US Patent 3,950,333: Scope, Claims, Expiration, and Cimetidine Patent Landscape

US Patent 3,950,333 covers a broad genus of substituted guanidine compounds, including cimetidine and multiple imidazole, pyrazole, pyrazine, and pyridazine analogs. The patent was assigned to SmithKline-related entities and expired in 1993 under the pre-Uruguay Round 17-year patent-term rule. It no longer creates a US barrier to generic cimetidine or to products containing the specifically claimed compounds.

The principal commercial compound within the claims is cimetidine, also known as Tagamet. Cimetidine received FDA approval in 1977 and is now available from multiple generic manufacturers. The patent remains important historically because it covered the chemical class that produced the first major H2-receptor antagonist product, but it has no current exclusionary force in the United States.[1][2]

What does US Patent 3,950,333 cover?

US 3,950,333 claims substituted guanidines connected through a two- or three-carbon chain to an unsaturated nitrogen heterocycle. The claimed heterocycle may be:

Imidazole
Pyrazole
Pyrimidine
Pyrazine
Pyridazine

The central structural arrangement is:

An unsaturated nitrogen-containing heterocycle.
A carbon-linked oxygen, sulfur, or amino bridge.
A two- or three-carbon chain.
A substituted guanidine terminal group.
Optional salts, including pharmaceutically acceptable addition salts.

The patent therefore claims a chemical genus rather than a single drug. Claims 8 through 22 identify individual compounds within that genus.

What are the principal structural limitations?

The supplied claim language imposes the following principal limitations:

Element	Scope
Heterocycle	Imidazole, pyrazole, pyrimidine, pyrazine, or pyridazine
Heterocycle substitution, X1	Hydrogen, lower alkyl, hydroxy, trifluoromethyl, benzyl, halogen, amino, or specified guanidine-related group
Heterocycle substitution, X2	Hydrogen, or lower alkyl or halogen when X1 is lower alkyl
Chain length	k = 0 to 2 and m = 2 or 3, with k + m = 3 or 4
Bridging atom, Y	Oxygen, sulfur, or NH
Guanidine substituent, E	NR2
R1	Hydrogen, lower alkyl, or di-lower-alkylamino-lower-alkyl
R2	Hydrogen, nitro, or cyano
Salt form	Pharmaceutically acceptable addition salts
Special proviso	The X1 guanidine-related substituent is permitted only where E is NH or N-cyano

The formula image is not reproduced in the supplied text. The claim language nevertheless identifies the relevant chemical limitations and the individual compounds expressly named in claims 8 through 22.

How broad is claim 1 of US 3,950,333?

Claim 1 is the broadest independent compound claim. It covers a Markush genus defined by multiple interchangeable heterocycles, bridge atoms, chain lengths, and guanidine substitutions.

Its breadth comes from five features:

Multiple heterocyclic cores

The claim is not limited to imidazole. It extends to five distinct heteroaromatic ring systems. This creates coverage for compounds with different electronic properties and different substitution patterns.

Multiple linker atoms

The bridge designated Y may be oxygen, sulfur, or NH. The sulfur embodiment is particularly important because cimetidine contains a thioether linkage.

Variable chain length

The k and m variables allow multiple arrangements while requiring a total carbon-chain relationship of three or four atoms. This captures homologous and positional variants of the side chain.

Broad guanidine substitution

The terminal guanidine group permits hydrogen, lower alkyl, nitro, and cyano substitution, subject to the claim's proviso. The cyano-substituted guanidine is the key feature of cimetidine.

Salt coverage

Claim 1 covers pharmaceutically acceptable addition salts. Claim 9 specifically names the sulfate salt of 2-(4-imidazolylmethylthio)ethyleneguanidine.

A compound would need to satisfy the full combination of limitations. A molecule containing an imidazole and a guanidine would not automatically fall within claim 1 unless the linker, chain length, substitution pattern, and terminal nitrogen substitutions also matched the claimed formula.

Which claims specifically cover cimetidine?

Claim 8 is the principal express cimetidine claim.

Cimetidine is commonly identified as:

N-cyano-N'-methyl-N''-[2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl]guanidine
N''-cyano-N-methyl-N'-[2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl]guanidine
Cimetidine
Tagamet

The nomenclature order varies between sources because of different guanidine numbering conventions. The structural identity is the same.

Claim 7 also narrows the genus to an imidazole compound with:

X1 as hydrogen, methyl, bromo, hydroxyl, or amino
X2 as hydrogen
Y as sulfur
R1 as methyl

Claim 8 then identifies one specific compound. For cimetidine, the critical structural combination is:

Cimetidine feature	Claim limitation
5-methyl imidazole	Imidazole nucleus with methyl substitution
Methylene-thioether linkage	Y = sulfur
Ethylene chain	m = 2, with the relevant carbon-link arrangement
N-cyano guanidine	R2 = cyano
N-methyl guanidine	R1 = methyl
Neutral active ingredient	Compound claim
Salt possibilities	Covered where applicable under claim 1

Claims 10, 12, 13, 14, and 15 cover close cimetidine analogs with changes to the guanidine group or imidazole substituents.

What compounds are covered by claims 8 through 22?

The dependent and species claims identify the following compounds:

Claim	Compound type	Key structural distinction
8	Cimetidine	4-methyl-5-imidazolyl methylthioethyl N-cyano-N-methylguanidine
9	Imidazole ethyleneguanidine sulfate	4-imidazolylmethylthioethyl guanidine sulfate
10	Nitroguanidine analog	4-methyl-5-imidazole and N-nitroguanidine
11	N-ethyl cyano guanidine	Ethyl substitution
12	Bromo-imidazole analog	4-bromo-5-imidazole
13	Unsubstituted N-cyano guanidine analog	No N-methyl group on one guanidine nitrogen
14	Positional N-methyl analog	N-methyl substitution at the alternative guanidine nitrogen
15	N-propyl analog	Propyl substitution
16	1-methyl imidazole analog	Ring N-methyl substitution
17	2-imidazolyl analog	Different imidazole attachment position
18	Trifluoromethyl imidazole analog	5-trifluoromethyl-4-imidazole
19	Oxygen-linked analog	Methoxy bridge instead of sulfur
20	Pyrazole analog	3-pyrazolylmethylthioethyl
21	Pyrazine analog	2-pyrazinylmethylthioethyl
22	Pyridazine analog	3-pyridazinylmethylthioethyl

These claims protect individual compounds rather than methods of treatment, manufacturing processes, dosage forms, or formulations.

What is the patent expiration date for US 3,950,333?

US 3,950,333 issued on April 13, 1976. For a US patent filed under the pre-1995 patent-term regime, the general term was 17 years from grant. The resulting nominal expiration date was April 13, 1993.[1]

Milestone	Date
US patent grant	April 13, 1976
Nominal 17-year expiration	April 13, 1993
Current status	Expired
Current generic blocking effect	None

The patent predates the modern 20-year term measured from the earliest effective nonprovisional filing date. It therefore does not receive the ordinary term analysis applied to patents filed after June 8, 1995.

No current US patent-term extension or pediatric exclusivity can revive the expired composition claims. Any historical regulatory exclusivity associated with cimetidine also expired decades ago.

When did cimetidine lose FDA and patent exclusivity?

Cimetidine lost its principal US patent protection in 1993. FDA approval occurred in 1977, and generic competition followed after the relevant patent barriers ended.

Event	Approximate timing
Cimetidine FDA approval	1977
Initial Tagamet commercial period	Late 1970s
US 3,950,333 expiration	April 1993
Generic cimetidine availability	1990s onward
Current product status	Generic, approved under ANDA pathways

The FDA Orange Book lists approved cimetidine drug products and historically listed patents associated with approved products. Expired patents may remain useful for historical regulatory analysis, but they do not prevent ANDA approval today.[2]

What is the Orange Book status of cimetidine?

Cimetidine is an approved small-molecule drug. Its generic products are reviewed through abbreviated new drug applications rather than the biosimilar pathway.

The relevant regulatory characteristics are:

Regulatory issue	Cimetidine status
FDA product type	Small-molecule drug
Reference product	Tagamet
Generic pathway	ANDA under section 505(j)
Biosimilar pathway	Not applicable
Orange Book role	Reference listed drug and patent-history resource
Current listed patent barrier from US 3,950,333	None because expired
Paragraph IV relevance	Historical only for expired patent claims

A current cimetidine ANDA applicant would not need to make a Paragraph IV certification against US 3,950,333 because the patent is expired. Paragraph IV certifications are used when an applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed before expiration. An expired patent does not present a current launch restriction.[2][3]

Were there Paragraph IV challenges to cimetidine?

Cimetidine was exposed to generic competition after the expiration of its core patent estate. Any historical Paragraph IV activity would have concerned patents still listed and unexpired at the time of the ANDA filing, rather than the expired US 3,950,333 patent itself.

For present purposes:

US 3,950,333 cannot support a current Paragraph IV dispute.
A generic applicant cannot infringe an expired claim by launching after expiration.
Historic litigation must be analyzed against the patent and product dates applicable at the time.
Formulation or process patents, if listed for a particular product and still unexpired at the relevant time, would have been analyzed separately from the core compound patent.

The supplied record does not identify a specific historical ANDA, challenger, district court case number, or settlement agreement tied to US 3,950,333. No such details can be attributed to this patent from the claims alone.

What formulation patents protect cimetidine products?

US 3,950,333 is a compound patent. It does not claim:

Tablets
Capsules
Syrups
Injectable compositions
Enteric coatings
Sustained-release systems
Specific excipients
Manufacturing processes
Dosage regimens
Treatment of gastric or duodenal ulcers

A later patent could have covered a formulation, salt, polymorph, manufacturing process, or delivery system. Such a patent would need to be analyzed independently. It would not expand the scope of US 3,950,333.

For generic cimetidine, formulation risk is generally limited because the product is an old, chemically stable small molecule with widely available immediate-release dosage forms. A generic applicant still must demonstrate pharmaceutical equivalence and bioequivalence to the reference product, but the presence of an old compound patent does not create a current formulation monopoly.[2][4]

Does US 3,950,333 cover methods of use?

No. The supplied claims are directed to compounds and salts.

The patent does not expressly claim:

Treating ulcers with cimetidine
Reducing gastric acid secretion
Treating gastroesophageal reflux disease
Treating Zollinger-Ellison syndrome
Administering a specified dose
Administering cimetidine for a particular patient population

A method-of-use patent would require separate claims reciting a therapeutic method. Claims 1 through 22 do not have that form.

How strong was the patent estate for cimetidine?

The core estate was strong during its effective term because claim 8 directly identified cimetidine and claim 1 covered a broader genus of related compounds. The estate had three layers of chemical protection:

A broad Markush genus in claim 1.
Narrower subgenus claims in claims 2 through 7.
Compound-specific claims in claims 8 through 22.

That structure gave the patent holder both genus and species positions. A challenger attacking only a narrow species claim could still face broader genus claims, while a challenger attacking the genus would need to address the full combination of heterocycle, linker, chain length, and guanidine limitations.

The current strength is different. The patent is legally expired. Its present value is limited to:

Historical prior-art analysis
Inventorship and priority review
Freedom-to-operate analysis for historical products
Patent-family mapping
Benchmarking of H2-antagonist discovery programs

Which companies challenged or competed with cimetidine?

Cimetidine competed first against other ulcer therapies and later against other H2-receptor antagonists.

Drug	Active ingredient	Principal originator	Commercial relationship to cimetidine
Tagamet	Cimetidine	SmithKline	First major H2 antagonist
Zantac	Ranitidine	Glaxo	Major successor H2 antagonist
Pepcid	Famotidine	Merck	Later H2 antagonist
Axid	Nizatidine	Eli Lilly	Later H2 antagonist
Generic cimetidine	Cimetidine	Multiple manufacturers	Post-expiration competition

Ranitidine and famotidine were not biosimilars or generic versions of cimetidine. They were separately patented small molecules with distinct chemical structures and independent regulatory histories.

How does the cimetidine patent estate compare with ranitidine and famotidine?

Cimetidine's estate was centered on an early chemical genus and a directly claimed commercial species. Later H2 antagonists were developed partly to improve potency, dosing frequency, tolerability, or adverse-effect profiles.

Issue	Cimetidine	Ranitidine	Famotidine
Drug class	H2 antagonist	H2 antagonist	H2 antagonist
Core patent period	Expired in 1993	Expired	Expired
FDA pathway	NDA, then ANDA generics	NDA, then ANDA generics	NDA, then ANDA generics
Biosimilar exposure	None	None	None
Current US core patent barrier	None	None	None
Main commercial issue	Low-cost generic competition	Withdrawal and safety history	Generic competition

Cimetidine's commercial differentiation declined after ranitidine and famotidine entered the market. The patent estate no longer supports a premium branded position.

What manufacturing and intellectual-property barriers remain?

The expired patent does not create a manufacturing barrier. A current manufacturer may produce cimetidine without infringing US 3,950,333, subject to compliance with other unexpired rights and regulatory requirements.

Potential technical issues include:

Control of starting-material purity
Regioselective synthesis of the substituted imidazole
Formation of the methylthioethyl side chain
Control of guanidine and N-cyano substitution
Removal of residual solvents and impurities
Salt selection and crystallization
Compliance with current Good Manufacturing Practice requirements

These are process and quality-control issues, not continuing rights under the expired patent.

Does the patent block manufacturing outside the United States?

US 3,950,333 has no current US blocking effect. Patent rights are territorial, so the US expiration does not establish the status of corresponding foreign patents.

A complete geographic freedom-to-operate analysis would require review of:

The priority family
National-phase filings
Foreign grants
Patent-term adjustments or extensions
Local supplementary protection regimes
Local litigation and settlement records

The United States patent itself cannot block manufacture or sale in Europe, Japan, China, India, or other jurisdictions.

What generic launch risks exist for cimetidine?

Current generic launch risk is low from the perspective of US 3,950,333.

Risk category	Current assessment
Core compound patent	No risk; expired
Paragraph IV litigation	No current risk from this patent
Biosimilar litigation	Not applicable
Formulation patent risk	Product-specific; generally limited for immediate-release products
Method-of-use risk	Not created by the supplied claims
Manufacturing patent risk	Requires separate process-patent review
Regulatory risk	ANDA quality, equivalence, labeling, and manufacturing compliance
Commercial risk	Low margins and established generic competition

The principal commercial risk is not patent exclusivity. It is commodity pricing, supply reliability, FDA manufacturing compliance, and the continuing market position of competing acid-suppression products.

What is the revenue exposure associated with US 3,950,333?

The patent supported the historical Tagamet franchise, which became one of the first blockbuster H2-antagonist products. The patent's commercial value was concentrated in the period before generic entry and before later H2 antagonists displaced part of the market.

There is no current branded revenue protected by US 3,950,333. Any present cimetidine revenue is attributable to generic sales, legacy retail demand, and institutional use rather than enforceable exclusivity.

A precise revenue estimate requires historical company-level sales data and a defined period. The patent record and claim text do not establish a reliable figure.

Key Takeaways

US 3,950,333 is a broad chemical genus patent for substituted guanidines linked to imidazole and related heterocycles.
Claim 8 expressly covers cimetidine.
The patent also claims numerous cimetidine analogs, including nitroguanidines, cyano guanidines, bromo-imidazoles, oxygen-linked compounds, pyrazoles, pyrazines, and pyridazines.
The patent issued on April 13, 1976, and nominally expired on April 13, 1993.
The claims are composition claims, not formulation, manufacturing, method-of-use, or dosage claims.
No current Paragraph IV challenge is relevant to the expired patent.
Cimetidine is regulated as an old small-molecule drug through the ANDA pathway, not the biosimilar pathway.
The patent has no current US generic launch-blocking effect.
Current risk analysis should focus on separately issued formulation, process, salt, polymorph, and product-specific patents, not US 3,950,333.

FAQs

Is cimetidine still protected by a US patent?

No. The core US patent identified in the claims, US 3,950,333, expired in 1993. Cimetidine is available from multiple generic manufacturers.

Does claim 8 of US 3,950,333 cover Tagamet?

Yes. Claim 8 identifies the compound generally known as cimetidine, the active pharmaceutical ingredient in Tagamet.

Can a company file an ANDA for cimetidine without addressing US 3,950,333?

Yes. Because US 3,950,333 is expired, it does not require a current Paragraph IV certification or create a patent-based delay to approval.

Are cimetidine salts covered by US 3,950,333?

Claim 1 includes pharmaceutically acceptable addition salts. Claim 9 specifically identifies a sulfate salt of an imidazole ethyleneguanidine compound.

Does US 3,950,333 cover ranitidine or famotidine?

No. Ranitidine and famotidine are chemically distinct H2 antagonists. Their patent rights were governed by separate patent families.

References

United States Patent and Trademark Office. (1976). US Patent No. 3,950,333, substituted guanidines. U.S. Department of Commerce.
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 submissions: Patent certifications and exclusivity. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	197080	⤷ Start Trial
Argentina	197093	⤷ Start Trial
Australia	3900972	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 3,950,333

Summary for Patent: 3,950,333