US Patent 4,366,145: Scope, Claim Construction, Expiration, and Ergot Alkaloid Patent Landscape

US Patent 4,366,145 covers stable soft gelatin capsules containing specified ergot alkaloids in polar, hydrophilic liquid fills, particularly polyethylene glycol-based fills containing ascorbic acid and, in certain claims, propylene glycol. The patent claims both a manufacturing method and the resulting capsule.

The patent issued on January 18, 1983. Under the pre-1995 U.S. patent-term regime, its 17-year term from issuance would have expired on January 18, 2000, absent an unusual term adjustment or extension. No current U.S. exclusivity or blocking right should be attributed to this patent.

What does US Patent 4,366,145 protect?

The patent protects a formulation and manufacturing approach intended to prevent degradation of ergot alkaloids in soft gelatin capsules.

Its technical combination has five principal elements:

An ergot alkaloid within a defined Markush formula.
A liquid, polar, hydrophilic softgel fill solvent.
A soft gelatin capsule shell.
A stability requirement based on retaining at least 90% of the original ergot alkaloid before encapsulation.
Optional formulation features involving ascorbic acid, polyethylene glycol, propylene glycol, dosage ranges, fill volumes, and shell configurations.

The disclosed active ingredients include:

Ergoloid mesylates.
Dihydroergotamine mesylate.
Bromocriptine mesylate.

The patent is formulation-focused. It does not claim the underlying pharmacological use of these compounds, their chemical structures as such, or a broad method of treating a disease.

How are the claims structured?

Claims 1 through 11: manufacturing-method claims

Claim 1 is the primary process claim. It requires:

Dissolving a therapeutically effective amount of a covered ergot alkaloid;
Using a pharmaceutically acceptable polar, hydrophilic softgel center-fill solvent;
Preparing a liquid fill solution;
Encapsulating that solution before the alkaloid concentration falls below 90% of the original amount.

Claims 2 and 3 narrow the timing requirement:

Claim	Encapsulation deadline
Claim 1	Before assay falls below 90%
Claim 2	Within 72 hours
Claim 3	Within 24 hours

Claims 4 through 11 narrow the active ingredient, excipient, and solvent:

Claim	Limitation
4	0.5 to 6 mg ergoloid mesylates
5	0.5 to 3 mg dihydroergotamine mesylate
6	1 to 3 mg bromocriptine mesylate
7	0.5% to 1.5% w/v ascorbic acid
8	About 1.5% w/v ascorbic acid
9	Polyethylene glycol, molecular weight about 200 to 600
10	Polyethylene glycol 400
11	About 10% by volume propylene glycol in the PEG 400 formulation

A product that practices claim 1 but is encapsulated after the specified degradation threshold is reached would not satisfy the express timing limitation. Claims 2 and 3 impose more specific time limits, but a formulation meeting claim 3 would also fall within claims 1 and 2 if all other limitations are present.

Claims 12 through 25: capsule-product claims

Claim 12 is the principal product claim. It covers a stable soft gelatin capsule consisting essentially of:

A soft gelatin shell; and
A liquid center fill;
Containing a covered ergot alkaloid dissolved in a pharmaceutically acceptable polar, hydrophilic solvent.

Claims 13 through 20 track the principal ingredient and excipient limitations in claims 4 through 10.

Claims 21 through 25 specify particular commercial-style formulations and shell formats. The key formulation is:

1 mg ergoloid mesylates or dihydroergotamine mesylate, or 2.5 mg bromocriptine mesylate;
7 mg ascorbic acid;
0.05 mL propylene glycol;
PEG 400 sufficient to bring the fill volume to approximately 0.500 mL.

Claim 23 covers a smaller ergoloid formulation:

1 mg ergoloid mesylates;
3 mg ascorbic acid;
0.02 mL propylene glycol;
PEG 400 to approximately 0.200 mL.

Claims 22 and 24 narrow the capsule shell by size, shape, and color. Claim 25 appears to duplicate the formulation in claim 21 and does not introduce a distinct limitation beyond the recited formulation.

What is the scope of the Markush ergot alkaloid definition?

Claim 1 defines a broad genus by substituent variables:

R1: hydrogen or halogen;
R2: hydrogen or C1-4 alkyl;
R3: isopropyl, sec-butyl, isobutyl, or benzyl;
R4: methyl, ethyl, or isopropyl;
R5 and R6: hydrogen, methoxy, or a combined additional bond.

The practical scope is narrower than the entire ergot-alkaloid field because the molecule must satisfy the complete substitution pattern. The claim then expressly identifies three commercial actives in dependent claims:

Ergoloid mesylates;
Dihydroergotamine mesylate;
Bromocriptine mesylate.

The claim language also creates a potential construction issue. “Ergoloid mesylates” is a mixture rather than a single chemically uniform compound. A product containing a defined mixture of hydrogenated ergot alkaloid derivatives could fall within the claim if the mixture satisfies the claimed formula and the formulation limitations.

The claim does not require a particular therapeutic indication. A capsule for migraine, dementia-related cognitive symptoms, Parkinsonian disorders, hyperprolactinemia, or another indication could theoretically fall within the technical formulation scope if the remaining limitations are met.

Which formulation elements are most important for infringement?

The strongest claim elements are the combined solvent and stabilizer limitations.

Polyethylene glycol 400

Claims 10, 19, 21, 23, and 25 focus on PEG 400. A formulation using PEG 400 is more exposed to the narrower claims than one using another hydrophilic solvent.

Claims 9 and 18 cover PEG molecular weights from approximately 200 to 600. A product using PEG 300, PEG 400, or PEG 600 may fall within those ranges, subject to the meaning of “about” and the other limitations.

Ascorbic acid

Ascorbic acid is not required by independent claim 1 or independent claim 12. It appears only in dependent claims 7, 8, 16, 17, 21, 23, and 25.

A formulation without ascorbic acid could still implicate claim 1 or claim 12 if it satisfies the other limitations. Conversely, ascorbic acid creates additional narrowing limitations rather than an independent requirement for all claims.

Propylene glycol

Propylene glycol is required only in claims 11, 20, 21, 23, and 25. The amount is approximately 10% by volume in claim 11 and is specified as 0.05 mL or 0.02 mL in the detailed formulations.

A formulation using glycerol, ethanol, water, or another co-solvent instead of propylene glycol would avoid these narrower claims, but not necessarily claims 1 or 12.

Encapsulation timing

The 90% assay limitation is central to claim 1. Claims 2 and 3 add explicit 72-hour and 24-hour limits.

The timing language is unusual because it ties infringement to an analytical stability result before encapsulation. An enforcement case would likely require evidence concerning:

The original alkaloid assay;
The assay immediately before encapsulation;
The analytical method;
Storage conditions before encapsulation;
The point at which the fill solution was prepared;
Whether the claimed degradation threshold was crossed.

How strong are the independent claims?

Claim 1

Claim 1 has meaningful technical specificity but several litigation vulnerabilities.

Potentially limiting features include:

The defined ergot alkaloid genus;
A polar, hydrophilic center-fill solvent;
The softgel manufacturing sequence;
The 90% pre-encapsulation stability threshold.

Potential claim-construction disputes include:

The meaning of “stable”;
The scope of “polar, hydrophilic”;
Whether the 90% limitation requires actual testing or can be shown through process records;
The meaning of “therapeutically effective amount”;
Whether the Markush formula covers each component of an ergoloid mixture.

A prior-art reference showing the same active ingredient in a hydrophilic softgel fill could be relevant. A reference showing only tablets, injections, dry-filled capsules, or nonpolar liquid fills would be less directly aligned with claim 1.

Claim 12

Claim 12 is more commercially significant because it claims the capsule itself rather than only the manufacturing process. It does not expressly include the 24-hour or 72-hour encapsulation periods.

Its scope remains limited by:

The covered ergot alkaloid;
The soft gelatin shell;
The liquid center fill;
The polar, hydrophilic solvent;
The “consisting essentially of” language.

“Consisting essentially of” generally permits additional ingredients that do not materially affect the basic and novel characteristics of the claimed formulation. That language can create disputes over preservatives, dyes, flavoring agents, buffering compounds, antioxidants, and other excipients.

When did US Patent 4,366,145 lose exclusivity?

US Patent 4,366,145 expired on January 18, 2000 under the ordinary 17-year term applicable to the relevant pre-1995 patent regime. The patent therefore does not create a current U.S. patent barrier to generic softgel manufacture.

Event	Date
Patent issued	January 18, 1983
Ordinary 17-year expiration	January 18, 2000
Current enforceability	None based on ordinary patent term

Patent-term adjustment generally applies to patents subject to the modern 20-year-from-earliest-effective-filing-date regime. The pre-1995 patent-term rules are materially different under 35 U.S.C. § 154. The patent’s age also makes patent-term extension under the Hatch-Waxman framework commercially implausible for current products.

What is the Orange Book status of this patent?

US Patent 4,366,145 should not be treated as a current Orange Book exclusivity right.

FDA Orange Book listing is product-specific. A patent may be submitted by an NDA holder for an approved drug product, but listing does not extend the patent term and does not convert an expired patent into an enforceable barrier. Current generic applicants would assess the relevant NDA, listed patents, pediatric exclusivity, regulatory exclusivity, and any live formulation or method-of-use patents separately under 21 C.F.R. § 314.53.

The patent’s age creates three practical conclusions:

It cannot support a current Paragraph IV challenge as an enforceable patent target.
It cannot block an ANDA solely because it once covered the formulation.
It may remain relevant as prior art against later patent applications claiming similar softgel formulations.

Which companies are challenging the patent?

There is no current Paragraph IV challenge of practical significance against US Patent 4,366,145 because the patent expired in 2000. Any historical ANDA filing would have lost its commercial relevance once the patent term ended.

The more relevant competitive question is whether later patents cover:

A specific ergot-alkaloid softgel formulation;
A particular fill composition;
A modified-release system;
A manufacturing process;
A dosage regimen;
A combination product;
A device or delivery system.

Those later rights would have to be analyzed independently. They cannot be inferred from US Patent 4,366,145.

What generic entry risks exist for ergot alkaloid softgels?

Current generic risk is driven by regulatory approval and later patent families, not by the expired patent.

Ergoloid mesylates

Ergoloid products have historically included oral tablets and capsules. A softgel using the claimed PEG, ascorbic acid, and propylene glycol architecture could have practiced the patent during its term. Today, a manufacturer would focus on:

FDA-approved reference products;
Bioequivalence requirements;
Product-specific inactive-ingredient acceptability;
Any current formulation patents;
Manufacturing reproducibility;
Alkaloid assay and degradation controls.

Dihydroergotamine mesylate

Dihydroergotamine has been commercialized in multiple dosage forms, including injectable and nasal products. Softgel exposure under this patent would depend on whether the product used the claimed liquid hydrophilic fill and the required alkaloid structure.

The principal modern barriers for dihydroergotamine products are more likely to involve delivery technology, device patents, nasal formulations, or method-of-use claims than this expired softgel patent.

Bromocriptine mesylate

Bromocriptine has been marketed in oral solid dosage forms and other product configurations. A bromocriptine softgel using the claimed ingredients would have been within the historical formulation landscape, but US Patent 4,366,145 no longer blocks entry.

Bromocriptine products may face different patent issues depending on indication, dose, formulation, and reference product.

What patent litigation affects this patent?

The available claim and patent-number information does not establish a current infringement case, settlement, consent judgment, or Paragraph IV litigation involving US Patent 4,366,145. Given the 2000 expiration date, any historical dispute would have to be evaluated from contemporaneous court and ANDA records.

No current litigation risk should be assigned to the patent itself. The relevant litigation screen is for later patents covering the same active ingredients, formulations, therapeutic indications, or delivery systems.

How does this patent compare with later formulation patents?

US Patent 4,366,145 is an early formulation patent with a relatively broad independent formulation concept and narrower dependent claims directed to commercial composition details.

Issue	US Patent 4,366,145
Technology	Immediate-release liquid softgel
Actives	Ergoloid mesylates, dihydroergotamine, bromocriptine and covered congeners
Core solvent	Polar, hydrophilic solvent
Preferred solvent	PEG 400
Stabilizer	Ascorbic acid
Co-solvent	Propylene glycol
Product type	Soft gelatin capsule
Process feature	Encapsulation before degradation below 90%
Method-of-use claim	None
Device claim	None
Current patent status	Expired
Current blocking value	None

Later patents are likely to be stronger where they claim a defined composition with exact ranges, a specific release profile, validated stability data, an approved dosage regimen, or an integrated delivery system.

What manufacturing and intellectual-property barriers remain?

The expired patent does not remove technical manufacturing challenges. Ergot alkaloids can present stability, assay, light-sensitivity, oxidation, and content-uniformity issues. A modern manufacturer would still need to control:

Raw-material identity and alkaloid composition;
Assay variability in ergoloid mixtures;
Oxidative degradation;
Fill viscosity and encapsulation performance;
Gel-shell compatibility;
Water migration between shell and fill;
Long-term stability;
Uniformity of dosage units;
Packaging and light protection.

These are regulatory and commercial barriers rather than continuing rights under the patent.

Key Takeaways

US Patent 4,366,145 claims stable ergot alkaloid softgel formulations and their manufacture.
The principal actives are ergoloid mesylates, dihydroergotamine mesylate, and bromocriptine mesylate.
The preferred formulation uses PEG 400, ascorbic acid, and propylene glycol.
Claim 1 is a process claim tied to retaining at least 90% of the original alkaloid before encapsulation.
Claim 12 is the principal capsule-product claim.
Claims 21 through 25 recite specific dosage, fill-volume, excipient, and shell configurations.
The patent issued January 18, 1983 and ordinarily expired January 18, 2000.
It presents no current U.S. patent blocking risk.
The patent may remain relevant as prior art against later formulation applications.
Current market exposure must be evaluated through later patents, FDA product records, Orange Book listings, regulatory exclusivities, and any active litigation involving the specific reference product.

FAQs

Does US Patent 4,366,145 cover all ergot alkaloid capsules?

No. It is limited to specified ergot alkaloid structures, soft gelatin capsules, liquid polar or hydrophilic fills, and the other claim limitations. Tablets, hard capsules, injections, nasal products, and formulations using materially different solvents are outside the literal scope unless another claim applies.

Does a PEG 400 formulation automatically infringe the patent?

No. PEG 400 is only one limitation. The product must also contain a covered ergot alkaloid, use a soft gelatin shell, satisfy the liquid-fill requirements, and meet the applicable independent and dependent claim limitations. The patent is expired in any event.

Is bromocriptine softgel formulation technology still patented under this patent?

No. US Patent 4,366,145 expired in 2000. A current bromocriptine softgel may be subject to later patents, but this patent cannot provide current exclusionary rights.

Does the patent claim the use of ergot alkaloids to treat disease?

No. The claims are directed to manufacturing a capsule and to the capsule formulation. They do not claim a therapeutic method for treating migraine, dementia, Parkinson’s disease, hyperprolactinemia, or another disease.

Can the patent be asserted against a modern generic manufacturer?

No, not as an unexpired U.S. patent. Its technical disclosures may be cited as prior art, but its claims cannot support a present infringement action after expiration.

References

United States Patent No. 4,366,145. (1983). Stable ergot alkaloid soft gelatin capsules. U.S. Patent and Trademark Office. https://patents.google.com/patent/US4366145A/en
U.S. Code, Title 35, § 154. (2024). Contents and term of patent; provisional rights. https://www.law.cornell.edu/uscode/text/35/154
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
U.S. Food and Drug Administration. (2024). Patent and exclusivity information. https://www.fda.gov/drugs/development-approval-process-drugs/orange-book-data-files
Code of Federal Regulations, Title 21, § 314.53. (2024). Submission of patent information. https://www.ecfr.gov/current/title-21/section-314.53

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	377533	⤷ Start Trial
Austria	383492	⤷ Start Trial
Austria	A151282	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,366,145

Summary for Patent: 4,366,145