United States Patent 4,526,892: Cabergoline Claims, Scope, Expiration, and Patent Landscape

U.S. Patent 4,526,892 covers a class of substituted ergoline ureas, including cabergoline, its pharmaceutically acceptable acid-addition salts, and pharmaceutical compositions for oral or parenteral administration. Claim 4 specifically covers cabergoline. The patent issued on July 2, 1985, and its ordinary pre-Uruguay Round patent term expired on July 2, 2002. It therefore presents no current U.S. patent barrier to generic cabergoline manufacture or sale.

Cabergoline is the principal commercial compound within the claimed group. In the United States, it was approved as Dostinex tablets under NDA 020664 for disorders associated with hyperprolactinemia. The relevant FDA regulatory exclusivity periods ended many years ago, and cabergoline is now subject to generic competition.[1][2]

What drug does U.S. Patent 4,526,892 protect?

The patent protects substituted ergoline-8β-carbonyl ureas. The commercial compound most directly associated with the patent is cabergoline, chemically identified as:

1-[(6-allylergolin-8β-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea.

The compound corresponds to claim 4:

1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'β-carbonyl)-urea.

Cabergoline is an ergot-derived dopamine D2 receptor agonist. The FDA-approved product is an oral tablet. Its principal U.S. indication is the treatment of hyperprolactinemic disorders, including conditions associated with pituitary prolactin secretion.[1]

The patent does not use the modern generic name “cabergoline” in the claim language supplied. Instead, it defines the compound by structural substituents and stereochemical nomenclature.

What is the scope of claim 1 of U.S. Patent 4,526,892?

Claim 1 is a genus claim. It covers a defined group of ergoline urea compounds with the following mandatory structural requirements:

Claim element	Permitted substituents
R1	Hydrogen or methyl
R2	Hydrogen only
R3	Hydrogen or methoxy
R4	Methyl, allyl, or propyl
R5	C1-C3 alkyl or 3-dimethylaminopropyl
R6	C1-C3 alkyl or 3-dimethylaminopropyl
R5/R6 proviso	At least one must be 3-dimethylaminopropyl
Salt form	Pharmaceutically acceptable organic or inorganic acid-addition salts

The claim therefore covers both the free-base compounds and their pharmaceutically acceptable acid-addition salts. Examples of possible salts include hydrochloride, hydrobromide, sulfate, phosphate, fumarate, maleate, citrate, and related acid-addition salts, provided the resulting salt is pharmaceutically acceptable.

How broad is the Markush structure?

On a simple substituent-count basis, claim 1 permits:

2 alternatives for R1;
1 alternative for R2;
2 alternatives for R3;
3 alternatives for R4; and
7 permitted ordered combinations for R5 and R6 after applying the requirement that at least one substituent be 3-dimethylaminopropyl.

That produces up to 84 nominal combinations before considering chemical identity, stereochemical equivalence, salt forms, and any overlap between structures. The practical scope is narrower than the mathematical count because the claim depends on the fixed ergoline core and the specific attachment geometry shown in the patent formula.

The R5/R6 proviso is commercially important. A compound bearing only two simple alkyl groups at those positions would fall outside claim 1. At least one position must contain the 3-dimethylaminopropyl substituent.

Which compounds are expressly listed in claim 2?

Claim 2 identifies four specific compounds within the claim 1 genus:

Claim 2 compound	Key structural feature
1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-methylergoline-8'β-carbonyl)-urea	6-methyl ergoline
1-ethyl-3-(3'-dimethylaminopropyl)-3-(10'α-methoxy-6'-methylergoline-8'β-carbonyl)-urea	10α-methoxy and 6-methyl substitution
1-(3'-dimethylaminopropyl)-3-ethyl-3-(6'-allylergoline-8'β-carbonyl)-urea	6-allyl ergoline
1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-n-propylergoline-8'β-carbonyl)-urea	6-n-propyl ergoline

The third compound is cabergoline, although its claim wording places the ethyl and dimethylaminopropyl groups in the reverse order relative to other nomenclature conventions. The structural identity is determined by the complete molecular formula and attachment positions, not by the order in which the two urea substituents are written.

Claim 2 is narrower than claim 1 but provides an express fallback position for the listed species. If the genus claim were challenged, the individually recited compounds would remain separately protected during the patent term, subject to validity and enforceability requirements.

What does claim 4 protect?

Claim 4 is the most commercially significant claim because it directly recites cabergoline.

Unlike claim 1, claim 4 does not depend on a broad set of alternatives. It is directed to one defined compound: the 6-allyl, 3-dimethylaminopropyl, N-ethyl ergoline urea.

A product containing cabergoline in the claimed molecular form would have been within claim 4 during the patent term. The claim would also have been relevant to cabergoline acid-addition salts through claim 1 and to formulations through claim 3, although the exact dependency and claim-construction relationship would be assessed from the issued patent’s complete claim set and prosecution history.

Claim 4 does not expressly claim:

A method of treating hyperprolactinemia;
A method of treating Parkinson’s disease;
A specific dose or dosing schedule;
A particular tablet strength;
A sustained-release formulation;
A polymorph;
A process for synthesizing cabergoline;
A specific excipient system;
A specific dissolution profile; or
A specific manufacturing step.

Those omissions limit the patent’s scope outside the claimed compound itself.

What pharmaceutical compositions are protected by claim 3?

Claim 3 covers a pharmaceutical composition containing a therapeutically effective amount of a claim 1 compound mixed with a pharmaceutically acceptable carrier for oral or parenteral administration.

The composition claim is broad in dosage-form terms. It can encompass tablets, capsules, solutions, suspensions, injectable preparations, and other oral or parenteral products, provided the composition contains a qualifying claim 1 compound and a pharmaceutically acceptable carrier.

The claim does not require:

A specific excipient;
A specific concentration;
A specific tablet weight;
A particular release profile;
A particular pharmacokinetic profile;
A particular indication; or
A particular manufacturing process.

For cabergoline, an oral tablet containing cabergoline and ordinary pharmaceutical excipients would have fallen within the literal scope of claim 3 during the patent term. The claim would not, however, extend indefinitely to every formulation containing cabergoline after the underlying patent expired.

When did U.S. Patent 4,526,892 expire?

U.S. Patent 4,526,892 issued on July 2, 1985.[3] Because it was prosecuted under the pre-Uruguay Round patent-term regime, its ordinary term was 17 years from issuance. The resulting expiration date was July 2, 2002.

Event	Date
U.S. patent grant	July 2, 1985
Ordinary 17-year term	July 2, 2002
Current status	Expired
Current enforceability against generic cabergoline	None

Foreign priority dates do not extend the U.S. term of a pre-URAA patent. Patent-term adjustment under the modern 35 U.S.C. § 154 regime generally does not apply in the manner applicable to later-filed patents.

The expired patent may remain visible in historical patent databases and in records associated with the original NDA. Its listing does not create a current exclusionary right.

What was the FDA status of cabergoline?

The FDA approved Dostinex, cabergoline tablets, under NDA 020664 on December 23, 1996.[1] The approved product was associated with Pharmacia & Upjohn Company and was indicated for the treatment of hyperprolactinemic disorders.

The FDA label identifies cabergoline as a dopamine receptor agonist and describes oral tablet strengths, dosing, contraindications, warnings, and adverse reactions.[1]

The approval date is separate from the patent expiration date. FDA approval did not extend the 17-year term of U.S. Patent 4,526,892. Any regulatory exclusivity attached to the original approval also expired long before the present date.

What is the Orange Book status of U.S. Patent 4,526,892?

Cabergoline was listed in the FDA Orange Book in connection with the original approved product and its patent information.[2] The relevant patent is now expired.

An expired Orange Book patent has no current blocking effect on an ANDA applicant. A generic applicant no longer needs to wait for the patent term to expire because that event has already occurred. The applicant may still need to address any other currently listed patents, regulatory exclusivity, labeling requirements, bioequivalence requirements, and applicable product-specific FDA standards.

The historical Orange Book listing should therefore be separated into two issues:

Historical patent linkage: the patent was associated with the approved cabergoline product.
Current legal effect: U.S. Patent 4,526,892 no longer prevents approval or launch of a cabergoline generic.

Were there Paragraph IV challenges to this patent?

A Paragraph IV certification is relevant when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. Because U.S. Patent 4,526,892 expired in 2002, present-day applicants would not need to rely on a Paragraph IV certification directed to that patent.

A historical Paragraph IV filing could have occurred before expiration, but the supplied record does not establish a specific applicant, filing date, district court action, settlement, or judgment. The patent’s expiration independently eliminates the current commercial significance of any earlier Paragraph IV dispute.

No active litigation based solely on U.S. Patent 4,526,892 can block present U.S. cabergoline entry after expiration.

Are biosimilar issues relevant to cabergoline?

No. Cabergoline is a chemically synthesized small molecule, not a biological product. Biosimilar and interchangeable-biologic pathways under the Public Health Service Act do not apply.

The relevant competitive pathway is the abbreviated new drug application, or ANDA, under section 505(j) of the Federal Food, Drug, and Cosmetic Act. Generic applicants generally must demonstrate pharmaceutical equivalence and bioequivalence to the reference listed drug rather than establish biosimilarity.

What generic-entry risks remain after patent expiration?

The principal patent-based risk from U.S. Patent 4,526,892 is eliminated. Remaining risks are operational and regulatory rather than attributable to this patent.

Regulatory risks

Generic applicants must address:

Bioequivalence to the reference product;
Product-specific FDA requirements;
Manufacturing compliance;
Labeling conformity;
Drug supply and quality controls; and
Any separately listed, unexpired patent or exclusivity right.

Manufacturing risks

The patent claims the compound, salts, and broad compositions. It does not, based on the supplied claims, claim a specific synthetic route. The patent therefore does not create a current process barrier against an independently developed cabergoline manufacturing process.

A manufacturer could still face practical barriers involving:

Control of ergoline impurities;
Stereochemical purity;
Residual solvents;
Crystallization and salt selection;
Batch consistency;
Stability;
Containment and occupational handling; and
FDA inspection findings.

Those are technical and regulatory barriers, not surviving exclusivity rights under this patent.

Formulation risks

Claim 3 is broad enough to have covered ordinary oral cabergoline tablets during the patent term. It does not create a current formulation monopoly. A later formulation patent would need to claim a distinct and still-valid technical feature, such as a particular release system, excipient combination, solid form, or manufacturing process.

How does cabergoline compare with competing dopamine agonists?

Product	Active ingredient	General regulatory category	Patent relationship to U.S. 4,526,892
Dostinex	Cabergoline	Small-molecule dopamine agonist	Directly covered by claim 4
Parlodel	Bromocriptine	Ergot-derived dopamine agonist	Separate active ingredient and patent estate
Requip	Ropinirole	Non-ergot dopamine agonist	No direct chemical overlap
Mirapex	Pramipexole	Non-ergot dopamine agonist	No direct chemical overlap
Norprolac	Quinagolide	Dopamine agonist	Separate chemical and regulatory estate

Cabergoline’s patent position was unusually direct because claim 4 recited the marketed active ingredient itself. After expiration, that advantage disappeared. Competitive positioning now depends primarily on clinical use, dosing convenience, supply reliability, reimbursement, physician preference, and generic pricing.

How strong was the patent estate for cabergoline?

During its term, the estate was strong against direct cabergoline copies because:

Claim 4 specifically covered cabergoline;
Claim 2 separately identified the same commercial compound;
Claim 1 provided a broader genus claim;
Claim 1 covered pharmaceutically acceptable acid-addition salts; and
Claim 3 covered pharmaceutical compositions for oral or parenteral administration.

The estate was weaker against noninfringing alternatives because it did not claim:

Other dopamine agonist molecules;
Treatment methods;
A mandatory dose;
A particular indication;
A proprietary delivery technology; or
A specific production process.

Today, the estate has no blocking strength because the patent has expired.

What licensing and settlement issues affect the patent?

The patent was associated with the development and commercialization of cabergoline, but the claim record alone does not establish the terms of any license, assignment, royalty agreement, Paragraph IV settlement, or supply arrangement.

Patent ownership, NDA sponsorship, product commercialization, and generic settlement rights are separate legal matters. A historical assignment or license would not revive an expired patent or create a post-expiration exclusion right.

The expiration of U.S. Patent 4,526,892 also means that any commercial agreement tied solely to the patent’s exclusionary term cannot prevent lawful generic entry after July 2, 2002.

Key Takeaways

U.S. Patent 4,526,892 covers substituted ergoline urea compounds, salts, and oral or parenteral pharmaceutical compositions.
Claim 4 specifically covers cabergoline.
Claim 1 is a Markush genus claim requiring at least one 3-dimethylaminopropyl substituent.
Claim 2 separately lists four compounds, including cabergoline.
Claim 3 covers broad pharmaceutical compositions containing a claim 1 compound.
The patent issued on July 2, 1985, and expired on July 2, 2002.
The patent creates no current U.S. barrier to generic cabergoline entry.
Cabergoline is a small molecule, so biosimilar law does not apply.
Current generic risks arise from FDA requirements, manufacturing quality, supply, and any separate unexpired patents, not from U.S. Patent 4,526,892.
The patent did not claim a specific method of treatment, dosage regimen, formulation technology, polymorph, or manufacturing process.

FAQs

What is the active ingredient covered by claim 4 of U.S. Patent 4,526,892?

Claim 4 covers cabergoline, an ergoline-derived dopamine D2 receptor agonist marketed in the United States as Dostinex.

Can a generic manufacturer still infringe U.S. Patent 4,526,892?

No. The patent expired on July 2, 2002. Expired patent claims cannot support a current infringement action against a generic cabergoline manufacturer.

Does claim 3 cover cabergoline tablets?

Yes. During the patent term, claim 3 could cover an oral pharmaceutical composition containing a claim 1 compound, including cabergoline, with a pharmaceutically acceptable carrier.

Does the patent protect cabergoline treatment for hyperprolactinemia?

The supplied claims do not recite a method of treating hyperprolactinemia. They cover the compound and pharmaceutical composition rather than a therapeutic method.

Is cabergoline subject to biosimilar competition?

No. Cabergoline is a small-molecule drug. Generic competition proceeds through the ANDA pathway, not the biosimilar pathway.

References

U.S. Food and Drug Administration. (1996). Dostinex (cabergoline) tablets, NDA 020664: Prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Patent and Trademark Office. (1985). U.S. Patent No. 4,526,892, Ergoline derivatives. USPTO.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Bulgaria	61058	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,526,892

Summary for Patent: 4,526,892