United States Drug Patent 4,014,986: Scope, Claims, Expiration, and Patent Landscape

U.S. Patent No. 4,014,986 protected iodinated benzene derivatives and aqueous X-ray contrast media containing those compounds or their pharmaceutically acceptable salts. The patent issued on March 29, 1977, and its original 17-year patent term expired on March 29, 1994. The claims therefore provide no current U.S. exclusivity, generic-entry barrier, Orange Book patent protection, or enforceable manufacturing restriction.

The patent’s commercial value was historically concentrated in dimeric, highly iodinated radiographic contrast agents, including the specifically claimed compound in claim 2. The core intellectual-property strategy combined composition-of-matter protection with claims directed to salts, aqueous formulations, concentration ranges, and use as an X-ray contrast medium.

What does U.S. Patent 4,014,986 protect?

The patent protects three related subject-matter categories:

A broad Markush genus of iodinated benzene derivatives.
A specifically identified dimeric iodinated compound.
Aqueous X-ray contrast media containing the claimed compound or its salt.

The claims cover pharmaceutical forms rather than only laboratory intermediates. Claim 1 reaches the chemical entity and certain derivatives. Claims 3 through 5 extend protection to an aqueous diagnostic formulation.

Claim	Subject matter	Principal protection
1	Markush genus of iodobenzene derivatives, lower alkyl esters, and pharmaceutically acceptable base salts	Broad chemical composition
2	Specifically named dimeric hexaiodinated compound	Narrow species protection
3	Aqueous X-ray contrast medium containing an effective amount of a salt of a claim 1 compound	Salt formulation
4	Claim 3 formulation containing 5-100 g of salt per 100 mL	Concentration-limited formulation
5	Aqueous X-ray contrast medium containing an effective amount of a claim 1 compound	Compound formulation

The patent is a pre-1995 U.S. patent. Its term was governed by the former 17-year period measured from grant, rather than the current 20-year period measured from the earliest effective nonprovisional filing date.[1]

What is the chemical scope of claim 1?

Claim 1 is a Markush claim covering a family of substituted, multiply iodinated benzene derivatives. Its principal structural features are:

One or more 2,4,6-triiodinated benzene rings.
Amide and amino substituents attached to the aromatic ring system.
Hydroxyalkyl, alkyl, alkanoyl, and alkanoyloxyalkyl substituents.
A variable number of linked substituent units, with “n” ranging from 1 to 5.
Mono- and bis-substituted embodiments through the variable “b,” which may be 1 or 2.
Lower alkyl ester forms.
Salts formed with pharmaceutically acceptable bases.

The claim permits certain substituents to be the same or different when two corresponding groups are present. That drafting technique materially expands the number of covered stereochemical and substitutional combinations.

Which structural elements drive infringement?

For a product to fall within claim 1, the relevant compound would generally need to satisfy all of the following elements:

It must be an iodobenzene derivative within the claimed structural formula.
The R-group substituents must fall within the expressly listed categories.
The number of repeated units must fall within the specified range of 1 to 5.
Any ester must be a lower alkyl ester.
Any salt must be formed with a pharmaceutically acceptable base.

The claim is not a general claim to all iodinated contrast media. It is limited to compounds having the claimed aromatic substitution pattern and the specified amide, amino, ester, or salt functionality.

The exact perimeter of the Markush structure depends on the chemical drawings incorporated into the original patent claim. The text supplied in the question substitutes “STR” placeholders for those drawings. The written definitions still show that the claim was designed to cover a broad family around a heavily iodinated aromatic core, but claim construction must use the patent’s original structural figures rather than the text alone.

How narrow is claim 2 compared with claim 1?

Claim 2 identifies one specific compound:

“2,4,6-triiodo-3-N-hydroxyethylcarbamyl-5-(2,4,6-triiodo-3-N-methylcarbamyl-5-N-methyl-N-acetylaminobenzoyl)-glycylamino-benzoic acid.”

This species has two 2,4,6-triiodinated benzene rings and a central benzoyl-glycylamino linkage. It also contains:

A hydroxyethylcarbamyl substituent.
An N-methylcarbamyl substituent.
An N-methyl-N-acetylamino group.
A benzoic acid group.
Six iodine atoms across the two aromatic rings.

Claim 2 is materially narrower than claim 1 because it fixes the identity of the substituents rather than leaving them within variable R-group categories. It would have been the strongest claim for the specifically disclosed compound, while claim 1 provided broader genus protection against close analogs.

A claim directed to a specific chemical species can remain valuable even when a broader Markush claim is vulnerable to prior-art or written-description challenges. Conversely, the narrow species claim does not protect structurally unrelated iodinated contrast agents.

What formulations are protected by claims 3 through 5?

Claims 3 through 5 protect aqueous contrast media containing the claimed chemical entity or a salt of that entity.

Claim 3: aqueous salt formulation

Claim 3 requires:

An aqueous solution.
An effective amount of the compound.
A pharmacologically acceptable salt.
Use as an X-ray contrast medium.

This claim is directed primarily to a formulated injectable or administrable diagnostic product rather than to the compound in isolation.

Claim 4: concentration range

Claim 4 narrows claim 3 by requiring that 100 mL of solution contain 5 to 100 grams of the salt.

That range corresponds to 50 to 1,000 mg/mL. The lower boundary is 5 g per 100 mL, and the upper boundary is 100 g per 100 mL.

Formulation parameter	Claimed range
Salt per 100 mL	5-100 g
Equivalent concentration	50-1,000 mg/mL
Dosage form described	Aqueous X-ray contrast solution

The concentration limitation could have been relevant to commercial formulations with defined iodine loading, osmolality, viscosity, and injection characteristics. It would not cover every aqueous solution containing the compound if the concentration fell outside the stated range, although claim 5 remains broader because it does not include the express 5-100 g limitation.

Claim 5: aqueous compound formulation

Claim 5 covers an aqueous X-ray contrast medium containing an effective amount of a claim 1 compound. Unlike claim 3, it is not expressly limited to a pharmaceutically acceptable salt. It therefore addresses the compound itself in aqueous solution, subject to the compound’s solubility and pharmaceutical acceptability.

When did U.S. Patent 4,014,986 lose exclusivity?

The patent issued on March 29, 1977. Under the pre-1995 patent-term rule, the patent expired 17 years after issuance, on March 29, 1994, absent a terminal disclaimer or an extraordinary term adjustment.[1]

Event	Date
Patent issued	March 29, 1977
Original statutory term	17 years from grant
Expected expiration	March 29, 1994
Current enforceability	None based on ordinary patent term

A patent that expired in 1994 cannot support a modern infringement action against a generic manufacturer, contrast-agent manufacturer, contract manufacturer, or API supplier. Patent expiration also places the claimed chemical subject matter in the public domain in the United States.

The expiration analysis is separate from regulatory exclusivity. Any FDA approval, marketing authorization, or product-specific regulatory protection would not revive the expired patent.

What is the Orange Book status of Patent 4,014,986?

U.S. Patent 4,014,986 has no current Orange Book exclusivity effect. The Orange Book identifies patents and regulatory exclusivities associated with approved drug products, but an expired patent does not block approval or commercial entry.[2]

The patent should be distinguished from:

FDA approval of a contrast medium.
New drug exclusivity.
Pediatric exclusivity.
Orphan-drug exclusivity.
Any later patent covering a different formulation or manufacturing process.

If a product once associated with the patent had an NDA, the patent’s historical listing would not create present-day protection. An Orange Book entry cannot extend an expired patent beyond its statutory term.

Are Paragraph IV challenges relevant to this patent?

Paragraph IV litigation is no longer commercially relevant to U.S. Patent 4,014,986 because the patent expired in 1994.

A Paragraph IV certification is used when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. The certification mechanism matters only while a qualifying patent remains listed and capable of delaying approval or supporting litigation.[3]

For this patent:

There is no remaining patent term to challenge.
A 30-month stay would not be available based on the expired patent.
A generic applicant would not need to file a Paragraph IV certification against the expired patent.
Any historical Paragraph IV dispute would have no present effect on market entry.

A current applicant would instead assess later patents, regulatory exclusivity, product-specific labeling, and whether the reference product remains commercially active.

What patent litigation affects the patent?

The patent’s expired status eliminates present infringement exposure under its claims. Historical litigation could have involved validity, infringement, ownership, formulation scope, or competing iodinated contrast agents, but the supplied claim text does not establish a litigation record.

The legally significant current conclusion is narrower: no new U.S. infringement claim can be based solely on claims 1-5 of U.S. Patent 4,014,986 after expiration.

The patent also cannot be used to block:

Manufacture of the claimed compound in the United States.
Importation of the compound into the United States, subject to other laws.
Sale of an aqueous solution meeting claims 3-5.
Development of a generic or alternative contrast medium based on the disclosed chemistry.

Trade-secret rights, regulatory requirements, quality systems, and later unexpired patents must be analyzed separately from this patent.

Does the patent contain method-of-use protection?

Claims 3 and 5 include an intended-use limitation: the composition must be an X-ray contrast medium. They are not broad treatment-method claims in the modern Orange Book sense.

The patent does not, based on the claims provided, separately claim:

A specific imaging procedure.
A named anatomical indication.
A particular route of administration.
A defined patient population.
A dosing schedule.
A disease-treatment method.

The use language links the composition to diagnostic imaging. It does not create an independent, surviving method-of-use right after patent expiration.

How strong was the patent estate?

The patent estate was structurally stronger than a single narrow compound claim because it used layered protection:

Protection layer	Claim coverage	Historical value
Chemical genus	Claim 1	Captured close analogs and salt/ester variants
Specific compound	Claim 2	Direct protection for the disclosed dimer
Salt formulation	Claim 3	Covered aqueous solutions of pharmaceutical salts
Concentration range	Claim 4	Added formulation specificity
Compound formulation	Claim 5	Covered aqueous media beyond the express salt limitation

Its principal weakness was age. The full estate expired before modern generic litigation and Orange Book strategies became central to most diagnostic drug markets.

Claim 1 also presents conventional validity pressure points for a broad chemical Markush claim:

Anticipation by an earlier iodinated contrast compound.
Obviousness based on known triiodobenzoic acid derivatives.
Written-description support for the full R-group combinations.
Enablement across the breadth of the claimed genus.
Definiteness of structural variables and substituent definitions.

Claim 2 would generally be more resistant to genus-wide invalidity arguments if the precise species was adequately disclosed and enabled. Its commercial scope, however, would be limited to the specifically claimed compound and equivalents recognized under applicable law.

Which companies are challenging or licensing the patent?

No current challenge, license, or settlement can have commercial effect against this expired patent. The patent number alone does not establish a surviving license obligation or a current exclusivity arrangement.

Historical commercial participants in iodinated X-ray contrast media included major diagnostic-imaging companies such as Schering, Bracco, Mallinckrodt, Guerbet, and Nycomed. Those companies held different product, formulation, regulatory, and manufacturing portfolios. A company’s participation in the contrast-media market does not establish ownership of U.S. Patent 4,014,986.

Any historical assignment or license would need to be distinguished from:

Patent ownership.
Product branding.
FDA sponsorship.
Distribution rights.
Manufacturing rights.
Later patents covering other contrast agents.

Because the patent expired, a licensee could not now claim patent-based exclusivity over the claimed chemistry.

What geographic coverage does the patent provide?

U.S. Patent 4,014,986 provides U.S. rights only. It does not establish protection in Europe, Japan, Canada, or other jurisdictions.

Foreign patent rights would depend on separate national or regional patents, their filing dates, prosecution histories, maintenance fees, and expiration dates. A foreign counterpart could have expired earlier or later than the U.S. patent, particularly if it was subject to a different term regime or supplementary protection certificate.

The U.S. expiration date cannot be imported into foreign-market analysis. Conversely, a live foreign patent would not restore U.S. protection.

What manufacturing and IP barriers remain?

The expired patent creates no current manufacturing barrier. Practical barriers may still exist, but they are not patent exclusivity under this patent. They include:

Synthesis of highly iodinated aromatic intermediates.
Control of regioisomeric impurities.
Removal of residual iodine-containing process impurities.
Control of osmolality and viscosity.
Sterility and endotoxin specifications.
Stability of concentrated aqueous solutions.
Injectable-product container compatibility.
FDA current good manufacturing practice compliance.
Analytical methods for identity, assay, iodine content, and degradants.

A later patent could still protect a particular process, polymorph, formulation excipient system, container, or manufacturing improvement. Such rights would require separate patent-by-patent review.

What generic launch risks exist today?

For U.S. Patent 4,014,986 alone, generic launch risk is unrestricted by patent term. The likely commercial scenarios are:

Scenario	Effect of Patent 4,014,986
Generic compound manufacture	No current patent barrier
Generic aqueous contrast solution	No current patent barrier
Salt or ester development	No current patent barrier
Alternative iodinated dimer	No current patent barrier
ANDA filing	No Paragraph IV issue based on this expired patent
Biosimilar filing	Not applicable
New NDA for a diagnostic agent	Governed by FDA requirements, not this patent

Biosimilar risk is not relevant because the claimed products are chemically synthesized small molecules, not biologic products regulated through the biosimilar pathway.[4] The relevant competitive pathway would be generic-drug approval, a 505(b)(2) application, or a new application depending on the reference product and formulation.

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

Modern contrast-agent portfolios usually rely on a combination of:

Composition-of-matter patents.
Specific stereochemical forms.
Formulation and concentration patents.
Manufacturing-process patents.
Device or injector patents.
Method-of-use patents.
Regulatory exclusivity.

U.S. Patent 4,014,986 contains several of those categories, but its term ended in 1994. A modern estate would normally have a longer effective life because the patent term is measured from filing rather than grant, and because later patents may be filed for commercial formulations and manufacturing improvements.

The patent remains relevant as prior art and as a historical example of layered protection for iodinated diagnostic agents. It is not a current exclusionary asset.

Key Takeaways

U.S. Patent 4,014,986 covers iodinated benzene derivatives and aqueous X-ray contrast media.
Claim 1 is a broad Markush composition claim covering defined iodinated aromatic derivatives, ester forms, and base salts.
Claim 2 is directed to one specific dimeric hexaiodinated compound.
Claims 3-5 cover aqueous contrast formulations, including a 5-100 g per 100 mL concentration range in claim 4.
The patent issued March 29, 1977, and expired March 29, 1994, under the pre-1995 17-year term rule.
The patent has no current U.S. Orange Book, Paragraph IV, biosimilar, or generic-entry blocking effect.
No current infringement litigation, settlement, or license can create patent exclusivity after expiration.
Foreign rights require separate family-level analysis.
Current commercial barriers would arise from later patents, FDA requirements, manufacturing capability, and product economics, not from this patent.

FAQs

Does U.S. Patent 4,014,986 protect all iodinated X-ray contrast agents?

No. It covers a defined family of iodinated benzene derivatives and formulations containing them. Structurally unrelated agents such as modern monomeric or dimeric contrast media fall outside the claims unless they satisfy the claimed chemical limitations.

Can a company manufacture the claim 2 compound in the United States?

Yes, from the standpoint of U.S. Patent 4,014,986. The patent expired in 1994. Other patents, regulatory requirements, or non-patent restrictions would require separate review.

Does claim 4 cover every concentration above 5 g per 100 mL?

No. Claim 4 recites a range of 5 to 100 g per 100 mL. A concentration above 100 g per 100 mL would not satisfy that limitation, although it could raise separate issues under another claim if all other limitations were met.

Is claim 2 a salt claim?

Claim 2 identifies the free acid compound. Claim 1 separately covers lower alkyl esters and pharmaceutically acceptable base salts within its chemical scope. Claims 3 and 4 specifically address aqueous solutions containing a pharmaceutically acceptable salt.

Could a later formulation patent still affect commercialization of the claimed contrast medium?

Yes. Expiration of U.S. Patent 4,014,986 does not eliminate later patents covering a distinct formulation, manufacturing process, container, injector system, or other patentable improvement. Such patents would need independent validity, claim-scope, and expiration analysis.

References

United States Patent and Trademark Office. (1977). U.S. Patent No. 4,014,986.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application approvals and patent certifications.
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	24169/74	May 31, 1974
	33900/74	Jul 31, 1974

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	205196	⤷ Start Trial
Argentina	207465	⤷ Start Trial
Austria	343638	⤷ Start Trial
Austria	345796	⤷ Start Trial
Austria	A409875	⤷ Start Trial
Austria	A969476	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,014,986

Summary for Patent: 4,014,986