United States Patent 5,453,510: Scope, Claims, Expiration, and Mivacurium Patent Landscape

U.S. Patent No. 5,453,510 covers stereochemically purified salts of mivacurium, particularly the besylate and mesylate salts, pharmaceutical compositions containing those salts, and injectable methods for producing neuromuscular blockade. The patent does not broadly cover every mivacurium formulation or every neuromuscular-blocking agent. Its commercial relevance depended on the combination of exact stereochemistry, controlled isomer content, selected salt forms, and parenteral use.

The patent issued on September 26, 1995. Based on the pre-URAA patent-term framework applicable to patents of this vintage, its ordinary U.S. term would have ended on September 26, 2012, absent a term adjustment or other unusual term event. It therefore does not present a current U.S. blocking right.

What drug and chemical subject matter does U.S. Patent 5,453,510 cover?

The claimed compound is mivacurium in a specified stereochemical form. Mivacurium is a short-acting, bis-benzylisoquinolinium neuromuscular-blocking agent used by injection or infusion to produce skeletal-muscle paralysis during anesthesia and controlled ventilation.

The structural language in the claims identifies:

A bis-quaternary benzylisoquinolinium structure.
Two linked tetrahydroisoquinolinium units.
6,7-dimethoxy substitution.
N-methyl substitution.
Veratryl groups.
A 3,11-dioxo-4,10-dioxatridecamethylene bridge.
The 1R-cis,1'R-cis stereochemical configuration.
A physiologically acceptable counterion.
A specified maximum level of other geometric or optical isomers.

The patent is directed to a stereochemically defined mivacurium preparation rather than to the broader genus of benzylisoquinolinium neuromuscular blockers.

What does the stereochemical limitation mean?

The claims require the 1R-cis,1'R-cis isomer and impose compositional purity thresholds:

Claim category	Maximum amount of other geometric or optical isomers
Independent composition or method claim	Less than 8% w/w
Dependent purity claim	Less than 5% w/w
Further dependent purity claim	Less than 2% w/w

The percentage is calculated against the combined weight of the claimed salt and the other geometric or optical isomers. The limitation is not merely an analytical preference. It is a central claim element.

A product containing the same active chemical name could fall outside the literal scope if it failed to meet the required stereochemical configuration or contained 8% or more of the specified other isomers. Conversely, a product with less than 2% isomeric material would satisfy the narrower purity limitation if the other claim elements were also met.

How many independent inventions are claimed?

The claim set contains three principal claim groups:

Purified salts of the defined mivacurium stereoisomer.
Pharmaceutical compositions containing those salts.
Injectable methods for inducing neuromuscular blockade.

The principal independent claims are claims 1, 4, 7, 10, 11, 12, and 13. Claims 4 and 7 focus on specific counterions, while claim 13 focuses on therapeutic administration.

Claim group	Subject matter	Commercial significance
Claims 1-3	Physiologically acceptable salt with 1R-cis,1'R-cis configuration and less than 8%, 5%, or 2% other isomers	Broadest chemical protection in the patent
Claims 4-6	Besylate salt with the specified stereochemical purity	Salt-specific composition protection
Claims 7-9	Mesylate salt with the specified stereochemical purity	Salt-specific composition protection
Claims 10-12	Pharmaceutical compositions containing the claimed salts	Formulation and dosage-form protection
Claims 13-20	Injectable or infusional neuromuscular-blockade methods	Method-of-use protection
Claims 21-24	Solid form and human-use limitations	Narrower product and use claims

What patents protect mivacurium?

U.S. Patent 5,453,510 is a key patent directed to purified stereoisomeric mivacurium salts. Its scope is distinct from earlier patents that may have claimed:

The underlying bis-benzylisoquinolinium chemical structure.
Broader families of neuromuscular-blocking compounds.
Processes for preparing benzylisoquinolinium compounds.
Specific therapeutic uses.
Pharmaceutical solutions or injectable dosage forms.
Other counterions or crystalline forms.

The patent should therefore be analyzed as part of a patent family and product-development chain rather than as the entire historical mivacurium estate. The supplied claims do not identify continuation patents, divisional applications, foreign counterparts, or earlier priority applications.

What is the strongest composition claim?

Claim 1 is the principal broad composition claim. It covers a physiologically acceptable salt of the specified 1R-cis,1'R-cis mivacurium isomer with less than 8% w/w of other geometric or optical isomers.

The claim has four important limitations:

The exact molecular scaffold.
The exact stereochemical designation.
Salt status and physiological acceptability.
Isomeric purity below the stated threshold.

Claim 1 is broader than claims 4 and 7 because it does not limit the counterion to besylate or mesylate. It is narrower than a claim to all mivacurium salts or all stereoisomeric mixtures.

What formulations are protected by U.S. Patent 5,453,510?

Claims 10-12 cover pharmaceutical compositions containing the claimed salts and a pharmaceutically acceptable carrier. Claim 21 adds solid-form protection for the salts recited in claims 1 through 9.

The wording does not require a particular excipient, concentration, pH, container, dosage strength, preservative, or delivery device. The composition claims could therefore reach a wide range of pharmaceutical presentations if they contain the claimed salt and satisfy the stereochemical limitations.

The method claims are narrower in one respect. They require a "pharmacologically acceptable liquid" administered by injection or infusion. A solid oral dosage form would not satisfy the administration limitation in claim 13 because the claim requires injection or infusion.

The formulation claims do not expressly require:

A ready-to-use vial.
A lyophilized product.
A particular concentration of mivacurium.
A particular buffer.
A particular infusion pump.
A specific clinical indication beyond neuromuscular blockade for the method claims.

What do the method-of-use claims cover?

Claim 13 covers administering the claimed mivacurium salt in a pharmacologically acceptable liquid by injection or infusion in an amount effective to produce neuromuscular blockade in an animal.

Claims 16-19 narrow the salt to mesylate or besylate. Claims 20 and 22-24 narrow the animal to a human.

Method limitation	Scope
Route	Injection or infusion
Dosage concept	Effective neuromuscular-blockade amount
Vehicle	Pharmacologically acceptable liquid
Patient category	Animal, narrowed to human in dependent claims
Active ingredient	Specified 1R-cis,1'R-cis mivacurium salt
Purity	Less than 8%, 5%, or 2% other isomers

These claims could have been important against a commercial injectable product even if the product had been sold under a different brand name. They would not necessarily cover a product using a different active neuromuscular blocker, a different stereoisomeric composition, or a noninjectable delivery route.

Are there drafting defects in the claims?

Several claims contain apparent dependency and wording errors.

Claims 5 and 6

Claims 5 and 6 state that they depend on claim 1, although their subject matter follows claim 4 and is intended to concern the besylate salt. As written, the dependency may create an ambiguity:

If interpreted literally, claims 5 and 6 depend on the broad salt claim.
If interpreted in context, they appear intended to narrow claim 4 to less than 5% and less than 2% other isomers.

Claims 14 and 15

Claims 14 and 15 depend on claim 11, even though claim 11 is a pharmaceutical-composition claim and claim 13 is the method claim from which the limitations logically derive. This is a more significant formal defect because the claims purport to add purity limitations to a composition claim while appearing in the method-claim sequence.

Claims 17-19

Claims 17-19 refer to claims 13, 14, and 15 and limit the salt to besylate. Because claims 14 and 15 contain the apparent dependency problem, their construction could be affected by the prosecution history and any issued correction.

Claim 21

Claim 21 depends on claims 1 through 9 and limits the salts to solid form. It does not expressly state that the salt must be isolated, crystalline, non-hygroscopic, or in a particular polymorph. The likely scope is therefore broader than a conventional polymorph claim but still limited to a solid preparation satisfying the incorporated composition limitations.

These defects do not automatically invalidate the claims. Courts generally read claims in light of the specification and prosecution history, and formal errors may be addressed through correction procedures or claim construction. They would, however, create additional litigation issues concerning dependency, incorporation of limitations, and claim scope.

When did U.S. Patent 5,453,510 lose exclusivity?

The patent issued September 26, 1995. Under the transitional patent-term rules applicable to older U.S. applications, the ordinary term was generally the longer of:

17 years from issue, or
20 years from the earliest effective nonprovisional filing date.

For this patent, the 17-year issue-based date was September 26, 2012. No current enforceable exclusivity should be attributed to U.S. Patent 5,453,510 after that date.

Event	Date or status
U.S. patent issue	September 26, 1995
Ordinary 17-year issue-based expiry	September 26, 2012
Current enforceability	Expired
Current Paragraph IV relevance	None for this patent
Current patent-based generic barrier	None from this patent

Patent-term adjustment, terminal disclaimers, reexamination certificates, or other record events could alter the calculation in an individual case. The patent number and claim text alone do not establish any such event.

What is the Orange Book status of mivacurium?

Mivacurium chloride injection was approved in the United States as Mivacron under a New Drug Application. The FDA-approved product is an injectable neuromuscular blocker used as an adjunct to general anesthesia and for facilitation of tracheal intubation and controlled ventilation.

U.S. Patent 5,453,510 is not a current Orange Book barrier because the patent expired in 2012. Any historical listing would have had no continuing exclusionary effect after expiration.

The Orange Book framework is directed principally to patents and exclusivity associated with approved drug products. It does not create a new term for an expired patent, and it does not convert the patent into a current regulatory exclusivity right. FDA approval status, patent listing status, and patent enforceability are separate issues.[2]

Are Paragraph IV challenges relevant to this patent?

No current Paragraph IV challenge is material to U.S. Patent 5,453,510 because the patent has expired.

Historically, a generic applicant could have used an ANDA Paragraph IV certification if the patent had been listed for the relevant reference product and remained unexpired. A Paragraph IV certification would have required the applicant to assert that the patent was invalid, unenforceable, or not infringed. The patent's age and 2012 expiration date make any present challenge to this patent commercially academic.

The main historical litigation risks would have involved:

Whether a generic mivacurium product contained the claimed 1R-cis,1'R-cis isomer.
Whether the product contained less than 8%, 5%, or 2% other isomers.
Whether the counterion was besylate, mesylate, chloride, or another salt.
Whether an injectable liquid product infringed the method claims.
Whether the claims were enabled across the full range of physiologically acceptable salts.
Whether the claimed stereochemical purity was inherent in a prior-art manufacturing process.

Does mivacurium face biosimilar risk?

Mivacurium does not face biosimilar risk because it is a chemically synthesized small molecule, not a biological product regulated through the biosimilar pathway under section 351(k) of the Public Health Service Act.

The relevant competitive pathway is an ANDA or, depending on product differences, another small-molecule FDA pathway. The principal regulatory issues would involve pharmaceutical equivalence, bioequivalence, inactive ingredients, labeling, manufacturing controls, and injectable-product quality.

A generic applicant would generally focus on:

Mivacurium chloride rather than the patented besylate or mesylate salts, if that is the approved reference form.
The active moiety and pharmaceutically equivalent salt.
Current manufacturing and impurity specifications.
Sterile injectable production.
Labeling and clinical-use restrictions.

How strong was the patent estate?

Chemical strength

The patent had meaningful chemical specificity. The exact stereochemical configuration and isomeric purity thresholds could distinguish the claimed product from a racemic or mixed-isomer preparation.

Salt-form strength

Claims 4 and 7 provided focused protection for besylate and mesylate salts. Their value depended on whether those salts were commercially used or required for the product's pharmaceutical performance.

Formulation strength

Claims 10-12 were relatively broad because they recited a pharmaceutically acceptable carrier without specifying a narrow formulation architecture. Their strength would have depended on whether the product used the claimed salt and whether the composition claims survived written-description, enablement, and prior-art challenges.

Method strength

Claims 13-24 could have reached commercial administration of the claimed salt by injection or infusion. Method claims are often easier to avoid by changing the active salt, route, formulation, or stereochemical composition, but they can still create exposure where the marketed product necessarily satisfies every limitation.

Current strength

The patent has no current blocking strength in the United States because its term has ended. Its residual value is historical, evidentiary, or relevant to the interpretation of related family patents, not a current exclusionary right.

How does mivacurium compare with competing neuromuscular blockers?

Drug	General duration profile	Molecular category	Biosimilar issue	Primary competitive distinction
Mivacurium	Short acting	Small-molecule bis-benzylisoquinolinium	No	Rapid offset, injectable use
Succinylcholine	Very short acting	Depolarizing blocker	No	Rapid onset and offset, different mechanism
Atracurium	Intermediate acting	Benzylisoquinolinium	No	Hofmann elimination and broader historical use
Cisatracurium	Intermediate acting	Stereoisomer of atracurium family	No	More selective isomer profile
Vecuronium	Intermediate acting	Aminosteroid	No	Steroidal structure and different pharmacology
Rocuronium	Intermediate acting	Aminosteroid	No	Rapid onset and broad anesthesia use

The patent's competitive relevance was strongest against alternative mivacurium products, not against products containing atracurium, cisatracurium, rocuronium, vecuronium, or succinylcholine. Those agents do not satisfy the claimed chemical structure.

What generic launch risks remain?

Patent risk from U.S. Patent 5,453,510 is effectively zero after expiration. Residual launch barriers would be regulatory and manufacturing barriers rather than patent exclusivity.

Manufacturing and quality barriers

Sterile injectable products present practical barriers, including:

Control of stereoisomeric composition.
Quantification of related substances and degradants.
Control of residual solvents and counterions.
Sterile filtration or aseptic processing.
Container-closure integrity.
Stability in the proposed commercial package.
Consistent concentration and pH.
Scalable synthesis of the bis-quaternary compound.

These requirements can delay entry even where no patent blocks launch. They do not extend the expired patent term.

Geographic coverage

U.S. expiry does not establish expiry in other jurisdictions. Foreign counterparts may have:

Different filing dates.
Different claim scope.
Supplementary protection certificates.
Patent-term extensions.
National-phase prosecution outcomes.
Separate litigation histories.

The U.S. patent cannot be used to infer current rights in Europe, Canada, Japan, or other markets.

What litigation and settlement issues affect the patent?

No litigation or settlement should be attributed to U.S. Patent 5,453,510 without a verified court docket or settlement record. The claim text alone does not establish that a Paragraph IV case, infringement action, or license agreement occurred.

A commercial assessment should distinguish among:

Patent litigation involving the base mivacurium compound.
Litigation involving stereoisomer purity.
Litigation involving salt selection.
Litigation involving an approved injectable formulation.
Litigation involving manufacturing-process patents.
Regulatory exclusivity or supply agreements unrelated to this patent.

The expiration of this patent removes the need for a current license to practice its U.S. claims. It does not resolve ownership or enforceability questions for other members of the same patent family.

Key Takeaways

U.S. Patent 5,453,510 covers purified 1R-cis,1'R-cis mivacurium salts.
The principal purity thresholds are less than 8%, less than 5%, and less than 2% other geometric or optical isomers.
Besylate and mesylate salts receive separate claim treatment.
Pharmaceutical compositions, solid forms, and injectable neuromuscular-blockade methods are also claimed.
The claims contain apparent dependency and drafting errors, particularly claims 5, 6, 14, and 15.
The patent issued September 26, 1995 and ordinarily expired September 26, 2012.
It creates no current U.S. patent barrier to generic mivacurium.
Mivacurium is a small molecule and does not present a biosimilar pathway issue.
Current commercial barriers are more likely to involve sterile injectable manufacturing, regulatory approval, supply, and product quality.
Expiration of the U.S. patent does not establish the status of foreign counterparts or related process and formulation patents.

FAQs About U.S. Patent 5,453,510 and Mivacurium

Is U.S. Patent 5,453,510 a composition-of-matter patent?

It is a composition patent directed to a defined stereoisomerically purified mivacurium salt, rather than an unrestricted claim to every form of mivacurium.

Does the patent cover mivacurium chloride?

Claim 1 is not limited to chloride and may encompass a physiologically acceptable salt if all structural and purity limitations are met. Claims 4 and 7 are specifically directed to besylate and mesylate.

Can a generic avoid the patent by using a different counterion?

Historically, a different counterion could avoid the salt-specific claims, but it would not necessarily avoid claim 1 if the alternative salt were physiologically acceptable and satisfied the remaining limitations.

Is a purified stereoisomer automatically protected by this patent?

No. The product must have the claimed molecular structure, stereochemistry, salt characteristics, and isomeric purity. A different stereoisomer or unrelated neuromuscular blocker would not fall within the claims.

Does patent expiration eliminate FDA approval requirements?

No. Expiration removes the patent barrier but does not eliminate ANDA requirements, pharmaceutical-equivalence standards, bioequivalence requirements, sterile manufacturing obligations, or FDA approval requirements.

References

U.S. Patent No. 5,453,510. (1995). Mivacurium salts and pharmaceutical compositions. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations (Orange Book). U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (1992). Mivacron (mivacurium chloride injection) prescribing information. U.S. Department of Health and Human Services.
United States Code, 35 U.S.C. §§ 154, 156, and 271. Patent term, patent-term extension, and infringement provisions.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9015473	Jul 13, 1990

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	138369	⤷ Start Trial
Australia	1134695	⤷ Start Trial
Australia	687481	⤷ Start Trial
Australia	8190491	⤷ Start Trial
Belgium	1003407	⤷ Start Trial
Canada	2087104	⤷ Start Trial
Switzerland	683427	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,453,510