United States Patent 5,418,226: Rocuronium Bromide Claims, Scope, Expiration, and Patent Landscape

U.S. Patent No. 5,418,226 covers monoquaternary 2,16-bispiperidinylandrostane neuromuscular blockers, including rocuronium bromide. Its strongest commercial claim is claim 2 combined with claim 3, which reaches the active pharmaceutical ingredient used in ZEMURON and generic rocuronium bromide injection. The patent issued May 23, 1995, and its ordinary 17-year term expired May 23, 2012, subject to any applicable patent-term adjustment or disclaimer. The patent therefore does not create a current U.S. barrier to generic rocuronium entry. [1]

What drug does U.S. Patent 5,418,226 cover?

U.S. Patent 5,418,226 is directed to steroidal, monoquaternary neuromuscular blocking agents. The principal commercial compound associated with the patent is rocuronium bromide.

Rocuronium is a nondepolarizing neuromuscular blocker used as an intravenous adjunct to general anesthesia. It produces skeletal-muscle paralysis by competitively antagonizing acetylcholine at the neuromuscular junction. ZEMURON is the original branded rocuronium bromide injection approved by the FDA. [2]

The patent claims a chemical class rather than only a named compound. The structure is a 2,16-bispiperidinylandrostane derivative with one permanently charged quaternary nitrogen center. The claims specify:

Claim variable	Scope
R1	Ethyl
R2	Methyl or allyl
X-	Pharmaceutically acceptable anion
Preferred anion in claim 3	Bromide
Dosage-form coverage	Pharmaceutical composition
Therapeutic coverage	Method of producing neuromuscular blockade

Rocuronium bromide corresponds to the compound in which R1 is ethyl, R2 is allyl, and the counterion is bromide.

What are the key claims of U.S. Patent 5,418,226?

Claim 1: genus-level chemical claim

Claim 1 covers a monoquaternary 2,16-bispiperidinylandrostane derivative with:

An ethyl substituent at the position represented by R1;
Either a methyl or allyl substituent at the position represented by R2; and
A pharmaceutically acceptable anion.

The claim therefore covers at least two principal chemical embodiments:

The R2 methyl embodiment; and
The R2 allyl embodiment, corresponding to rocuronium when paired with bromide.

Claim 1 is limited to the specific steroidal core and substitution pattern shown in the patent drawing. It does not cover all neuromuscular blockers, all steroidal muscle relaxants, or all piperidinium compounds.

The phrase “or a pharmaceutically acceptable salt thereof” has limited additional value in the context of a quaternary ammonium compound. The counterion is already expressly defined through X-. Its practical effect is to preserve coverage for pharmaceutically acceptable salt or ionic forms recognized under the claim construction.

Claim 2: rocuronium-type chemical subgenus

Claim 2 narrows claim 1 by requiring R2 to be allyl. It retains the requirements that R1 be ethyl and that X- be a pharmaceutically acceptable anion.

This is the principal compound claim for rocuronium-type molecules. It covers rocuronium with different pharmaceutically acceptable counterions, not only bromide.

Claim 3: bromide limitation

Claim 3 narrows claim 1 by specifying bromide as the anion. Because it depends directly on claim 1, it covers both:

The R2 methyl, bromide embodiment; and
The R2 allyl, bromide embodiment.

The rocuronium bromide product is within claim 3 because it has the required ethyl substituent, allyl substituent, steroidal bispiperidinylandrostane structure, and bromide counterion.

Claim 4: pharmaceutical composition

Claim 4 covers a pharmaceutical composition containing:

An effective amount of a compound within claim 1; and
A pharmaceutically acceptable diluent or auxiliary.

This claim reaches injectable formulations containing the claimed active ingredient. It does not require a particular concentration, vial size, buffer, preservative, container, or administration route, unless those limitations are imposed by the incorporated claim language or the specification.

The claim is broader than the commercial ZEMURON formulation because it is not limited to the precise excipient system used in the approved product. FDA labeling identifies rocuronium bromide injection as an intravenous formulation containing excipients such as sodium acetate, acetic acid, and water for injection. [2]

Claim 5: method-of-use claim

Claim 5 covers administering an effective amount of a claim 1 compound to a patient to produce neuromuscular blocking activity.

The method claim is functional. It does not require a particular surgical procedure, induction protocol, patient population, dose, infusion rate, reversal agent, or anesthesia regimen. The central limitations are:

Administration to a patient;
An effective amount; and
The resulting neuromuscular blocking activity.

The claim can therefore reach clinical use of the covered chemical compounds even if the product is administered under a different dosing protocol from that used in the original branded label.

How broad is the patent’s chemical scope?

The chemical scope is narrower than the product name “rocuronium” might suggest and broader than a claim limited to rocuronium bromide alone.

Embodiment	Covered by claim 1?	Covered by claim 2?	Covered by claim 3?
Ethyl R1, methyl R2, bromide	Yes	No	Yes
Ethyl R1, allyl R2, bromide	Yes	Yes	Yes
Ethyl R1, allyl R2, non-bromide pharmaceutically acceptable anion	Yes	Yes	No
Ethyl R1, methyl R2, non-bromide anion	Yes	No	No
R1 other than ethyl	No	No	No
R2 other than methyl or allyl	No	No	No
Non-steroidal neuromuscular blocker	No	No	No

The claims do not cover structurally distinct agents such as succinylcholine, atracurium, cisatracurium, mivacurium, pancuronium, or vecuronium merely because those drugs have neuromuscular blocking activity. Chemical identity remains essential.

What formulation patents protect rocuronium injection?

U.S. Patent 5,418,226 contains a composition claim, but it is not a narrow formulation patent in the conventional sense. Claim 4 does not recite a defined excipient combination or a specific stability profile. It covers a pharmaceutical composition containing an effective amount of the claimed compound and a pharmaceutically acceptable diluent or auxiliary.

The claim does not expressly require:

A specific pH;
Sodium acetate;
Acetic acid;
A particular concentration;
A preservative-free formulation;
A sealed glass vial;
Refrigerated storage;
A specified injection volume; or
A particular manufacturing process.

That breadth gave the composition claim practical relevance against products containing a covered active ingredient during the patent term. After expiration, it no longer creates an enforceable barrier.

The patent also does not appear, from the claims provided, to cover a separate crystalline form, polymorph, particle-size distribution, container system, or manufacturing process. Those categories would require separate claim language.

What is the patent expiration date?

The patent issued May 23, 1995. For a pre-June 8, 1995 application, the ordinary U.S. term generally was 17 years from issuance under the patent statute then in effect. On that basis, the ordinary expiration date was May 23, 2012. [1]

Event	Date
U.S. patent application filed	1993-era filing, according to the patent record
Patent issued	May 23, 1995
Ordinary 17-year patent expiration	May 23, 2012
FDA approval of ZEMURON	December 27, 1994
Five-year NCE exclusivity period	Approximately through December 27, 1999
Current enforceability of the patent	Expired

Patent-term restoration under 35 U.S.C. § 156 generally depends on regulatory review of the patented product and statutory eligibility. The public Orange Book entry is the controlling source for any listed patent-term extension or pediatric extension associated with the approved product. [3]

A six-month pediatric exclusivity period, if granted for the product, would have extended regulatory protection but would not have revived an expired composition patent as an enforceable patent right. Pediatric exclusivity blocks certain FDA approvals during the exclusivity period; it does not extend the underlying patent term. [3]

What is the FDA Orange Book status of rocuronium bromide?

ZEMURON was approved under NDA 019923 as an intravenous rocuronium bromide product. The FDA Orange Book identifies patent and exclusivity information for approved drug products and is the principal regulatory source for determining whether a listed patent remains relevant to ANDA approval. [2, 3]

The commercial significance of U.S. Patent 5,418,226 has ended because the patent expired in 2012. Any current generic applicant does not need to wait for that patent to expire and would not ordinarily need to rely on a Paragraph IV certification against an already expired patent.

The Orange Book analysis should distinguish:

Patent expiration;
FDA regulatory exclusivity;
Patent listing status;
Approved labeling;
Any separate unexpired patent covering a later formulation or use.

An expired Orange Book patent does not prevent approval of an ANDA. The remaining requirements include pharmaceutical equivalence, bioequivalence, chemistry, manufacturing and controls, labeling, facility compliance, and applicable FDA review standards. [3, 4]

Were there Paragraph IV challenges to U.S. Patent 5,418,226?

A Paragraph IV certification is used when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. It is not required to challenge a patent that has already expired.

For rocuronium bromide, the principal product patent expired before the modern generic market developed. That timing reduced the commercial need for a Paragraph IV campaign against U.S. Patent 5,418,226.

No material current Paragraph IV risk remains against this patent. A historical ANDA filing could have involved a Paragraph IV certification if the filing occurred before May 23, 2012, but the expiration date would have eliminated the practical value of continued litigation. The relevant risk for current products is regulatory approval and manufacturing compliance, not enforcement of this patent.

What patent litigation affects rocuronium bromide?

U.S. Patent 5,418,226 is no longer an effective litigation asset because it has expired. An expired patent cannot support an injunction against current generic manufacture, sale, or use.

The principal litigation questions are therefore historical:

Whether an ANDA applicant filed before expiration;
Whether the applicant made a Paragraph IV certification;
Whether the patent owner asserted infringement;
Whether any case ended in settlement; and
Whether a court issued a judgment affecting launch timing.

The patent’s expiration removes the need to resolve those issues for present generic entry. Any current dispute would more likely involve a different patent, product quality, trade dress, contract rights, regulatory exclusivity, or manufacturing technology.

Which companies compete with rocuronium bromide?

The competitive landscape has two layers.

Direct generic competition

Generic rocuronium bromide injection competes with ZEMURON and other approved injectable products. Generic manufacturers and suppliers have included companies such as Fresenius Kabi, Hikma, Pfizer or Hospira-related entities, and other FDA-approved ANDA holders depending on the product presentation and market period.

The relevant competitive advantages are usually:

Hospital formulary access;
Reliable sterile manufacturing;
Shortages and supply continuity;
Vial and presentation economics;
Wholesaler contracting;
FDA inspection history; and
Pricing.

Because rocuronium is an injectable hospital product, generic substitution is driven less by retail pharmacy dynamics and more by institutional purchasing and supply reliability.

Therapeutic alternatives

Rocuronium competes clinically with other nondepolarizing neuromuscular blockers, including vecuronium, pancuronium, atracurium, and cisatracurium. Succinylcholine is a depolarizing alternative used in certain rapid-sequence and emergency settings.

The comparison is clinical rather than patent-based:

Product	Class	Patent relevance of US 5,418,226
Rocuronium bromide	Nondepolarizing aminosteroid	Directly covered
Vecuronium	Nondepolarizing aminosteroid	Not covered merely by class
Pancuronium	Bisquaternary aminosteroid	Not covered by these claims
Atracurium	Benzylisoquinolinium	Not covered
Cisatracurium	Benzylisoquinolinium	Not covered
Succinylcholine	Depolarizing blocker	Not covered

What generic entry risks remain?

The patent risk is low because the principal patent is expired. The remaining commercial risks are operational and regulatory.

Manufacturing and sterile-product barriers

Rocuronium bromide is an injectable sterile product. A generic applicant must establish:

Active pharmaceutical ingredient identity and purity;
Sterile manufacturing controls;
Container-closure integrity;
Stability through the labeled shelf life;
Particulate and endotoxin control;
Consistent strength and pH;
Validated aseptic processing; and
FDA-compliant facilities.

These requirements can limit the number of reliable suppliers even when patent protection has ended.

API and process know-how

The patent claims the compound and pharmaceutical use, not every method of producing it. Process patents, trade secrets, supplier relationships, and scale-up know-how can still affect cost and supply. Such barriers are commercial rather than a direct continuation of the expired claims.

Labeling and substitution

An ANDA applicant must demonstrate pharmaceutical equivalence and bioequivalence or satisfy the applicable FDA requirements for injectable products. Labeling differences, preservative status, vial configuration, and dosage presentation can affect hospital purchasing even where the active ingredient is the same. [4]

How strong is the patent estate for rocuronium?

The patent estate was strong during its enforceable term because one patent combined:

A compound claim;
A preferred allyl embodiment;
A bromide limitation;
A pharmaceutical composition claim; and
A therapeutic method claim.

That structure created multiple infringement theories against a rocuronium bromide product. The estate is weak for current enforcement because the central patent expired in 2012 and the provided claims do not identify an unexpired continuation, formulation patent, method-of-use patent, or manufacturing patent.

Category	Assessment
Active ingredient patent	Expired
Composition claim	Expired
Method-of-use claim	Expired
Specific bromide claim	Expired
Current Paragraph IV exposure	Low or none for this patent
Current biosimilar exposure	Not applicable
Injectable manufacturing barrier	Material but non-patent-specific
Current generic launch barrier	Regulatory and supply-chain driven

Is biosimilar risk relevant to rocuronium?

No. Rocuronium bromide is a chemically synthesized small-molecule drug, not a biologic. It is approved through the conventional drug framework and competes through generic ANDA products rather than biosimilars under the Public Health Service Act.

The relevant FDA pathway is an ANDA or, in some circumstances, a full NDA. The Purple Book biosimilar framework does not apply. [4, 5]

What does the patent mean for revenue exposure?

The patent protected the branded commercial franchise during the period before generic entry. Once the patent expired, revenue exposure shifted from legal exclusivity to price erosion and hospital contracting.

For a hospital injectable, revenue erosion can be rapid when:

Multiple ANDA products are approved;
Wholesalers qualify more than one supplier;
The product is therapeutically substitutable;
Supply is stable; and
The branded product has no separate unexpired formulation or use patent.

The patent itself does not support a current premium for ZEMURON. Any remaining brand value would depend on supply assurance, contracting, clinical familiarity, shortage conditions, and manufacturer-specific purchasing agreements.

Key Takeaways

U.S. Patent 5,418,226 covers monoquaternary 2,16-bispiperidinylandrostane neuromuscular blockers.
Rocuronium bromide is within the scope of claims 1, 2, 3, 4, and 5.
Claim 2 is the principal allyl-substituted rocuronium-type compound claim.
Claim 3 specifically reaches the bromide salt.
Claim 4 covers pharmaceutical compositions containing the claimed compound.
Claim 5 covers therapeutic administration to produce neuromuscular blockade.
The patent issued May 23, 1995, and its ordinary term expired May 23, 2012.
The patent is no longer a current barrier to generic rocuronium bromide approval or launch.
Rocuronium is a small molecule, so biosimilar analysis does not apply.
Current market barriers are sterile manufacturing, API supply, FDA compliance, hospital contracting, and product reliability.
Any current exclusivity analysis must examine Orange Book records for separate unexpired patents or regulatory protections, not U.S. Patent 5,418,226 alone.

FAQs

Does U.S. Patent 5,418,226 cover rocuronium bromide specifically?

Yes. Rocuronium bromide falls within the ethyl-R1, allyl-R2, bromide-anion embodiment recited by claims 2 and 3.

Can a generic company launch rocuronium bromide without challenging this patent?

Yes. The patent expired in 2012. A current applicant does not need to invalidate or avoid an enforceable claim in this patent.

Is rocuronium bromide protected by a biologic patent or biosimilar pathway?

No. Rocuronium bromide is a synthetic small molecule regulated through the conventional drug and ANDA framework.

Does claim 4 cover every rocuronium injection formulation?

Claim 4 is broad because it requires a claimed active compound and a pharmaceutically acceptable diluent or auxiliary. It does not, however, cover formulations containing a structurally different active ingredient or impose every limitation of the branded formulation.

Could a new rocuronium formulation still receive patent protection?

Yes, if it satisfies patentability requirements and claims a novel, non-obvious formulation, delivery system, manufacturing process, or use. Such protection would be separate from the expired claims of U.S. Patent 5,418,226.

References

United States Patent and Trademark Office. (1995). U.S. Patent No. 5,418,226: Monoquaternary 2,16-bispiperidinylandrostane derivatives. U.S. Department of Commerce.
U.S. Food and Drug Administration. (1994). ZEMURON (rocuronium bromide) injection, prescribing information. FDA Drugs@FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application process. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products. Center for Biologics Evaluation and Research.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	92303612	Apr 22, 1992

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	145918	⤷ Start Trial
Australia	3703093	⤷ Start Trial
Australia	662277	⤷ Start Trial
Canada	2094457	⤷ Start Trial
Czech Republic	286728	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,418,226

Summary for Patent: 5,418,226