United States Drug Patent 4,402,949: Claim Scope, Expiration, FDA Status, and Patent Landscape

U.S. Patent No. 4,402,949 protects stable injectable solutions combining dihydroergotamine or specified related ergot compounds with heparin, water, alcohol-based solvents, and urea or calcium/magnesium EDTA salts. The patent also covers defined pH ranges, solvent ratios, stabilizer concentrations, anesthetic additives, unit-dose ampoules, and a two-solution manufacturing process.

The patent issued on September 6, 1983. Under the pre-1995 U.S. patent-term regime, its 17-year term expired on September 6, 2000. It no longer blocks generic manufacture, formulation development, regulatory filing, licensing, or commercial sale in the United States.

What does U.S. Patent 4,402,949 cover?

The patent covers a pharmaceutical composition in stable solution form containing five core elements:

An ergot compound within the claimed Markush formula.
Heparin or a pharmaceutically acceptable heparin salt.
Water.
A pharmaceutically acceptable mono- or polyalcohol.
Urea or a calcium or magnesium salt of EDTA.

The principal commercial embodiment is dihydroergotamine, usually dihydroergotamine mesylate, combined with sodium heparin in an aqueous-alcoholic injection vehicle containing CaNa2 EDTA.

The patent is formulation-focused. It does not claim dihydroergotamine as a chemical compound, heparin as a substance, or the therapeutic use of either ingredient standing alone. Its center of gravity is the stabilization of a liquid combination product.

Core claim architecture

Claim group	Subject matter	Main limitation
Claims 1-2	Broad composition	Ergot compound, heparin, water, alcohol, urea or EDTA salt; pH 4-6
Claims 3-8	Specific ergot compounds	Dihydroergotamine, dihydroergovaline, or specified ergopeptine derivatives
Claims 9-11	Heparin form and ratio	Sodium heparin; 1 mg ergot compound per 500-70,000 IU heparin
Claims 12-17	Solvent system	Water and alcohol ranges; ethanol/triethylene glycol or glycerol/propylene glycol ratios
Claims 18-22	EDTA stabilizer	Calcium or magnesium EDTA salts, especially CaNa2 EDTA
Claims 23-29	Anesthetic and dosage form	Lidocaine, Hostacain, Baycain; unit dose and injectable ampoules
Claims 30-32	Manufacturing process	Separate preparation of ergot and heparin solutions, combination, pH adjustment, protective gas
Claims 33-39	Narrow DHE formulations	Dihydroergotamine, defined solvent ratios, CaNa2 EDTA, heparin ranges, and anesthetic

What chemical compounds fall within the patent?

Claim 1 uses a Markush definition for the ergot component. The substituents are limited as follows:

Variable	Claimed alternatives
R	Hydrogen or C1-4 alkyl
R1	Methyl, ethyl, or isopropyl
R2	Isopropyl, sec-butyl, isobutyl, or benzyl
X	Hydrogen or methoxy

The dependent claims identify three principal compounds:

Dihydroergotamine.
Dihydroergovaline.
6-nor-6-isopropyl-9,10-dihydro-2'-methyl-5'-benzyl-ergopeptine.

The claims also cover pharmaceutically acceptable acid-addition salts. The most important expressly claimed salt is dihydroergotamine methanesulfonate, commonly called dihydroergotamine mesylate.

The chemical limitation is material. A formulation containing a different ergot derivative would fall outside claims 3-8 and 33-39, but could still fall within claim 1 if the derivative satisfies the Markush formula.

How broad is independent claim 1?

Claim 1 is broad in formulation design but narrow in product architecture.

A potentially infringing formulation must include all of the following:

A qualifying formula I ergot compound or salt.
Heparin or a heparin salt.
Water.
A mono- or polyalcohol.
Urea, a calcium EDTA salt, a magnesium EDTA salt, or a combination.
A stable solution form.

The claim does not require:

A specific injection route.
A specific vial, ampoule, syringe, or cartridge.
A particular concentration of the ergot compound.
A particular molecular-weight distribution for heparin.
A particular alcohol.
A particular amount of EDTA.
A particular therapeutic indication.

The breadth is constrained by the requirement that all components coexist in a stable solution. A dry powder, tablet, suspension, emulsion, or two-compartment product that is not a stable solution would not literally meet claim 1.

The patent’s claim language also creates a potential construction issue around “stable solution form.” Stability is likely assessed in the context of the patent specification and ordinary pharmaceutical meaning, including retention of active ingredient, absence of unacceptable precipitation or degradation, and suitability for storage and administration. The term is not equivalent to any solution that remains visually clear for a short period.

What formulations are protected by the dependent claims?

The dependent claims progressively narrow the composition and create several formulation-specific positions.

pH

Claim 2 requires a pH of 4 to 6. Claims 32 and 39 repeat or incorporate this acidic formulation concept through dependent claim structure.

A product outside pH 4-6 could still implicate claim 1 if it satisfies the other limitations, but it would not meet claim 2 or the claims that expressly depend on the pH-limited embodiments.

Solvent system

Claims 12-17 establish the principal vehicle limitations:

Water: 45% to 72% by total volume.
Alcohol component: 28% to 55% by total volume.
Alcohols include ethanol, propylene glycol, polyethylene glycol, diethylene glycol, triethylene glycol, glycerol, or mixtures.
Ethanol and triethylene glycol may be present in ratios from 1:6 to 1:10.
Glycerol and propylene glycol may be present in ratios from 1:8 to 1:12.
Claim 17 narrows those ratios to 1:8 for ethanol/triethylene glycol or 1:10 for glycerol/propylene glycol.

The 1:10 glycerol/propylene glycol embodiment is central to claims 34-39.

EDTA stabilizer

Claims 18-22 protect the use of calcium or magnesium EDTA salts. Claim 20 specifically identifies CaNa2 EDTA.

The claimed amount is:

Approximately 2 to 20 mg per 5,000 IU heparin under claim 21.
Approximately 2 to 5 mg per 5,000 IU heparin under claim 22 and the narrower DHE claims.

The patent therefore reaches beyond conventional disodium EDTA formulations if the selected EDTA salt contains calcium or magnesium in the claimed manner.

Anesthetic

Claims 23-26 and 37-38 add an injectable local anesthetic. The claims identify acetanilide anesthetics, including:

Lidocaine.
Hostacain.
Baycain.

The anesthetic concentration is 1% to 2% by total weight under claim 26.

Dose and presentation

Claims 27-29 cover unit-dose and ampoule presentations. Claim 29 identifies a formulation containing:

0.5 mg of formula I compound.
2,500 or 5,000 IU heparin.
An acetanilide anesthetic.

Claims 34-39 narrow the formulation to DHE mesylate, sodium heparin, a 1:10 glycerol/propylene glycol mixture, and CaNa2 EDTA.

Does the patent cover a marketed DHE product?

The patent’s formulation resembles an injectable DHE-heparin combination rather than the principal modern DHE products marketed in the United States.

Current U.S. DHE products have included:

Dihydroergotamine mesylate injection.
Dihydroergotamine mesylate nasal spray.

D.H.E. 45 injection is an approved prescription product for the acute treatment of migraine attacks, with dihydroergotamine mesylate as the active ingredient. The FDA labeling describes the product as an injectable DHE formulation and does not establish that the marketed product contains heparin, CaNa2 EDTA, or the claimed glycerol/propylene glycol vehicle.[2]

This distinction matters. A DHE product without heparin is outside claim 1. A DHE product containing heparin but lacking the required alcohol and EDTA components may also avoid literal infringement. The patent does not capture every injectable or nasal DHE formulation.

What is the patent expiration date?

Event	Date
U.S. patent grant	September 6, 1983
Statutory term under pre-1995 rule	17 years from grant
Expiration	September 6, 2000
Current enforceability	Expired
Current Paragraph IV relevance	None as to this patent

The patent was granted before the Uruguay Round Agreements Act changed the ordinary U.S. patent term to 20 years from the earliest effective nonprovisional filing date. Patents in this older category generally retained a 17-year term from grant, subject to applicable statutory exceptions.[1]

No current patent-term extension, pediatric extension, or regulatory exclusivity can revive this expired formulation patent.

What is the Orange Book status of U.S. Patent 4,402,949?

U.S. Patent 4,402,949 is not a current Orange Book barrier for DHE products.

The Orange Book lists patents submitted for approved drug products, including eligible patents covering drug substances, drug products, or approved methods of use. The patent’s term expired in 2000, and it is not a current patent that can support a listed-patent certification or delay generic approval.[3]

The practical status is:

Regulatory issue	Status
Current Orange Book blocking patent	No
Current 30-month stay basis	No
Current Paragraph IV litigation risk	No
DHE active-ingredient exclusivity	Expired
Heparin-DHE combination exclusivity from this patent	Expired

An expired patent can remain relevant to historical product development, freedom-to-operate analysis, and prior-art review. It cannot support a present infringement action.

What process does claim 30 protect?

Claim 30 covers a manufacturing sequence rather than only the final composition:

Prepare the ergot solution in the alcohol medium, with anesthetic if used.
Prepare the heparin solution in water containing the EDTA component.
Combine the two solutions.
Add additional water or alcohol as needed.

Claims 31 and 32 add:

Protective gassing during solution preparation.
Adjustment to pH 4-6.

The process claim is important because it addresses compatibility and stability risks during manufacture. A process using the same final ingredients but adding them in a materially different order could avoid literal infringement of claim 30, although the final product claims would remain separately relevant during the patent term.

Protective nitrogen or other inert-gas processing is not independently protected by the patent. It is protected only when practiced with the other limitations of the process claim.

How strong was the patent estate?

The patent estate was moderately strong for a narrow product configuration and weak against design-around formulations.

Strengths

Claim 1 combined multiple formulation elements that were difficult to omit in the disclosed injectable product.
The claims covered both the composition and manufacturing process.
Claims 33-39 provided narrow positions directed to DHE mesylate, sodium heparin, CaNa2 EDTA, and defined solvent ratios.
The claims covered several commercially relevant dosage forms, including unit-dose ampoules.

Weaknesses

The patent did not claim DHE itself.
Heparin was mandatory.
The formulation had to be a stable solution.
The EDTA limitation excluded many conventional chelator systems.
The solvent-ratio claims could be avoided by changing the alcohol system or proportions.
The patent did not cover nasal, oral, transdermal, or dry-powder DHE products absent the claimed solution architecture.
The patent expired more than two decades ago.

The estate had meaningful formulation specificity but limited platform breadth. Its commercial value depended on adoption of the particular DHE-heparin injectable concept.

Were there Paragraph IV challenges or patent settlements?

No current Paragraph IV challenge, settlement agreement, or active U.S. litigation can affect U.S. Patent 4,402,949 because the patent expired in 2000.

Paragraph IV certifications apply to patents listed in connection with an abbreviated new drug application. A generic applicant may certify that a listed patent is invalid, unenforceable, or will not be infringed. An expired patent does not create a future-entry block or a 30-month stay under the Hatch-Waxman framework.[4]

No present generic launch needs to wait for this patent.

What generic entry risks exist for DHE products?

The principal generic risks for DHE products do not arise from Patent 4,402,949. They arise from:

Product-specific formulation patents, if any remain unexpired.
Device or delivery-system patents for nasal products.
Manufacturing patents.
FDA product-specific requirements.
Complex formulation or bioequivalence issues.
Controlled-substance and supply-chain requirements.
Exclusivity or regulatory status associated with a particular approved product.

For a DHE-heparin solution matching the claimed historical formulation, the patent risk from U.S. Patent 4,402,949 is zero because the claims are expired. A current applicant would instead evaluate later patents, FDA approval requirements, formulation equivalence, preservative systems, container closure, sterility, and heparin characterization.

Does biosimilar law apply?

Biosimilar law is not the principal pathway for a DHE-heparin combination.

Dihydroergotamine mesylate is a small-molecule drug. A product containing DHE and heparin would require a pathway determined by the reference product and the proposed formulation. If the reference is an approved small-molecule drug, an ANDA may be available where sameness and bioequivalence requirements can be met. If the proposed product differs materially in formulation, route, or clinical profile, a 505(b)(2) application may be more appropriate.

Heparin is biologically derived and structurally heterogeneous, but that fact does not convert the entire DHE-heparin combination into a biosimilar application. The regulatory analysis would focus on the approved reference product, active-ingredient sameness, formulation differences, and FDA requirements for the combination.

What licensing or commercial exposure was associated with the patent?

The patent itself is a formulation patent and does not establish a current royalty stream. Its value would historically have depended on commercial use of a DHE-heparin injectable product, particularly an ampoule containing 0.5 mg DHE and 2,500 or 5,000 IU heparin.

The patent record does not create current licensing leverage because:

The patent expired in 2000.
No continuing exclusionary right remains.
No present generic delay is available.
A license cannot extend the statutory patent term.

Any historical licensing or supply arrangement would have commercial significance only as a matter of contract history, not current patent exclusivity.

How does this patent compare with later DHE patent strategies?

Patent strategy	U.S. Patent 4,402,949	Later DHE strategy
Active ingredient	Markush ergot compounds	Often DHE mesylate specifically
Delivery route	Injectable solution and ampoule	Injection, nasal, or other delivery systems
Formulation	Water/alcohol/heparin/EDTA	Device-specific or excipient-specific
Manufacturing	Separate solution preparation and protective gas	Process, filling, sterilization, or device assembly
Use claims	No dominant migraine-use claim	May include acute migraine or cluster-headache use
Current status	Expired	Depends on individual patent and term

The 1983 patent is best understood as an early formulation and compatibility patent. It is not a current platform patent for all DHE products.

Key Takeaways

U.S. Patent 4,402,949 claims stable solutions combining an ergot compound, especially DHE, with heparin, water, alcohol, and urea or calcium/magnesium EDTA.
The strongest narrow embodiments use DHE mesylate, sodium heparin, CaNa2 EDTA, and a 1:10 glycerol/propylene glycol vehicle.
Claims 30-32 separately protect a two-solution manufacturing process with optional protective gassing and pH adjustment.
The patent issued September 6, 1983 and expired September 6, 2000.
It is not a current Orange Book barrier and cannot support a present Paragraph IV stay or infringement action.
The claims do not cover DHE products that lack heparin or do not use the claimed stable-solution architecture.
Current DHE generic risk must be assessed against later product, device, manufacturing, and formulation patents, not this expired patent.
The patent did not create biosimilar exclusivity and does not control current FDA pathway selection.

FAQs

Can a company sell a DHE injection without infringing U.S. Patent 4,402,949?

Yes. The patent expired on September 6, 2000. A current DHE injection also would not have met claim 1 if it lacked heparin, the required alcohol component, or urea/calcium/magnesium EDTA.

Does CaNa2 EDTA make a DHE formulation patent-protected today?

No. CaNa2 EDTA was a key limitation in claims 20, 34, and later claims, but those claims expired with the patent.

Did U.S. Patent 4,402,949 cover dihydroergotamine nasal spray?

No. The claims require a stable solution containing heparin and the specified vehicle components. A nasal DHE product without that combination is outside the patent’s literal scope.

Could the process claims have a later expiration date than the composition claims?

No. The composition and process claims were in the same patent and expired together on September 6, 2000.

Is heparin-DHE combination therapy protected by current exclusivity?

Not by U.S. Patent 4,402,949. Any current exclusivity would have to arise from a later patent, regulatory exclusivity, or product-specific FDA protection.

References

United States Patent and Trademark Office. (1983). U.S. Patent No. 4,402,949: Pharmaceutical compositions containing an ergot alkaloid and heparin.
U.S. Food and Drug Administration. (n.d.). D.H.E. 45 (dihydroergotamine mesylate) injection prescribing information.
U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application approvals and patent certifications.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	2945636	Nov 12, 1979

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	371997	⤷ Start Trial
Austria	A550480	⤷ Start Trial
Australia	535357	⤷ Start Trial
Australia	6426580	⤷ Start Trial
Belgium	886008	⤷ Start Trial
Canada	1165692	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,402,949

Summary for Patent: 4,402,949