United States Drug Patent 5,500,413: Claim Scope, Validity, Expiration, and Desmopressin Patent Landscape

US Patent 5,500,413 covers a specific manufacturing route for 1-deamino-8-D-arginine vasopressin, commonly called desmopressin or DDAVP. Its core limitation is the protected-peptide assembly of the nonapeptide followed by iodine oxidation in a protic solvent, preferably under acidic conditions. The patent does not broadly claim desmopressin as a molecule, and it does not create a current market-exclusivity barrier because the patent expired in 2013 under the pre-Uruguay Round patent-term regime. The principal residual relevance is historical process technology and prior art against later process patents.

What does US Patent 5,500,413 cover?

US 5,500,413 covers:

A process for synthesizing desmopressin.
Specific protected peptide intermediates used in that process.
Acidic iodine oxidation of the assembled nonapeptide.
Purification by cation-exchange chromatography.
Product-by-process and therapeutic-use claims directed to desmopressin made by the claimed method.

The patent is directed to the manufacture of 1-deamino-8-D-arginine vasopressin, not to the general discovery or composition of matter of desmopressin. The claimed molecule is a synthetic vasopressin analog containing:

A deaminated N-terminal residue, identified as Mpa.
D-arginine at position 8.
A glycinamide C-terminus.
An intramolecular disulfide bridge between the Mpa and cysteine residues.

The patent’s principal commercial subject is desmopressin, usually marketed as desmopressin acetate in tablets, orally disintegrating tablets, nasal products, and injectable products.[1]

What is the independent process claim in US 5,500,413?

Claim 1 requires four sequential operations:

Claim step	Required operation	Technical significance
1(a)	Preparation of Mpa(R1)-Tyr-Phe-Gln-Asn-Cys(R2)-Pro-OH	Provides a protected heptapeptide
1(b)	Condensation with (R3)-D-Arg(HCl)-Gly-NH2	Adds the D-arginine-glycinamide dipeptide
1(c)	Formation of the protected nonapeptide	Produces the linear desmopressin precursor
1(d)	Oxidation with iodine in a protic solvent	Forms the disulfide-containing desmopressin product

A process must satisfy the combination of these limitations to fall within the literal scope of claim 1. The claim is therefore narrower than a general claim to any process for making desmopressin.

The process is characterized by convergent peptide synthesis. The heptapeptide and dipeptide are prepared separately and then coupled. This approach differs from a purely stepwise assembly of the full nonapeptide and can reduce the number of sequential operations on the entire chain.

How do claims 2 through 11 narrow the synthesis process?

Claims 2 through 11 add specific chemical or purification limitations.

Claims 2 and 3: sulfhydryl-protecting groups

Claim 2 lists permissible protecting groups for R1 and R2:

Acetamidomethyl
tert-Butyl
tert-Butylsulfenyl
p-Methylbenzyl
p-Methoxybenzyl
2-(3-nitropyridine sulfenyl)
Ethylcarbamoyl
Triphenylmethyl
9-Fluorenylmethyl

Claim 3 narrows the process to the use of acetamidomethyl protection at both sulfur atoms. This is a material narrowing because a process using a different protecting-group pair would not literally satisfy claim 3, although it could still fall within claim 1.

Acetamidomethyl protection is particularly relevant because it stabilizes the thiol groups during peptide coupling and permits later conversion into the disulfide bridge during oxidation.

Claim 4: N-tert-butyloxy protection

Claim 4 specifies that R3 is N-tert-butyloxy, generally understood as a tert-butyloxycarbonyl-type amino-protecting group. The claim requires the D-arginine component to carry this acid-sensitive protection during the coupling sequence.

A process using a different acid-sensitive amino-protecting group could avoid claim 4 but would remain potentially relevant to claim 1 if the other limitations were met.

Claims 5 through 8: heptapeptide preparation

Claim 5 covers preparation of the protected heptapeptide by coupling:

Mpa(R1)-Tyr-Phe-X; and
R3-Gln-Asn-Cys(R2)-Pro-OH.

X replaces the carboxyl hydroxyl group of the Phe residue and acts as a reactive acylating moiety.

Claim 6 identifies three categories of X:

Alkoxy
Aryloxy
Azido

Claim 7 specifies succinimidoxy as the alkoxy example. Claim 8 specifies p-nitrophenyloxy as the aryloxy example.

These claims protect an activated-fragment coupling strategy. They do not broadly cover every method for preparing the heptapeptide. A process using a conventional carboxyl activation reagent, a different coupling reagent, or a different fragment boundary could fall outside claims 5 through 8.

Claims 9 and 10: acidic iodine oxidation

Claim 9 requires iodine oxidation at pH below 5.0. Claim 10 narrows this range to pH 1.5 to 4.3.

The pH limitation is a central process feature. It distinguishes the claimed oxidation from neutral or alkaline iodine oxidation and is likely directed to controlling side reactions, oxidation selectivity, and product quality during disulfide formation.

A process that uses a different oxidant, such as air, ferricyanide, peroxide, or another iodine system outside the stated conditions, would not literally satisfy the full combination of claim 1 and claims 9 or 10. It could still raise equivalence questions in a live patent, but that issue is no longer commercially significant because the patent has expired.

Claim 11: cation-exchange purification

Claim 11 requires purification of the oxidized product by ion-exchange chromatography on a cation-exchange resin equilibrated with an acid.

This is a downstream purification limitation. It does not apply to every process under claim 1. A process using reversed-phase chromatography, anion exchange, crystallization, precipitation, or another purification sequence would not literally satisfy claim 11.

What is the scope of claims 12 through 15?

Claims 12 through 15 extend beyond manufacturing.

Claim	Subject matter	Scope assessment
12	Treatment method using desmopressin prepared under claim 1	Method-of-treatment claim tied to the manufacturing process
13	Compound prepared according to claim 1 and having the stated structure	Product-by-process claim
14	Therapeutic comprising the compound of claim 13	Product or therapeutic composition claim
15	Treatment method using the compound of claim 13	Use claim dependent on the product-by-process definition

The claims use the term “diurea.” That wording appears in the supplied claim text. Desmopressin is ordinarily used for central diabetes insipidus, nocturnal enuresis, nocturia associated with nocturnal polyuria, and certain bleeding disorders, including hemophilia A and von Willebrand disease.[2] “Diurea” is not the conventional indication terminology for desmopressin and may reflect a drafting or transcription error.

How strong is the product-by-process claim?

Claim 13 is not a conventional broad composition-of-matter claim. It identifies the compound by reference to the process used to make it and also requires the depicted chemical structure.

Under US patent law, a product-by-process claim is assessed as a product claim for patentability, but the process language can function as a limitation for infringement analysis. The Federal Circuit has treated process limitations in product-by-process claims as relevant to infringement, even where the resulting product may be chemically identical to a product made by another process.[3]

That distinction matters less today because the patent is expired. During the patent term, claim 13 could have created litigation risk for a manufacturer producing structurally identical desmopressin, depending on proof that the accused product was made by the claimed process or its equivalent.

When did US Patent 5,500,413 expire?

US 5,500,413 issued on March 19, 1996.[1] The patent was subject to the former 17-year term measured from grant because it was filed before the June 8, 1995 transition date created by the Uruguay Round Agreements Act.

On that basis, the ordinary expiration date was March 19, 2013. No current enforceable patent right remains under US 5,500,413.

Event	Date
Patent issued	March 19, 1996
Ordinary term	17 years from issue
Expected expiration	March 19, 2013
Current enforcement status	Expired

Patent expiration eliminates infringement liability for activities occurring after expiration. It does not eliminate the patent’s value as prior art or as evidence of technical disclosure.

What is the Orange Book status of US 5,500,413?

US 5,500,413 is a process patent and is not, by itself, a conventional Orange Book product patent for desmopressin.

The FDA Orange Book identifies patents submitted by NDA holders for approved drug products, including patents claiming the drug substance, drug product, or approved method of use.[4] A manufacturing-process patent generally does not qualify for Orange Book listing unless it falls within the statutory categories for a patent that claims the approved drug or an approved method of using it.

The patent’s process claims therefore should not be treated as an Orange Book barrier to generic desmopressin. A generic applicant would ordinarily address any currently listed drug-substance, drug-product, or method-of-use patents associated with the relevant desmopressin product, not an expired process patent from 1996.

When did desmopressin lose US market exclusivity?

Desmopressin’s regulatory exclusivity and patent exclusivity arose from several different rights:

FDA regulatory exclusivity for the original products.
Drug-substance or formulation patents.
Method-of-use patents.
Device or delivery-system patents.
Manufacturing-process patents such as US 5,500,413.

These rights must be analyzed separately. Expiration of US 5,500,413 did not itself determine the end of all desmopressin exclusivity. The relevant product, dosage form, NDA, and listed patents must be reviewed separately in the Orange Book and FDA product records.[4,5]

Desmopressin is now available in generic forms in multiple dosage presentations. Generic competition is established for at least some tablet and injectable presentations, while nasal formulations and delivery systems have historically involved distinct regulatory and patent considerations.

Were there Paragraph IV challenges involving US 5,500,413?

A current Paragraph IV challenge to US 5,500,413 would have no practical purpose because the patent expired in 2013. Paragraph IV certifications are used against unexpired patents listed for an approved drug product. An expired patent cannot support a current patent-based delay of FDA approval or a 30-month stay.

The patent could have been relevant to an ANDA filed while it was unexpired if it had been properly listed and if the applicant’s product or manufacturing process implicated the claims. The supplied claim set does not establish that US 5,500,413 was listed in the Orange Book for a particular desmopressin NDA.

Which companies challenged or licensed the patent?

The patent document itself does not establish a licensing agreement, settlement, or Paragraph IV litigation history. The patent was associated with the protected synthesis of desmopressin, a product historically commercialized by Ferring and its predecessors or affiliates. Commercial supply arrangements, API licenses, and generic settlements must be distinguished from ownership of US 5,500,413.

Because the patent expired before current generic desmopressin competition became the principal commercial issue, the patent is unlikely to be a live settlement asset. Any historical agreement would require review of court dockets, SEC filings, assignment records, or transaction documents.

What generic entry risks exist for desmopressin?

The expired patent does not create a current generic-entry risk. A generic manufacturer can use a different process without concern under US 5,500,413, and it can also use the claimed process without infringement liability after expiration.

Current risk areas are more likely to involve:

Formulation patents

Relevant issues can include:

Tablet excipient systems.
Orally disintegrating tablet compositions.
Nasal spray formulations.
Preservative systems.
Stability-enhancing formulations.
Low-dose delivery systems.

Method-of-use patents

Potential method claims may address:

Nocturnal enuresis.
Nocturia.
Central diabetes insipidus.
Hemostatic use in hemophilia A.
Von Willebrand disease.
Dosing schedules and patient-selection criteria.

Device and delivery patents

Nasal products can raise distinct issues involving:

Metered-dose pump mechanisms.
Dose uniformity.
Spray geometry.
Container-closure systems.
Intranasal absorption technologies.

Regulatory requirements

Generic applicants must establish pharmaceutical equivalence and bioequivalence for the relevant dosage form. Nasal products can involve more complex comparative requirements than conventional immediate-release tablets because local delivery, spray performance, and device characteristics may affect approval.[5]

How strong is the patent estate for desmopressin?

US 5,500,413 has no current blocking strength because it is expired. Its historical strength was moderate and focused.

Attribute	Assessment
Molecule coverage	Weak; no broad standalone composition claim
Core synthesis coverage	Moderate; specific protected-fragment route
Protecting-group coverage	Narrow to listed groups and dependent combinations
Oxidation coverage	Narrow but technically specific
Purification coverage	Narrow
Method-of-use coverage	Limited by the “prepared according to” language
Current enforceability	None after expiration
Prior-art value	Material for later desmopressin process patents

The patent’s main vulnerability was design-around potential. A competitor could seek to avoid infringement by changing the peptide coupling sequence, protecting groups, activated ester, oxidation chemistry, pH, or purification method. The patent did not prevent manufacture of desmopressin by independent chemistry.

How does US 5,500,413 compare with a broad desmopressin composition patent?

A composition-of-matter patent covering desmopressin itself would generally have been commercially stronger than US 5,500,413 because it could cover the molecule regardless of manufacturing route. US 5,500,413 instead requires a defined sequence of synthetic operations.

Patent type	Typical scope	Relevance of US 5,500,413
Composition patent	Desmopressin molecule or salt	Not supplied by this patent
Formulation patent	Tablet, nasal, injectable, or delivery composition	Not covered directly
Method-of-use patent	Treatment of a specified condition	Claims 12, 14, and 15 are narrower
Process patent	Manufacturing route	Core subject of US 5,500,413
Purification patent	Isolation or purification procedure	Claim 11 provides limited coverage

What geographic coverage did the patent provide?

US 5,500,413 provided rights only in the United States. Corresponding foreign applications or patents could have created separate rights in Europe, Japan, Canada, or other jurisdictions, but a US patent does not extend outside the United States.

Foreign family members would require separate analysis of:

National-phase filing dates.
Local claim amendments.
Patent-term calculations.
Supplementary protection certificates.
Opposition or revocation proceedings.
Local enforcement and settlement records.

The US expiration date cannot be used as the expiration date for a foreign counterpart.

What manufacturing and intellectual-property barriers remain?

US 5,500,413 no longer presents a US manufacturing barrier. Current barriers are more likely to be technical and regulatory:

Maintaining peptide purity and stereochemical integrity.
Controlling disulfide formation and aggregation.
Removing closely related peptide impurities.
Achieving consistent low-dose uniformity.
Demonstrating stability in the selected dosage form.
Meeting nasal-device performance specifications.
Establishing bioequivalence for nonstandard delivery systems.
Protecting supply of peptide intermediates and specialized manufacturing capacity.

The patent’s disclosure may also reduce freedom-to-operate risk for later applicants because it is prior art against claims directed to substantially similar protected-fragment assembly and iodine-mediated cyclization.

Key Takeaways

US 5,500,413 is principally a desmopressin manufacturing-process patent.
Claim 1 requires protected heptapeptide preparation, coupling with protected D-Arg-Gly-NH2, nonapeptide formation, and iodine oxidation in a protic solvent.
Dependent claims narrow the scope through specific sulfur protections, N-tert-butyloxy protection, activated peptide intermediates, acidic pH, and cation-exchange purification.
Claims 13 through 15 use product-by-process language and do not operate as a broad standalone composition patent.
The patent issued March 19, 1996, and expired approximately March 19, 2013.
It is not a current US patent barrier to generic desmopressin manufacture.
Paragraph IV risk under this patent is obsolete because the patent is expired.
Current desmopressin freedom-to-operate analysis should focus on active formulation, method-of-use, device, and delivery patents associated with the relevant NDA and dosage form.
The patent remains relevant as prior art against later desmopressin process claims.
The claim text’s reference to treatment of “diurea” is atypical for desmopressin and should be read against the patent specification and prosecution history.

FAQs About US Patent 5,500,413 and Desmopressin

Does US 5,500,413 claim desmopressin itself?

No. The patent’s principal independent claim is a synthesis method. The product-by-process claims identify desmopressin made according to that method but do not resemble a broad composition-of-matter claim.

Can a company manufacture desmopressin using the patented process today?

Yes, in the United States, because the patent expired in 2013. Other active patents, regulatory requirements, or foreign rights may still be relevant to a particular product or territory.

Does the patent cover desmopressin acetate formulations?

No. The supplied claims do not recite tablets, nasal sprays, injectables, excipients, acetate salt formulations, containers, or delivery devices.

Is US 5,500,413 relevant to biosimilar approval?

No. Desmopressin is a chemically synthesized peptide drug, not a biologic ordinarily regulated through the biosimilar pathway under section 351(k) of the Public Health Service Act. Generic-drug pathways are generally more relevant.

What is the most important design-around feature in the patent?

The most important design-around opportunities are the convergent protected-fragment assembly, the specified protecting groups, and iodine oxidation under acidic conditions. Altering those process elements could avoid literal infringement even while producing the same desmopressin molecule.

References

United States Patent and Trademark Office. (1996). U.S. Patent No. 5,500,413: Process for the preparation of 1-deamino-8-D-arginine vasopressin.
U.S. Food and Drug Administration. (2020). DDAVP (desmopressin acetate) prescribing information.
United States Patent and Trademark Office. (2023). Manual of Patent Examining Procedure § 2113: Product-by-process claims.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs database.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	204296	⤷ Start Trial
Canada	2166297	⤷ Start Trial
China	1040648	⤷ Start Trial
China	1125952	⤷ Start Trial
Germany	69427985	⤷ Start Trial
Denmark	0710247	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,500,413

Summary for Patent: 5,500,413