United States Drug Patent 4,462,983: Scope, Claims, Expiration, and Ergot Alkaloid Patent Landscape

US Patent No. 4,462,983 covered nasal administration of selected ergot peptide alkaloids, including dihydroergotamine, bromocriptine, and dihydroergotoxine. The patent was granted on July 31, 1984, from an application claiming priority to October 1, 1981. Its enforceable term ended in 2002. The patent therefore creates no current barrier to generic nasal dihydroergotamine development, although later patents may protect specific formulations, devices, or delivery systems.

The patent’s commercial importance came from its method claims covering systemic delivery through the nasal mucosa. The claims were not limited to migraine treatment, a particular disease, or a specific branded product.

What does US Patent 4,462,983 cover?

US 4,462,983 covers a method of systemically administering a therapeutically effective amount of a defined ergot peptide alkaloid by locally administering the active agent to the nasal mucous membranes.

The patent’s central elements are:

Element	Scope
Active ingredient	Selected ergot peptide alkaloids within the claimed formula, including dihydroergotamine, bromocriptine, dihydroergotoxine, and dihydroergocristine
Administration route	Local administration to the nasal mucous membranes
Therapeutic objective	Systemic administration
Dosage form	Spray, including powder or liquid spray
Device	Atomizer, including one using a propellant
Propellant	Halogenated hydrocarbon under claim 7
Dose	0.1 to 5 mg per administration under claim 8
Solution concentration	0.1 to 5 mg/mL under claim 11
Salt form	Pharmaceutically acceptable acid addition salts under claim 12

The patent is a route-of-administration patent with formulation and device limitations added through dependent claims. It does not claim the underlying ergot alkaloid molecules as such.

What is the legal scope of independent claim 1?

Claim 1 is the broadest claim and controls the principal patent scope. It requires four core conditions:

A pharmaceutically effective amount of a qualifying ergot peptide alkaloid.
Systemic administration.
Local administration to nasal mucous membranes.
Use of an active agent falling within the specified structural formula or the expressly identified compounds.

The claim includes multiple structural alternatives. It covers compounds in which the substituents R1 through R6 fall within specified combinations and separately identifies dihydroergocristine. Claim 1 also covers pharmaceutically acceptable acid addition salts.

The claim is broader than a claim limited to dihydroergotamine nasal spray. It can reach a nasal product using any listed compound, whether delivered as a powder, liquid, aerosol, or another nasal dosage form, provided the product produces systemic administration.

The phrase "systemically administering" is important. A product intended only for local nasal action would not satisfy that limitation. Conversely, a product that deposits the drug on nasal tissue and produces systemic exposure can fall within the claim even if the formulation is designed to improve local absorption.

The claim also lacks a disease limitation. It is not restricted to migraine, cluster headache, Parkinson’s disease, hyperprolactinemia, or another named indication.

Which compounds are expressly covered by US 4,462,983?

Dihydroergotamine

Claim 2 narrows claim 1 to dihydroergotamine, commonly administered as dihydroergotamine mesylate. This is the commercially significant branch of the patent because Migranal was approved as a nasal spray containing dihydroergotamine mesylate.

Bromocriptine

Claim 3 covers bromocriptine. Bromocriptine is an ergot-derived dopamine agonist used in several endocrine and neurologic indications. The claim does not require the product to use the later-developed oral or vaginal dosage forms associated with bromocriptine.

Dihydroergotoxine

Claim 4 covers dihydroergotoxine. The claim is directed to nasal systemic administration of that active agent and is separate from the dihydroergotamine limitation in claim 2.

Dihydroergocristine

Dihydroergocristine is expressly included in claim 1. The patent therefore does not depend exclusively on the Markush structural definition for coverage of that compound.

How do claims 5 through 12 narrow the patent scope?

Claims 5 through 12 add delivery, dose, concentration, and salt limitations.

Claim	Limitation
5	Administration in the form of a spray
6	Spray produced by an atomizer containing a propellant
7	Propellant is a halogenated hydrocarbon
8	0.1 to 5 mg per administration
9	Powder spray
10	Liquid spray
11	Solution contains 0.1 to 5 mg/mL active agent
12	Active agent is a pharmaceutically acceptable acid addition salt

Claims 9 and 10 are alternative dosage-form claims. A powder product may infringe claim 9 without infringing claim 10. A liquid product may infringe claim 10 without using a propellant and therefore may avoid claims 6 and 7.

Claim 11 concerns concentration, not necessarily delivered dose. A product containing 1 mg/mL could fall within claim 11 even if the device delivers less than 1 mg per actuation. Claim 8 addresses the amount administered per administration.

Claim 7 has limited modern relevance because many current nasal delivery systems do not use halogenated hydrocarbon propellants. The broader spray claim in claim 5 is commercially more important.

What products were historically associated with the patent?

The patent is closely associated with nasal dihydroergotamine products, particularly Migranal.

Product or substance	Relevance to US 4,462,983
Dihydroergotamine mesylate	Primary commercial compound associated with the patent
Migranal nasal spray	FDA-approved nasal dihydroergotamine product historically linked to the patent
Bromocriptine	Expressly covered by claim 3, but not the principal commercial application of the patent
Dihydroergotoxine	Expressly covered by claim 4
Dihydroergocristine	Included in claim 1
Trudhesa	Later dihydroergotamine nasal product using a different delivery platform; later patents may apply

The FDA approved Migranal as a nasal spray for the acute treatment of migraine attacks, with or without aura. FDA labeling described dihydroergotamine mesylate delivered intranasally through spray administration.[2]

FDA approval does not establish patent validity or infringement. Regulatory approval and patent rights are separate systems.

When did US Patent 4,462,983 expire?

US 4,462,983 is expired.

Event	Date
Earliest claimed priority	October 1, 1981
US filing	1982
Patent grant	July 31, 1984
Statutory term	Expired in 2002
Current enforceability	None

The patent was filed before the 1995 change to a term based primarily on 20 years from the earliest effective US filing date. For pre-1995 applications, the applicable term generally used the longer of 17 years from grant or 20 years from filing. Public patent records report the term as ending in 2002.[1]

No current patent exclusivity can be asserted from US 4,462,983 alone.

What was the Orange Book status of US 4,462,983?

US 4,462,983 was historically relevant to the FDA-approved Migranal nasal spray. The patent’s significance was its method coverage of nasal systemic administration of dihydroergotamine rather than protection of the dihydroergotamine molecule.

The Orange Book distinguishes between:

patents claiming the active ingredient;
patents claiming a drug product or formulation; and
patents claiming an approved method of use.

A method patent may be listed when it claims an approved use of the drug. A listed patent can trigger a Paragraph IV certification in an abbreviated new drug application, but listing does not prevent an applicant from challenging validity, enforceability, or relevance.

Because US 4,462,983 expired in 2002, it does not create a current Paragraph IV obstacle. Current applicants must evaluate the Orange Book for the specific reference-listed product and any later-listed formulation or device patents.[3]

Were there Paragraph IV challenges to this patent?

A present Paragraph IV challenge to US 4,462,983 would have no commercial value because the patent is expired.

Historically, an ANDA applicant seeking approval for a generic nasal dihydroergotamine product could have addressed the patent through:

a Paragraph III certification, agreeing to wait until expiration;
a Paragraph IV certification, asserting that the patent was invalid, unenforceable, or not infringed; or
a statement that the patent did not claim the proposed product or approved use.

The patent’s expiration removed the principal timing benefit of a Paragraph IV challenge. A modern generic applicant instead faces the remaining regulatory requirements and any unexpired patents covering a particular formulation, delivery device, or manufacturing process.

What formulation and device patents may affect later nasal dihydroergotamine products?

The expired patent should be separated from later product-specific estates.

Conventional nasal sprays

A conventional liquid nasal spray containing dihydroergotamine mesylate may be evaluated against claim 5 and claim 10 of US 4,462,983, but those claims are no longer enforceable. The commercial barriers now arise from:

formulation stability;
preservative systems;
dose uniformity;
spray-plume performance;
container-closure systems;
nasal deposition;
manufacturing controls; and
any later unexpired patents.

Propellant systems

Claims 6 and 7 address atomizers using propellants, including halogenated hydrocarbons. Modern nasal products often use mechanical metered pumps rather than chlorofluorocarbon-based systems. A mechanical pump would not satisfy the propellant limitation in claim 6, although it could have fallen within the broader spray language of claim 5 during the patent term.

Powder sprays

Claim 9 covers powder sprays. Powder formulations can raise separate patent issues involving particle size, carrier materials, dispersibility, moisture control, and device geometry. Those technical features are not required by claim 9 itself but can be protected by later patents.

Liquid formulations

Claim 10 covers liquid sprays. Claim 11 further requires a solution containing 0.1 to 5 mg/mL of active agent. The claim does not require a particular pH, buffer, preservative, viscosity, or surfactant system.

How does Trudhesa compare with the technology covered by US 4,462,983?

Trudhesa is a later dihydroergotamine mesylate nasal product developed by Impel Pharmaceuticals using its Precision Olfactory Delivery system. It was approved by FDA in 2021 for the acute treatment of migraine with or without aura in adults.[4]

Issue	US 4,462,983	Trudhesa
Active agent	Includes dihydroergotamine	Dihydroergotamine mesylate
Route	Nasal mucosal administration	Nasal administration
Core technical concept	Systemic absorption through nasal mucosa	Device-assisted delivery intended to improve deposition and absorption
Patent status	Expired	Later device, formulation, and method patents may remain relevant
Disease limitation	None	Approved for acute migraine treatment
Commercial risk	No current blocking right	Later patents and regulatory exclusivity must be reviewed separately

Trudhesa may satisfy the expired claim language of US 4,462,983, but that does not create present infringement. Its commercial protection depends on later patents, regulatory exclusivity, trade secrets, device manufacturing, and the ability to reproduce the delivery system.

What is the generic launch risk for nasal dihydroergotamine?

The expired patent materially reduces the patent risk for a conventional generic nasal dihydroergotamine product. The principal remaining risks are regulatory and technical.

Risk category	Assessment
US 4,462,983	No current blocking risk
Dihydroergotamine molecule	Historical compound protection expired
Conventional nasal spray	Potentially accessible, subject to current Orange Book review
Proprietary delivery device	Higher risk if the product copies a protected device platform
Formulation	Patent risk depends on later composition and stability claims
ANDA approval	Requires pharmaceutical equivalence, bioequivalence or an accepted alternative, quality data, and labeling conformity
Device combination product	May require device compatibility and performance evidence
Biosimilar pathway	Not applicable

For a conventional liquid nasal spray, the most defensible design-around strategy would avoid copying a later proprietary device, use an independently developed formulation, and establish dose uniformity and nasal deposition through the applicable FDA pathway.

Is there biosimilar risk for dihydroergotamine?

No. Dihydroergotamine is a small-molecule ergot alkaloid, not a biologic. A competitor would generally pursue an ANDA or, depending on the product and formulation, another drug application pathway. The FDA’s biosimilar framework under the Public Health Service Act does not apply to conventional dihydroergotamine products.[5]

The relevant competitive category is generic drug entry, not biosimilar substitution.

How strong is the patent estate for US 4,462,983?

The historical patent was commercially broad but is legally exhausted.

Strength factor	Assessment
Chemical coverage	Moderate; limited to specified ergot alkaloids and structural alternatives
Route coverage	Broad during term; covers nasal mucosal administration for systemic delivery
Disease limitation	None, increasing historical breadth
Dosage-form coverage	Broad spray coverage with powder, liquid, and propellant-specific branches
Formulation specificity	Limited; few excipient or device details
Current enforceability	None
Design-around potential during term	Available through non-nasal routes, non-systemic local delivery, or non-covered active agents
Current commercial value	Historical only

The patent’s strongest feature was the combination of a broad route claim with no disease limitation. Its principal weakness was the absence of detailed protection for modern device architecture, excipient systems, particle engineering, or manufacturing controls.

Key Takeaways

US 4,462,983 covers systemic nasal administration of selected ergot peptide alkaloids.
Dihydroergotamine, bromocriptine, dihydroergotoxine, and dihydroergocristine are expressly covered.
The patent includes spray, powder, liquid, propellant, dose, concentration, and salt limitations.
The patent was granted on July 31, 1984, and expired in 2002.
It provides no current blocking right against generic nasal dihydroergotamine.
The patent is historically associated with Migranal nasal spray.
Trudhesa uses a later delivery platform and must be evaluated against later device and formulation patents.
No biosimilar pathway applies; competitive entry proceeds through generic-drug mechanisms.
Current risk is concentrated in later Orange Book-listed patents, proprietary devices, formulation patents, manufacturing know-how, and FDA requirements.

Frequently Asked Questions

Does US 4,462,983 claim dihydroergotamine itself?

No. It claims a method of administering dihydroergotamine through the nasal mucosa. It does not claim the chemical compound as a composition of matter.

Does the patent cover migraine treatment only?

No. The claims do not limit the method to migraine. They cover systemic nasal administration of the listed ergot alkaloids regardless of the particular therapeutic indication.

Would a nasal dihydroergotamine powder have fallen within the patent?

Yes, claim 9 expressly covers a powder spray, provided the other claim 1 requirements were satisfied. The claim is now expired.

Is a mechanical nasal pump covered by claim 6?

Not necessarily. Claim 6 requires an atomizer containing a propellant. A mechanical pump without a propellant would not satisfy that limitation, although it could have raised issues under the broader spray claim 5 during the patent term.

Can a company launch a generic nasal dihydroergotamine product based only on this patent’s expiration?

No. Expiration of US 4,462,983 removes one historical patent barrier, but launch still depends on current Orange Book listings, later patents, FDA approval requirements, formulation equivalence, device compatibility, and manufacturing capability.

Sources

United States Patent and Trademark Office. (1984). Nasal administration of ergot alkaloids, U.S. Patent No. 4,462,983.
U.S. Food and Drug Administration. (1997). Migranal (dihydroergotamine mesylate) nasal spray prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
U.S. Food and Drug Administration. (2021). Trudhesa (dihydroergotamine mesylate) nasal spray approval and prescribing information.
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	14575/76	Nov 19, 1976
Switzerland	6989/77	Jun 07, 1977

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	368881	⤷ Start Trial
Austria	A825477	⤷ Start Trial
Australia	3078377	⤷ Start Trial
Australia	520754	⤷ Start Trial
Belgium	860938	⤷ Start Trial
Canada	1103585	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,462,983

Summary for Patent: 4,462,983