,647

Title:	Process for waste nitrogen removal
Abstract:	A process for controlling waste nitrogen accumulation diseases in humans which comprises administering an effective amount of at least one compound selected from the group consisting of benzoic acid, phenylacetic acid and the non-toxic, pharmaceutically-acceptable salts of the acids to a human suffering from waste nitrogen accumulation.
Inventor(s):	Saul W. Brusilow, Mark L. Batshaw, Norman S. Radin
Assignee:	Johns Hopkins University
Application Number:	US06/135,685
Patent Claim Types: see list of patent claims	Compound; Process;

United States Drug Patent 4,284,647: Claim Scope, Expiration, and Current Patent Landscape

US Patent 4,284,647 covers a method of treating human waste-nitrogen accumulation, particularly hyperammonemia associated with urea-cycle disorders, by administering benzoic acid, phenylacetic acid, or pharmaceutically acceptable salts. The patent issued on August 18, 1981, to The Johns Hopkins University and expired in 1998 under the pre-1995 17-year patent term measured from issuance.[1,2]

The patent is historically important because it claims the nitrogen-scavenging mechanism later used in sodium phenylacetate, sodium phenylbutyrate, and glycerol phenylbutyrate products. It is no longer an enforceable barrier to generic or branded products. Current commercial protection rests on later patents covering formulations, prodrugs, dosing systems, manufacturing, and product-specific technologies.

What does US Patent 4,284,647 cover?

US 4,284,647 claims a therapeutic process rather than a drug composition. The core method requires:

1. A human patient with a disease involving impaired urea synthesis or impaired nitrogen excretion.
2. Administration of benzoic acid, phenylacetic acid, or a non-toxic pharmaceutically acceptable salt.
3. An amount sufficient to react with waste nitrogen.
4. Formation of an amino-acid acylation product.
5. Urinary elimination of that product as nitrogen.

The principal biological pathways are:

Administered compound	Nitrogen-scavenging product	Primary nitrogen-excretion pathway
Benzoic acid or benzoate	Hippuric acid, also called benzoylglycine	Glycine conjugation followed by urinary excretion
Phenylacetic acid or phenylacetate	Phenylacetylglutamine	Glutamine conjugation followed by urinary excretion
Phenylbutyrate	Converted metabolically to phenylacetate	Indirectly produces phenylacetylglutamine

The patent does not claim phenylbutyric acid, sodium phenylbutyrate, or glycerol phenylbutyrate by name. Those products operate through the same phenylacetate nitrogen-scavenging pathway but are not literal compounds in the asserted claims.

When did US Patent 4,284,647 expire?

US 4,284,647 expired in 1998. The patent was filed before the change to the modern 20-year patent term, so its term was generally 17 years from issuance under the law then applicable.[1,2]

Patent item	Information
Patent	US 4,284,647
Title	Treatment of hyperammonemia
Assignee	The Johns Hopkins University
Inventors	Saul W. Brusilow and Mark L. Batshaw
Filing date	November 30, 1979
Issue date	August 18, 1981
Original statutory term	17 years from issuance
Expiration	1998
Current enforceability	Expired
Current Orange Book relevance	None

No patent term extension or pediatric extension can revive the expired patent. Patent term adjustment was not available in its modern form for this patent, and an expired patent cannot be asserted in an infringement action.

What are the scope and limitations of claim 1?

Claim 1 is the broadest independent claim. It covers administration of either:

• benzoic acid;
• phenylacetic acid; or
• a non-toxic, pharmaceutically acceptable salt of either acid.

The claim is broad in disease coverage but narrower in chemical coverage than a modern product patent.

Disease scope

The claim applies to humans suffering from waste-nitrogen accumulation caused by:

• impaired normal synthesis of urea;
• impaired excretion of nitrogen;
• urea-cycle enzymopathies;
• uremia;
• hepatic disorders; and
• Reye's syndrome.

The functional opening language could reach diseases beyond named urea-cycle disorders if the patient has the claimed nitrogen-accumulation mechanism. The dependent claims, however, identify specific disease categories and would not expand the literal chemical scope beyond benzoate and phenylacetate.

Amount and mechanism

The phrase "effective amount" is tied to a functional requirement: the dose must be sufficient to react with waste nitrogen and produce an amino-acid acylation product suitable for urinary excretion.

This requirement has two implications:

• Mere administration of benzoic acid or phenylacetic acid is not enough.
• The treatment must be directed to nitrogen removal through the claimed conjugation mechanism.

The claim does not specify a fixed dose, route, dosage form, treatment duration, patient age, or concentration. Those omissions made the claim clinically broad but potentially dependent on the specification for interpretation and enablement.

Human treatment limitation

The claim expressly requires treatment of "a human." It does not cover veterinary use on its face. It also requires an existing waste-nitrogen accumulation disease or condition, rather than prophylactic administration to a healthy person.

How do claims 2 through 9 narrow the patent?

Claim	Limitation	Commercial significance
1	Benzoic acid, phenylacetic acid, or salts administered to a human with nitrogen-accumulation disease	Core treatment claim
2	Mixture of benzoic acid and phenylacetic acid, or salts	Covers combination scavenger therapy
3	Administration continues until accumulated nitrogen is discharged in urine	Adds treatment-duration language
4	Patient has a urea-cycle enzymopathy	Directly targets inherited urea-cycle disorders
5	Patient suffers from uremia	Covers renal nitrogen-retention disease
6	Patient suffers from a hepatic disorder	Covers liver-associated hyperammonemia
7	Patient suffers from Reye's syndrome	Covers a named acute metabolic condition
8	Expressly identifies hippuric acid and phenylacetylglutamine as products	Clarifies the biochemical mechanism
9	Salt is a sodium salt	Narrows the salt form to sodium benzoate or sodium phenylacetate

Claim 8 is important for prosecution and construction analysis because it identifies the expected metabolites. It confirms that the invention is based on alternative nitrogen disposal through glycine and glutamine conjugation.

Claim 9 is narrower than claim 1 and would cover sodium benzoate and sodium phenylacetate, subject to the other limitations of claim 1.

Does the patent cover Buphenyl or Ravicti?

It does not literally claim either product by active pharmaceutical ingredient.

Buphenyl

Buphenyl contains sodium phenylbutyrate. Sodium phenylbutyrate is converted in the body to phenylacetate, which conjugates with glutamine to form phenylacetylglutamine.[3]

The product therefore uses the biological pathway described in US 4,284,647, but the claim language does not recite phenylbutyrate. A literal infringement theory would require the administered compound to be phenylacetic acid, benzoic acid, or a salt of one of those acids.

Because US 4,284,647 expired in 1998, the distinction has no current enforcement consequence.

Ravicti

Ravicti contains glycerol phenylbutyrate, a liquid prodrug that is metabolized to phenylacetate.[4] The product was designed to provide nitrogen scavenging with different dosing and administration characteristics from sodium phenylbutyrate.

Glycerol phenylbutyrate is not a claimed compound in US 4,284,647. Later Ravicti patent protection focused on the prodrug, liquid formulation, pharmaceutical composition, dosing, and related product characteristics rather than relying on the expired Johns Hopkins method claim.

What FDA products relate to the patent?

The patent's mechanism is reflected in FDA-approved therapies for urea-cycle disorders and related hyperammonemia.

Product	Active ingredient	FDA status	Relationship to US 4,284,647
Buphenyl	Sodium phenylbutyrate	FDA-approved for chronic management of urea-cycle disorders	Uses downstream phenylacetate pathway
Ravicti	Glycerol phenylbutyrate	FDA-approved for chronic management of urea-cycle disorders	Prodrug converted to phenylacetate
Sodium phenylacetate injection products	Sodium phenylacetate, often with sodium benzoate	Used for acute hyperammonemia under FDA-approved or emergency treatment frameworks	Closest commercial implementation of claimed compounds
Sodium benzoate products	Sodium benzoate	Use depends on product and regulatory status	Directly corresponds to claim 9's sodium-salt concept

FDA labeling for Buphenyl and Ravicti describes the conversion of phenylbutyrate to phenylacetate and the subsequent formation of phenylacetylglutamine, which is eliminated in urine.[3,4]

What is the Orange Book status of US 4,284,647?

US 4,284,647 is not a current Orange Book-listed patent. The Orange Book lists patents associated with approved drug products, and an expired 1981 method patent is not a continuing product-specific barrier.[5]

The relevant distinction is:

• US 4,284,647: historical method patent, expired.
• Buphenyl: later product and regulatory rights, with generic competition possible under applicable FDA pathways.
• Ravicti: later product-specific patents and orphan exclusivity, some of which created a separate commercial protection period.

A patent need not be listed in the Orange Book to have been historically significant. But the absence of a current listing means it does not trigger a present-day paragraph IV certification or block an ANDA.

When did Buphenyl and Ravicti lose exclusivity?

Buphenyl

Buphenyl received FDA approval in the 1990s for chronic treatment of urea-cycle disorders. Its market position was not protected by the 1981 patent after 1998. Generic sodium phenylbutyrate products can compete based on their own FDA approvals, subject to any active product-specific patents and regulatory exclusivities.

Ravicti

Ravicti was approved by FDA in 2013.[4] Its orphan-drug exclusivity period provided seven years of protection for the approved indication, generally extending through early 2020. Orphan exclusivity is separate from patent rights and does not prevent approval of a competing product for a different indication.

Protection type	Buphenyl	Ravicti
US 4,284,647 method patent	Expired before modern commercial period	Expired
Small-molecule drug	Sodium phenylbutyrate	Glycerol phenylbutyrate
Orphan-drug exclusivity	Historical approval-era rights	Approximately 2013-2020
Patent value today	Limited to historical significance	Later product patents may remain relevant
Biosimilar pathway	Not applicable	Not applicable
Generic pathway	ANDA or applicable abbreviated pathway	ANDA subject to listed patents and exclusivity

Are there biosimilar risks for these products?

No. Buphenyl and Ravicti are small-molecule products, not biologics. Biosimilar approval under the Public Health Service Act is not the relevant pathway.

Competitive products would generally arise through:

• ANDA approval for a therapeutically equivalent small-molecule product;
• 505(b)(2) approval for a product with a different formulation, route, or clinical bridge; or
• a full NDA for a substantially differentiated therapy.

The main competitive risk is therefore generic or follow-on small-molecule entry, not biosimilar substitution.

Which patents now matter more than US 4,284,647?

The current patent landscape is concentrated in later patent families covering:

Prodrug and active-ingredient design

Glycerol phenylbutyrate differs from the claimed benzoate and phenylacetate salts. Patents covering the prodrug can address:

• the glycerol ester structure;
• hydrolysis to phenylbutyrate and phenylacetate;
• pharmacokinetic control;
• reduced dosing frequency; and
• improved palatability or tolerability.

Liquid formulations

Ravicti's commercial differentiation depends heavily on its oral liquid formulation. Formulation patents may cover:

• concentration;
• excipient selection;
• stability;
• dosing by body weight;
• administration through feeding tubes; and
• organoleptic properties.

Method-of-use patents

Later patents may claim:

• use in specific patient populations;
• treatment of particular urea-cycle defects;
• dosing schedules;
• switching from sodium phenylbutyrate to glycerol phenylbutyrate;
• treatment of patients with swallowing or feeding limitations; and
• use in acute or chronic hyperammonemia settings.

Manufacturing and formulation processes

Manufacturing patents may protect:

• esterification and purification;
• control of residual impurities;
• pharmaceutical-grade synthesis;
• conversion to oral liquid dosage forms; and
• packaging and stability systems.

These rights are commercially more relevant than US 4,284,647 because they can remain enforceable after the foundational mechanism patent has expired.

How strong is the patent estate represented by US 4,284,647?

The patent was strong as an early platform patent but weak as a current commercial asset.

Factor	Assessment
Mechanism coverage	Broad
Named compounds	Limited to benzoic acid, phenylacetic acid, and salts
Product coverage	Does not expressly claim phenylbutyrate or glycerol phenylbutyrate
Patient coverage	Broad human disease language
Dosage restrictions	Minimal
Formulation coverage	None of significance in the claims provided
Manufacturing coverage	None in the claims provided
Current enforceability	None
Historical blocking potential	High for direct benzoate/phenylacetate treatment before expiration
Current blocking potential	None

The claim set would have been most relevant to direct administration of sodium phenylacetate or sodium benzoate. It was less directly tailored to modern oral phenylbutyrate products.

Which companies are challenging the patent?

No current paragraph IV challenge can target US 4,284,647 because the patent expired decades ago. Paragraph IV litigation applies to unexpired patents listed for an FDA-approved drug, not to an expired foundational patent.

The competitive field instead includes:

• manufacturers of generic sodium phenylbutyrate;
• suppliers of sodium phenylacetate and sodium benzoate products;
• manufacturers developing 505(b)(2) nitrogen-scavenger formulations; and
• branded sponsors commercializing glycerol phenylbutyrate or other nitrogen-scavenging therapies.

Any current litigation would concern later patents associated with a particular approved product, not the expired 1981 patent.

What licensing deals are associated with the patent?

The patent was assigned to The Johns Hopkins University, and commercialization of the underlying nitrogen-scavenging technology involved university-originated intellectual property and subsequent product development. The patent itself does not establish the terms of any historical license, royalty arrangement, field restriction, or sublicense.

Expiration eliminates patent-based exclusivity, but it does not automatically eliminate contractual obligations under a historical license. A license may contain surviving royalty, know-how, confidentiality, or milestone provisions. Those contractual issues are separate from the public patent right and cannot create a new patent exclusion period.

What generic launch risks exist?

For direct sodium phenylacetate or sodium benzoate products, US 4,284,647 creates no launch risk. The patent is expired, and the claims cannot support an injunction or damages claim.

For sodium phenylbutyrate and glycerol phenylbutyrate products, launch risk depends on later rights:

Product strategy	Main risk
Generic sodium phenylbutyrate tablet	Bioequivalence, labeling, inactive ingredients, and any active Orange Book patents
Generic sodium phenylbutyrate powder	Powder formulation, dosing device, and bioequivalence
Follow-on glycerol phenylbutyrate liquid	Product-specific formulation and method-of-use patents
Sodium phenylacetate injection	FDA pathway, formulation, supply, and manufacturing controls
New nitrogen scavenger	Clinical differentiation, regulatory exclusivity, and new composition patents

The major commercial barrier for a generic Ravicti-type product is likely to be formulation and product-specific patent coverage rather than the expired foundational method patent.

What geographic coverage does the patent have?

US 4,284,647 has territorial effect only in the United States. Any foreign counterparts would have required separate national or regional rights and would have expired under their own applicable terms.

A freedom-to-operate analysis outside the United States must separately examine:

• European Patent Office records;
• national patents in major markets;
• patent-term adjustments or supplementary protection certificates;
• local regulatory exclusivities; and
• later formulation and prodrug families.

The expiration of the US patent does not establish freedom to operate in Europe, Japan, China, Canada, or other jurisdictions.

Key Takeaways

• US 4,284,647 claims treatment of human nitrogen-accumulation disease with benzoic acid, phenylacetic acid, or their pharmaceutically acceptable salts.
• Claims 8 and 9 specifically identify hippuric acid, phenylacetylglutamine, and sodium salts.
• The patent issued August 18, 1981, and expired in 1998.
• It does not literally claim sodium phenylbutyrate or glycerol phenylbutyrate.
• The patent has no current Orange Book or paragraph IV significance.
• Buphenyl and Ravicti rely on later product, formulation, dosing, and regulatory rights.
• Biosimilar competition is irrelevant because these are small-molecule drugs.
• Current generic risk depends on later listed patents, FDA exclusivities, formulation barriers, and manufacturing know-how.
• The patent remains important as prior art and as the foundational disclosure for nitrogen-scavenging therapy, but it has no present blocking power.

FAQs About US Patent 4,284,647

Does US 4,284,647 cover sodium benzoate?

Yes. Claim 9 expressly narrows the claimed salt to a sodium salt, which includes sodium benzoate and sodium phenylacetate when the other claim limitations are satisfied. The patent expired in 1998.

Does US 4,284,647 cover phenylacetylglutamine?

No. The patent claims the treatment process that produces phenylacetylglutamine. It does not claim phenylacetylglutamine itself as a composition.

Can an expired patent still block FDA approval?

No. An expired patent cannot support a current patent-based injunction or a paragraph IV challenge. FDA approval may still require compliance with labeling, exclusivity, and other active patent requirements.

Is glycerol phenylbutyrate an infringing compound under claim 1?

No literal infringement follows from the claim language provided because glycerol phenylbutyrate is not benzoic acid, phenylacetic acid, or a salt of either acid. In any event, the patent is expired.

What is the main commercial legacy of this patent?

Its main legacy is the disclosed nitrogen-scavenging treatment concept: conjugating benzoate with glycine and phenylacetate with glutamine to convert waste nitrogen into urinary-excretable products. Later products commercialized related chemistry through phenylbutyrate prodrugs and differentiated formulations.

References

1. U.S. Patent No. 4,284,647. (1981). Treatment of hyperammonemia. The Johns Hopkins University.
2. 35 U.S.C. § 154. Patent term provisions applicable to patents issued from pre-1995 applications.
3. U.S. Food and Drug Administration. (n.d.). Buphenyl (sodium phenylbutyrate) prescribing information.
4. U.S. Food and Drug Administration. (n.d.). Ravicti (glycerol phenylbutyrate) prescribing information.
5. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.

Drugs Protected by US Patent 4,284,647

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 4,284,647

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	1175750