United States Patent 4,094,966: Claim Scope, Expiration, and Iodinated Contrast-Media Patent Landscape

U.S. Patent 4,094,966 covers a class of highly iodinated benzene derivatives, three specifically identified derivatives, and aqueous X-ray contrast media containing those compounds or their pharmaceutically acceptable salts. The patent issued on July 11, 1978, and its original 17-year U.S. patent term expired on July 11, 1995. It therefore presents no current U.S. patent exclusivity barrier.

What does U.S. Patent 4,094,966 claim?

The patent has three substantive claim categories:

A broad Markush genus of substituted iodobenzene derivatives.
Three specifically named chemical species and their pharmaceutically acceptable salts.
Aqueous X-ray contrast media containing the claimed compounds or salts.

The claims are directed to low- or non-ionic, water-soluble iodinated contrast agents based on a triiodinated benzene ring and multiple amide, acetamide, carbamyl, hydroxyalkyl, and aminoacetamide substituents.

Claim structure

Claim	Subject matter	Scope
1	Generic iodobenzene derivative and its salts or lower-alkyl esters	Broad chemical genus
2	Specific N-methylcarbamyl derivative	Narrow compound claim
3	Specific N-methylacetamido derivative	Narrow compound claim
4	Specific N-methylacetamido derivative with N-methyl substitution	Narrow compound claim
5	Aqueous X-ray contrast medium containing a claim 1 compound	Composition claim
6	Aqueous X-ray contrast medium containing a pharmaceutically acceptable salt	Salt-based composition claim
7	Claim 6 composition containing 5-100 grams of salt per 100 mL	Concentration-limited composition claim

How broad is claim 1?

Claim 1 is a Markush claim covering a family of substituted triiodinated benzene compounds. Its breadth comes from both the core structure and the permitted substituent alternatives.

Core chemical architecture

The claimed compounds have:

A benzene ring substituted with three iodine atoms.
An aminoacetamide-linked side-chain arrangement.
Additional amide or carbamyl-substituted iodinated phenyl groups.
A carboxylic acid group, lower-alkyl ester, or pharmaceutically acceptable salt.
Variable N-substitution, including hydrogen, lower alkyl, lower hydroxyalkyl, and lower alkanoyl groups.

The repeated triiodinated aromatic units are important. Each iodinated ring contributes three iodine atoms, producing compounds with a high iodine content suitable for X-ray attenuation.

Permitted R-group variations

The claim allows the relevant R groups to be:

Hydrogen.
Lower alkyl.
Lower hydroxyalkyl.
Lower alkanoyl.
Amide-derived substituents.
Carbamyl or hydroxyalkylcarbamyl groups.
Lower-alkyl esters at the carboxyl group.
Pharmaceutically acceptable salts.

The claim therefore covers multiple substitution patterns rather than one defined clinical compound. A compound can fall within claim 1 even if it differs from the named compounds in the identity of the amide nitrogen substituents, provided the substituted groups remain within the claimed definitions.

Functional significance

The claim does not depend on a specific diagnostic indication. It is structurally focused. The compound must have the claimed chemical architecture; it does not need to be used for angiography, urography, computed tomography, or another named procedure to satisfy the compound claim.

The composition claims add a use-related limitation. Claims 5-7 require an aqueous X-ray contrast medium containing the claimed compound or salt. A dry intermediate, a nonaqueous formulation, or a compound used outside an X-ray contrast application would not, based on the claim language alone, satisfy those composition limitations.

What compounds are specifically protected by claims 2, 3, and 4?

Claims 2-4 identify three individual derivatives. They narrow the generic scope of claim 1 by fixing particular N-substituents.

Claim 2

Claim 2 covers:

2,4,6-triiodo-3-N-methylcarbamyl-5-bis {[2,4,6-triiodo-3,5-bis(N-hydroxyethylcarbamyl)phenyl]carbamyl-methyl} aminoacetamidobenzoic acid

and its pharmaceutically acceptable salts.

The structure contains:

Two 2,4,6-triiodinated aromatic rings.
N-hydroxyethylcarbamyl substituents.
An N-methylcarbamyl group.
An aminoacetamide linkage.
A terminal benzoic acid group.

Claim 3

Claim 3 covers the corresponding N-methylacetamido derivative:

2,4,6-triiodo-3-N-methylacetamido-5-bis {[2,4,6-triiodo-3,5-bis(N-hydroxyethylcarbamyl)phenyl]carbamyl-methyl} aminoacetamidobenzoic acid

and its salts.

The key distinction from claim 2 is the replacement of the N-methylcarbamyl functionality with an N-methylacetamido group.

Claim 4

Claim 4 covers:

2,4,6-triiodo-3-N-methylcarbamyl-5-bis {[2,4,6-triiodo-3,5-bis(N-hydroxyethylcarbamyl)phenyl]carbamyl-methyl} amino-N-methylacetamidobenzoic acid

and its salts.

Claim 4 adds N-methyl substitution to the aminoacetamide portion. That alteration creates a separate specifically claimed species rather than relying solely on the broad genus in claim 1.

What formulations are protected by claims 5-7?

Claims 5-7 cover aqueous X-ray contrast media.

Claim 5

Claim 5 requires:

An aqueous solution.
An effective amount of a compound within claim 1.
Use as an X-ray contrast medium.

The claim does not specify a concentration range, pH, osmolarity, excipient, container, injection route, or diagnostic procedure.

Claim 6

Claim 6 covers an aqueous solution containing a pharmacologically acceptable salt of a claim 1 compound. This language is important because the claimed compounds contain a carboxylic acid group and can be formulated as salts to improve water solubility.

Claim 7

Claim 7 limits claim 6 to a solution containing:

At least 5 grams of salt per 100 mL; and
No more than 100 grams of salt per 100 mL.

This corresponds to a concentration range of 5% to 100% weight per volume, subject to the precise interpretation of the claim’s stated measurement basis.

The formulation claims do not expressly claim:

A prefilled syringe.
A vial or bottle.
A specific preservative.
A surfactant.
A particular injection device.
A particular imaging protocol.
A defined osmolality or viscosity.
A manufacturing process.

Those omissions limit the formulation scope compared with later contrast-agent patents that claimed pharmaceutical presentations, excipient systems, pH control, sterilization, or ready-to-use containers.

When did U.S. Patent 4,094,966 lose exclusivity?

U.S. Patent 4,094,966 issued July 11, 1978. Under the pre-Uruguay Round patent regime, the patent term was generally 17 years from issuance. On that basis, the patent expired July 11, 1995. [1]

Event	Date
U.S. patent issued	July 11, 1978
Original statutory term	17 years from issuance
Expected expiration	July 11, 1995
Current enforceability	Expired
Patent term extension relevance	None apparent for this patent
Current blocking value	None in the United States

The patent is too old to support a present-day U.S. infringement action. Any continuation, divisional, or foreign-family patent would require separate review. The claims supplied do not establish a live related patent.

Does the patent have Orange Book significance?

The patent is not, by itself, an Orange Book-listed exclusivity right. FDA Orange Book listing applies to patents submitted for approved drug products under the Hatch-Waxman framework, including qualifying patents covering the active ingredient, formulation, composition, or approved method of use. [2]

For an old iodinated contrast agent, the commercial relevance of an Orange Book listing would depend on:

Whether the specific compound received an FDA-approved new drug application.
Whether the patent was submitted to FDA for that product.
Whether the listed patent remained unexpired during the product’s marketed life.
Whether an abbreviated new drug application pathway existed for the relevant product.

Because U.S. Patent 4,094,966 expired in 1995, it cannot create current Orange Book patent protection. It also cannot support a current Paragraph IV challenge. A Paragraph IV certification would be legally immaterial against this patent because there is no remaining enforceable term. [3]

Were Paragraph IV challenges or settlements likely to affect this patent?

No current Paragraph IV risk exists against U.S. Patent 4,094,966.

A Paragraph IV certification addresses an unexpired patent listed for an approved reference drug. The patent’s 1995 expiration eliminates the basic legal predicate for a present challenge. Any historical ANDA activity would have occurred after the patent had expired or near the end of its term and would not create current litigation exposure.

The supplied information does not establish:

A Paragraph IV notice letter.
An ANDA litigation docket.
A patent settlement.
A consent judgment.
A license agreement.
A covenant not to sue.

No such transaction should be inferred from the claim text.

How strong is the patent estate?

Scope strength

The patent had meaningful historical breadth because claim 1 covered a genus of structurally related iodinated compounds, while claims 2-4 protected selected species. Claims 5-7 extended coverage into aqueous contrast-media formulations.

Its strongest historical features were:

Multiple triiodinated aromatic rings.
A defined family of hydroxyalkylcarbamyl and aminoacetamide substituents.
Coverage of both free-acid and salt forms.
Composition claims directed to the commercial use of the compounds.
A concentration-specific dependent claim.

Scope limitations

The patent also had material limitations:

The Markush definitions constrain the permitted substituents.
The claim requires a particular iodinated benzene framework.
The composition claims require an aqueous X-ray contrast medium.
Claim 7 requires the stated concentration range.
The claims do not broadly cover all iodinated contrast media.
They do not cover unrelated monomeric triiodobenzoic acids merely because those compounds are used for imaging.
They do not cover every dimeric iodinated contrast agent.

The patent’s current strength is zero as an exclusionary right because the term has expired. Its remaining value is historical, technical, and potentially relevant to prior-art analysis.

How does this patent compare with competing contrast-agent patent estates?

U.S. Patent 4,094,966 belongs to an earlier generation of iodinated contrast-agent patents. The relevant competitive field included ionic monomeric agents, ionic dimeric agents, nonionic monomers, and later nonionic dimers.

Contrast-agent group	Representative examples	Typical patent focus
Ionic monomers	Diatrizoate, iothalamate, metrizoate	Triiodobenzoic acid salts and injectable solutions
Ionic dimers	Iodipamide, ioglycamic acid, ioxaglic acid	Dimeric iodinated structures and lower toxicity
Nonionic monomers	Iohexol, iopamidol, iopromide, ioversol, ioxilan	Hydroxyalkyl amides, low osmolality, water solubility
Nonionic dimers	Iodixanol	Dimeric nonionic structures and iso-osmolar formulations

The patent at issue is structurally closer to dimeric iodinated contrast-agent technology than to simple diatrizoate-type agents. Its hydroxyethylcarbamyl groups indicate an effort to increase hydrophilicity and reduce the ionic burden of the molecule.

Later patent estates generally claimed:

More specific nonionic substitution patterns.
Improved osmolality profiles.
Pharmaceutical formulations.
Manufacturing and purification processes.
Stability and sterilization conditions.
Specific clinical uses.
Ready-to-administer presentations.

Those later estates should be analyzed separately. Structural similarity does not establish literal infringement, particularly where the later compound changes the aminoalkyl, hydroxyalkyl, amide, or linker arrangement.

What manufacturing and IP barriers did the patent create?

During its term, the patent could have affected manufacture of compounds containing:

Multiple triiodinated aromatic rings.
The claimed aminoacetamide linkages.
N-hydroxyethylcarbamyl groups.
The specified N-methylcarbamyl or N-methylacetamido substituents.
Salts used in aqueous injection products.

The manufacturing burden for these agents would also have created practical barriers independent of the patent. Relevant technical steps include:

Controlled iodination of aromatic intermediates.
Protection and deprotection of amino and hydroxy groups.
Formation of multiple amide bonds.
Control of regioisomeric impurities.
Removal of residual iodine-containing intermediates.
Salt formation and pH adjustment.
Sterile filtration or terminal sterilization.
Control of endotoxins, particulate matter, and degradation products.

Those process barriers do not expand the legal scope of the claims. A process patent would need separate claim analysis. The supplied claims do not expressly cover a manufacturing method.

What generic launch risks exist today?

There is no current U.S. generic-launch risk arising from this patent. The patent expired approximately three decades ago.

A modern entrant would instead need to assess:

FDA approval requirements for the specific contrast agent.
Whether the product is an NDA drug, an ANDA-eligible product, or subject to another FDA pathway.
Current formulation, process, device, and method-of-use patents.
Drug Master File and supplier dependencies.
CMC requirements for iodine-containing impurities.
Clinical and postmarketing requirements.
Product-specific patent listings unrelated to U.S. Patent 4,094,966.

Contrast agents are small-molecule drugs, so biosimilar risk is not applicable. A biosimilar pathway under section 351(k) of the Public Health Service Act is intended for biological products, not conventional iodinated small-molecule contrast media. [4]

What is the geographic coverage?

The supplied claims are U.S. claims only. They have no direct legal effect in:

Canada.
Europe.
Japan.
China.
India.
Australia.
Any other foreign jurisdiction.

A corresponding foreign-family patent could have had different claims, prosecution history, term, or expiration date. Foreign protection cannot be inferred from the U.S. patent number or the U.S. claim language.

Key Takeaways

U.S. Patent 4,094,966 claims a genus of substituted triiodinated benzene derivatives.
Claims 2-4 protect three specifically identified chemical species and their pharmaceutically acceptable salts.
Claims 5-7 cover aqueous X-ray contrast media, including a 5-100 g/100 mL salt concentration range in claim 7.
The patent issued July 11, 1978, and expired July 11, 1995.
It creates no current U.S. patent blocking position.
It cannot support a current Paragraph IV challenge or patent litigation.
It is not a biosimilar-relevant patent because the claimed products are small-molecule contrast agents.
Its remaining commercial value is limited to historical technology, prior-art analysis, and possible identification of related patent-family developments.
Current freedom-to-operate analysis must focus on later compound, formulation, process, device, and method-of-use patents.

FAQs

Is U.S. Patent 4,094,966 still enforceable?

No. Based on its 1978 issue date and the pre-1995 17-year patent term, it expired in 1995.

Does the patent cover all iodinated X-ray contrast agents?

No. It covers a defined genus of substituted triiodinated benzene derivatives and aqueous compositions containing those compounds or salts.

Can a pharmaceutically acceptable salt infringe the patent?

It could have fallen within the claims during the patent term because claims 1-4 expressly include pharmaceutically acceptable salts. The patent is now expired.

Does claim 7 protect a particular commercial formulation?

Claim 7 protects an aqueous solution containing 5-100 grams of the claimed salt per 100 mL. It does not claim a particular vial, syringe, excipient, pH, or injection device.

Is this patent relevant to current iodixanol, iohexol, or iopamidol launches?

Not as an enforceable patent. Structural or commercial comparisons may be relevant to prior-art and historical landscape work, but current launch risk would depend on later unexpired patents and FDA requirements.

References

U.S. Patent No. 4,094,966. (1978). Iodobenzene derivatives and X-ray contrast media containing them. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Code, 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.
U.S. Code, 42 U.S.C. § 262(k). Licensure of biological products as biosimilars.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	205196	⤷ Start Trial
Argentina	207465	⤷ Start Trial
Austria	343638	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,094,966

Summary for Patent: 4,094,966