United States Patent 4,166,182: Pergolide Scope, Claims, Expiration, and Patent Landscape

US 4,166,182 covers a class of substituted ergoline compounds and specifically claims pergolide-related molecules, including D-6-n-propyl-8β-methylmercaptomethylergoline and its mesylate salt. The patent issued on August 28, 1979, and its original 17-year United States patent term expired on August 28, 1996. The patent therefore no longer creates an enforceable exclusion right against generic pergolide, salts, formulations, or manufacturing processes.

The principal commercial compound associated with the claims is pergolide, generally administered as pergolide mesylate. Pergolide was marketed in the United States as Permax for Parkinson's disease until commercial withdrawal in 2007 following safety concerns involving cardiac valvulopathy.[1]

What drug does US Patent 4,166,182 protect?

US 4,166,182 protects a Markush class of substituted ergoline compounds, with several claims directed specifically to pergolide structures.

The commercially relevant molecule is:

Item	Description
Generic name	Pergolide
Common salt	Pergolide mesylate
Chemical class	Ergoline dopamine agonist
Principal substituents	6-n-propyl and 8β-methylthiomethyl
Pharmacology	Dopamine receptor agonist
Historical indication	Parkinson's disease
Historic US brand	Permax
Historic sponsor	Eli Lilly and Company
US approval	Late 1980s
US commercial withdrawal	2007

The claim language uses "methylmercaptomethyl" for the sulfur-containing substituent. Modern chemical nomenclature more commonly describes the same structural feature as methylthiomethyl.

The core pergolide structure corresponds to the claim 3 subject matter:

D-6-n-propyl-8β-methylmercaptomethylergoline.

Claim 6 expressly covers the mesylate salt:

D-6-n-propyl-8β-methylmercaptomethylergoline mesylate.

That claim is the closest claim to the pharmaceutical form historically used in Permax tablets.

What is the legal status and expiration date of US 4,166,182?

US 4,166,182 is expired.

Event	Date
Patent issued	August 28, 1979
Applicable pre-Uruguay Round patent term	17 years from grant
Original expiration	August 28, 1996
Current enforceability	None
Current ability to block generic entry	None

Because the patent issued before the change to a term measured from the earliest effective nonprovisional filing date, the applicable term was generally 17 years from issuance. No patent-term extension or pediatric extension can revive this expired patent.

The expiration date has two commercial consequences:

A generic manufacturer no longer needs a license from the patent owner to practice the claimed pergolide compounds.
A current abbreviated new drug application, or ANDA, cannot be blocked by this patent through an Orange Book Paragraph IV certification.

The patent may remain relevant as prior art, historical evidence of the invention, or a source of chemical disclosure. It does not provide current exclusivity.

How broad is claim 1 of US 4,166,182?

Claim 1 is a Markush composition claim. Its scope is broader than pergolide alone.

The claim fixes some substituents and varies others:

Claim variable	Permitted alternatives
Y	O, SO, SO2, or S
R1	n-propyl
X	H, Cl, or Br
R2, R3, R4 individually	Hydrogen
R2 and R3 together	Double bond with the attached carbon atoms
R3 and R4 together	Double bond with the attached carbon atoms
Salt form	Pharmaceutically acceptable acid addition salts

The claim therefore covers several related ergoline and ergolene configurations, including oxygen-, sulfoxide-, sulfone-, and sulfur-containing analogues.

The broadest practical feature set is:

an ergoline or ergolene nucleus;
a 6-n-propyl substituent;
a variable 8-position substituent represented through Y;
hydrogen, chlorine, or bromine at the X position;
permitted double-bond arrangements in the ring system; and
pharmaceutically acceptable acid-addition salts.

Claim 1 is a product claim. It does not depend on a particular therapeutic use, dosage, tablet composition, excipient, manufacturing process, or patient population.

What do claims 2 through 8 add?

Claim 2: sulfur analogues

Claim 2 narrows claim 1 by requiring:

Y is S.

This limitation selects the methylthio or methylmercapto series. Pergolide falls within this sulfur-containing subgroup.

Claim 3: D-6-n-propyl-8β-methylmercaptomethylergoline

Claim 3 identifies a specific stereochemical compound. The 8β configuration is important because it distinguishes the claimed molecule from stereoisomers that may have different pharmacological and legal status.

This is a species claim within the genus of claim 1.

Claim 4: D-6-n-propyl-8-methylmercaptomethyl-8-ergolene

Claim 4 covers the 8-ergolene unsaturation pattern. It differs from the fully saturated ergoline structure identified in claim 3.

The claim is directed to a specific ring-system configuration rather than merely the broader Markush alternatives.

Claim 5: D-6-n-propyl-8β-methylmercaptomethyl-9-ergolene

Claim 5 covers the 9-ergolene configuration with the 8β methylmercaptomethyl substituent.

Claims 4 and 5 are therefore positional and structural isomers of the broader class. Their inclusion reduces the risk that an alternative placement of unsaturation would fall outside the named species claims.

Claim 6: pergolide mesylate

Claim 6 covers:

D-6-n-propyl-8β-methylmercaptomethylergoline mesylate.

The claim protects the acid-addition salt used in the commercial product. It is narrower than the free-base compound claim but was commercially significant because the drug was supplied as pergolide mesylate.

Claim 7: sulfur, hydrogen, and n-propyl limitations

Claim 7 requires:

Y = S;
X = H; and
R1 = n-propyl.

It retains the permitted ring unsaturation alternatives from claim 1 unless otherwise limited by the claim construction. Claim 7 is a narrower generic claim centered on the sulfur-containing, unsubstituted-X series.

Claim 8: methoxy analogue

Claim 8 identifies:

D-6-n-propyl-8β-methoxymethylergoline mesylate.

This claim is structurally distinct from the sulfur-containing pergolide mesylate claim. The term "methoxymethyl" corresponds to the oxygen-containing Y = O branch of claim 1.

The supplied text contains a nomenclature distinction that matters:

"methylmercaptomethyl" or "methylthiomethyl" indicates a sulfur-containing substituent and corresponds to pergolide.
"methoxymethyl" indicates an oxygen-containing substituent and is a different chemical species.

Claim 8 should therefore not be treated as another name for pergolide mesylate.

Does US 4,166,182 cover pergolide mesylate?

Yes. Claim 6 expressly recites pergolide mesylate by its chemical name.

Claim 1 also covers pharmaceutically acceptable acid-addition salts of the claimed bases. Claim 6 removes any need to rely solely on the generic salt language by identifying the mesylate species directly.

The patent thus contains three relevant protection layers for the commercial product:

A genus claim covering sulfur-containing substituted ergolines.
A species claim covering the D-6-n-propyl-8β compound.
A salt claim covering pergolide mesylate.

Those layers were commercially meaningful during the patent term. They no longer create market exclusivity because the patent expired in 1996.

What was the Orange Book status of pergolide?

Pergolide was historically listed in the FDA Orange Book in connection with Permax and its approved dosage forms. The regulatory listing was separate from patent enforceability.

The Orange Book distinction is important:

Issue	Status
Historical NDA	Permax, pergolide mesylate
FDA therapeutic category	Dopamine agonist for Parkinson's disease
Listed patent	US 4,166,182 was historically relevant
Patent status today	Expired
Current Paragraph IV leverage	None from US 4,166,182
Brand availability	Withdrawn from US market
Regulatory effect of withdrawal	Does not revive or extend the patent

The FDA accepted the voluntary withdrawal of Permax from the US market after reports associated pergolide with cardiac valvular disease. FDA stated that the risk-benefit balance was unfavorable for Parkinson's disease treatment and that other dopamine agonists were available.[1]

Withdrawal of the reference product does not itself eliminate the possibility of an ANDA or other regulatory pathway. FDA may continue to maintain a discontinued product in the Orange Book for regulatory purposes, depending on the basis for discontinuation. A withdrawn drug can also be subject to separate questions involving market availability, bioequivalence reference standards, and FDA approval history.

When did pergolide lose market exclusivity?

Pergolide lost the relevant composition-patent exclusivity on August 28, 1996.

The commercial timeline is:

Period	Event
1979	US 4,166,182 issued
Late 1980s	Permax approved in the United States
1996	US 4,166,182 expired
2000s	Generic and regulatory availability developed around the expired compound rights
2007	Permax withdrawn from the US market because of valvular-heart-disease concerns

Any FDA orphan-drug exclusivity, labeling exclusivity, or other regulatory protection would have been separate from the patent and would not extend the patent term. The available commercial history does not make those regulatory periods relevant to current US exclusivity.

Were Paragraph IV challenges possible against this patent?

Yes, but only before expiration.

An ANDA applicant seeking approval for pergolide mesylate could have addressed US 4,166,182 through one of the Hatch-Waxman certifications:

Paragraph I, if no relevant patent was listed;
Paragraph II, if the patent had already expired;
Paragraph III, if approval was deferred until expiration; or
Paragraph IV, if the applicant asserted that the patent was invalid, unenforceable, or not infringed.

After August 28, 1996, a Paragraph IV challenge to this patent would no longer provide meaningful commercial value because the patent had already expired. A current applicant would not need to invalidate the patent to practice its claims.

The patent’s age also means that any historical litigation or settlement would have to be evaluated against the expiration date, not present-day patent rights.

What patent rights remain for pergolide today?

US 4,166,182 does not leave enforceable rights. Potentially relevant rights would have to arise from later patents, including:

new formulations;
controlled-release dosage forms;
combination products;
specific methods of treatment;
manufacturing or purification methods;
polymorphs or crystalline forms;
new salts or solvates;
veterinary uses; or
process-specific intermediates.

Those rights would not automatically be covered by US 4,166,182. A later patent would need its own valid claims, an unexpired term, and a legally relevant scope.

The supplied patent claims do not cover:

a particular tablet excipient system;
a sustained-release device;
a transdermal or injectable delivery system;
a specific dose or dosing schedule;
treatment of a named disease;
a manufacturing process;
a polymorph;
a particle-size distribution; or
a combination with levodopa, carbidopa, or another dopamine agonist.

The patent is therefore primarily a composition patent, with a salt claim, rather than a complete product-life-cycle patent estate.

How strong was the patent estate?

During its term, the estate was structurally strong for the original active pharmaceutical ingredient.

Strength factor	Assessment
Core compound claim	Strong, because claim 3 identifies pergolide specifically
Salt protection	Strong, because claim 6 expressly covers pergolide mesylate
Genus coverage	Broad across sulfur, oxygen, sulfoxide, and sulfone analogues
Stereochemical coverage	Material, through the 8β limitations
Formulation coverage	Not shown in the supplied claims
Method-of-use coverage	Not shown in the supplied claims
Manufacturing coverage	Not shown in the supplied claims
Current enforceability	None because the patent expired
Generic blocking power	None today

The most valuable claims were claims 3 and 6. Claim 1 supplied genus-level coverage, while claim 6 directly targeted the commercial salt. Claims 4, 5, 7, and 8 added related chemical species and analogues rather than broadening the commercial pergolide claim.

How does pergolide compare with cabergoline and bromocriptine?

Pergolide, cabergoline, and bromocriptine are ergot-derived dopamine agonists, but their patent estates and commercial histories differ.

Drug	Principal use	Historical US brand	Patent position today	Key safety or commercial issue
Pergolide	Parkinson's disease	Permax	Original composition patent expired in 1996	US withdrawal in 2007 for valvular risk
Cabergoline	Hyperprolactinemia; other dopamine-related uses	Dostinex	Original composition rights expired or are historical; later rights require separate analysis	Valvular-risk monitoring
Bromocriptine	Parkinson's disease, hyperprolactinemia, diabetes-related uses	Parlodel and others	Multiple historical patent and formulation issues	Long commercial history

Pergolide had a direct composition patent covering the marketed mesylate. Its current commercial risk is driven more by regulatory and market-access constraints than by US patent exclusivity.

What generic entry risks exist?

The expired patent creates no current patent barrier to a conventional pergolide mesylate product. The principal barriers are regulatory and commercial:

availability of an FDA-recognized reference product;
bioequivalence strategy;
market demand after withdrawal of the brand;
safety labeling and postmarketing requirements;
manufacturing controls for the active ingredient;
supplier qualification for a low-volume ergot-derived compound; and
the commercial viability of entering a market with limited US demand.

A generic manufacturer would also need to evaluate whether later patents cover a particular formulation, process, polymorph, or method. Those issues are separate from US 4,166,182.

What manufacturing and IP barriers does the patent create?

The patent historically disclosed and claimed the compounds, but the supplied claims do not claim the synthetic route. A competitor could therefore avoid any process limitation because the patent claims are product-focused.

The expired patent may still disclose:

synthesis of substituted ergolines;
stereochemical control;
oxidation-state variants of sulfur;
acid-addition salt formation; and
preparation of ergoline and ergolene analogues.

Those disclosures may assist development but do not create current exclusivity. A modern manufacturer would still face technical barriers involving impurity control, stereochemical purity, residual solvents, genotoxic impurities, and consistent salt formation. Those are manufacturing challenges, not continuing rights under the expired patent.

Key Takeaways

US 4,166,182 is a composition patent for substituted ergoline compounds.
Pergolide is the principal commercial compound within the claimed class.
Claim 6 expressly covers pergolide mesylate.
Claim 1 is a broad Markush claim covering sulfur, oxygen, sulfoxide, and sulfone analogues.
Claims 3 and 6 are the most commercially important claims for pergolide.
The patent issued on August 28, 1979, and expired on August 28, 1996.
The patent has no current US blocking effect against generic pergolide.
The patent does not, based on the supplied claims, cover formulations, methods of treatment, or manufacturing processes.
Permax was withdrawn from the US market in 2007 because of cardiac valvulopathy concerns.
Current market-entry risk is primarily regulatory, technical, and commercial rather than patent-based.
Claim 8 covers an oxygen-containing methoxymethyl analogue, not the sulfur-containing pergolide molecule.

FAQs

Is pergolide mesylate still protected by a US patent?

Not by US 4,166,182. The patent expired on August 28, 1996.

Does claim 6 cover the free base of pergolide?

No. Claim 6 specifically recites the mesylate salt. The free base is addressed through the compound claims, including claim 3 and the broader claim 1.

Is claim 8 another claim to pergolide?

No. Claim 8 recites a methoxymethyl compound, which is an oxygen-containing analogue. Pergolide has a methylthiomethyl or methylmercaptomethyl substituent.

Can a company launch a pergolide generic without challenging US 4,166,182?

Yes. Because the patent expired, an applicant does not need to overcome it through a current Paragraph IV litigation strategy.

Does withdrawal of Permax restore exclusivity to the patent owner?

No. Commercial withdrawal does not extend or revive an expired composition patent. It affects regulatory and market conditions, not the patent term.

Sources

U.S. Food and Drug Administration. (2007). FDA patient safety information: Pergolide products and valvular heart disease. https://www.fda.gov
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book
United States Patent and Trademark Office. (1979). U.S. Patent No. 4,166,182: Ergoline derivatives. https://patents.google.com/patent/US4166182
U.S. Food and Drug Administration. (1988). Permax (pergolide mesylate) prescribing information. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (2007). FDA announces withdrawal of pergolide products from the U.S. market. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0003667	⤷ Start Trial	SPC/GB93/063	United Kingdom	⤷ Start Trial
Argentina	228341	⤷ Start Trial
Austria	371817	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,166,182

Summary for Patent: 4,166,182