United States Patent 4,001,323: Iopamidol Claims, Scope, Expiration, and Patent Landscape

U.S. Patent 4,001,323 covers a class of nonionic, tri-iodinated isophthalamide compounds, including the contrast-agent active ingredient iopamidol. The patent issued on January 4, 1977, and its original 17-year U.S. patent term expired on January 4, 1994. It no longer blocks generic iopamidol development, manufacturing, approval, or sale in the United States.

The patent’s commercial importance came from claims directed to compounds bearing two hydroxyalkyl amide substituents and, in narrower claims, the specific stereochemical form of the compound. The protected technology was used for injectable X-ray and computed-tomography contrast media marketed under the Isovue brand.

What drug does U.S. Patent 4,001,323 protect?

U.S. Patent 4,001,323 is associated with iopamidol, a nonionic, water-soluble iodinated contrast agent. The compound is used for intravascular, intravenous, intra-arterial, and other radiographic imaging procedures.

Iopamidol is generally identified chemically as:

N,N'-bis(2,3-dihydroxypropyl)-5-[(2-hydroxyacetyl)amino]-2,4,6-triiodoisophthalamide

Its commercial formulation is an aqueous injection containing iopamidol at different iodine concentrations, commonly 200, 250, 300, and 370 mg iodine/mL, depending on the indication and product presentation.

Item	Data
Active ingredient	Iopamidol
Drug class	Nonionic iodinated contrast medium
Chemical family	Triiodinated isophthalamide
U.S. brand	Isovue
Original U.S. patent	U.S. Patent 4,001,323
Patent issue date	January 4, 1977
Original patent expiration	January 4, 1994
FDA pathway	New drug application
Current patent status	Expired
Biosimilar framework	Not applicable
Generic pathway	Abbreviated New Drug Application

The patent claims should be read against the complete chemical formula in the issued patent. The formula is not reproduced in the text supplied with the question, but the patent is conventionally identified with the iopamidol compound family and its related stereoisomers.

What does claim 1 of U.S. Patent 4,001,323 cover?

Claim 1 is the principal genus claim. It covers compounds having the patented triiodinated isophthalamide core with each of the two designated substituents, R and R1, selected from:

1,3-dihydroxyisopropyl; or
2,3-dihydroxypropyl.

The claim is broader than a claim to one named commercial compound. It covers every compound within the claimed core structure in which the two substituent positions independently contain one of the two specified dihydroxypropyl configurations.

The independent-selection structure is important. Unless the claim language or specification limits the selections, claim 1 potentially reaches:

R substituent	R1 substituent	Covered by claim 1?
1,3-dihydroxyisopropyl	1,3-dihydroxyisopropyl	Yes
1,3-dihydroxyisopropyl	2,3-dihydroxypropyl	Yes
2,3-dihydroxypropyl	1,3-dihydroxyisopropyl	Yes
2,3-dihydroxypropyl	2,3-dihydroxypropyl	Yes

The claim therefore has two dimensions of scope:

Structural scope: the fixed iodinated aromatic amide framework shown in the patent formula.
Substituent scope: either of two specified dihydroxypropyl arrangements at each R position.

Claim 1 does not, on its face, cover arbitrary polyhydroxyalkyl groups, non-iodinated analogues, different iodine substitution patterns, or compounds with unrelated amide substituents. The fixed core and the listed R/R1 groups are material limitations.

What does claim 2 add to the patent scope?

Claim 2 narrows claim 1 by requiring that both R and R1 be 1,3-dihydroxyisopropyl.

Its scope is therefore limited to the symmetric disubstituted species:

R = 1,3-dihydroxyisopropyl; and
R1 = 1,3-dihydroxyisopropyl.

Compared with claim 1, claim 2 excludes compounds containing either of the mixed substituent combinations or two 2,3-dihydroxypropyl groups.

Claim 2 has narrower literal coverage but can provide a more focused position against the specific compound selected for development. A claim of this type is useful when the commercial candidate has a defined symmetric substitution pattern and the broader genus claim could face prior-art or enablement challenges.

What does claim 3 protect?

Claim 3 depends on claim 2 and requires the compound to be optically active.

The claim therefore covers an optically active species within the claim 2 structure. It does not cover the full racemic or stereochemically unspecified population unless the compound is also optically active as claimed.

The practical effect is to create a stereochemical fallback position:

Claim	Scope
Claim 1	Genus covering specified R and R1 dihydroxypropyl configurations
Claim 2	Symmetric species with both R and R1 equal to 1,3-dihydroxyisopropyl
Claim 3	An optically active species within claim 2

Stereochemistry matters because the two hydroxy-bearing carbon atoms can create enantiomeric or diastereomeric forms. A process producing a single stereoisomer, an enriched stereoisomer, or a defined stereochemical mixture may raise different infringement and validity questions depending on the precise claim construction and product composition.

When did U.S. Patent 4,001,323 expire?

The patent issued in 1977, when the standard U.S. patent term was 17 years from grant. On that basis, the patent expired on January 4, 1994.

Milestone	Date
Patent issued	January 4, 1977
Original statutory term	17 years from issue
Expiration	January 4, 1994
Current status	Expired and unenforceable

The patent predates the modern 20-year term measured from the earliest effective nonprovisional filing date. It also predates the Hatch-Waxman patent-term-restoration framework. The record does not establish a restoration period that would extend this patent into the modern generic-entry period.

Because the patent expired before the principal commercial generic disputes involving iopamidol, it does not create a current Paragraph IV barrier.

What was the FDA regulatory status of iopamidol?

Iopamidol was approved by the FDA as a prescription iodinated contrast agent. The Isovue product line is marketed by Bracco Diagnostics and contains iopamidol injection in multiple iodine concentrations.

The FDA-approved product uses include radiographic procedures such as:

intra-arterial digital subtraction angiography;
intravenous digital subtraction angiography;
computed tomography;
intravenous excretory urography;
peripheral arteriography; and
coronary or visceral angiography, depending on concentration and labeling.

The regulatory product is an aqueous injectable formulation. The patent claims are directed primarily to the chemical compound, not to a complete commercial formulation containing a particular concentration, container, preservative system, or administration device.

What is the Orange Book status of iopamidol?

Iopamidol products are prescription drugs, but U.S. Patent 4,001,323 is expired and does not provide a current Orange Book patent barrier.

The Orange Book analysis must distinguish three issues:

Approved drug listing: iopamidol injection products are FDA-approved drug products.
Patent listing: any listed patents must be evaluated by product, dosage form, and NDA.
Current enforceability: the 1977 patent cannot be asserted because it expired in 1994.

There is no biosimilar issue. Iopamidol is a small-molecule chemical drug, not a biologic. A competing manufacturer generally proceeds through the ANDA pathway, subject to demonstrating pharmaceutical equivalence, bioequivalence where applicable, manufacturing compliance, and conformity with the relevant reference product.

Are there active Paragraph IV challenges to U.S. Patent 4,001,323?

No current Paragraph IV challenge can be commercially meaningful against U.S. Patent 4,001,323 because the patent expired nearly three decades ago.

A Paragraph IV certification is relevant when an ANDA applicant contends that a listed patent is invalid, unenforceable, or will not be infringed. For an expired patent, the applicant does not face the ordinary future patent-exclusion period associated with an unexpired Orange Book patent.

The economic distinction is direct:

Issue	Effect for U.S. Patent 4,001,323
Paragraph IV certification	No practical blocking effect
30-month stay	Not available for an expired patent
Patent-term exclusivity	None
Generic launch date	Not restricted by this patent
Litigation exposure	No ongoing enforcement value from this patent

What formulations are protected by the patent?

The patent’s claims are compound claims. They do not expressly claim every formulation of iopamidol.

A commercial iopamidol injection may include:

iopamidol;
water for injection;
sodium or calcium adjustment components;
pH-adjusting agents; and
packaging and container components.

A formulation patent would require separate claim language directed to the composition, concentration range, stability profile, excipient combination, container, or method of use. U.S. Patent 4,001,323 should not be treated as a broad formulation patent merely because the patented compound is administered in an injectable formulation.

The distinction affects freedom to operate. A manufacturer could avoid the expired compound patent but still need to evaluate later patents covering:

a specific iodine concentration;
a low-osmolality formulation;
a particular pH range;
stability during storage;
a prefilled syringe or vial;
a manufacturing impurity profile; or
a specific imaging indication.

Those later rights would need to be assessed independently from the 1977 patent.

What method-of-use rights protect iopamidol?

The three supplied claims are composition claims. They do not claim the use of iopamidol for a specific imaging procedure.

Method-of-use patents would require separate claims directed to administering the compound for a defined indication, patient population, imaging protocol, dose, or route. Such claims could include angiography, CT imaging, renal imaging, or vascular imaging, but the supplied claims do not establish those rights.

The expiration of the compound patent does not automatically eliminate every later method-of-use or formulation patent. It does, however, remove the foundational chemical-compound barrier represented by U.S. Patent 4,001,323.

How strong was the patent estate for iopamidol?

The original patent estate was commercially strong during the protected period because it combined:

a defined triiodinated isophthalamide core;
hydroxyalkyl substituent coverage;
a broad genus claim;
a narrower symmetric-species claim; and
a stereochemical fallback claim.

Its principal weakness today is temporal rather than technical: every claim in the patent is expired.

Strength factor	Assessment
Core compound coverage	Strong during term
Genus claim	Broad relative to the three-claim set
Symmetric commercial-species claim	Narrow but commercially focused
Stereochemical claim	Useful fallback for defined active forms
Formulation coverage	Not established by supplied claims
Method-of-use coverage	Not established by supplied claims
Current enforceability	None
Generic blocking value	None

The patent does not create a manufacturing barrier today. A competitor can synthesize iopamidol or procure it from a qualified supplier without infringing this expired patent, subject to compliance with current FDA requirements and any later, unexpired rights.

Which companies compete with iopamidol?

Iopamidol competes in the low-osmolality, nonionic iodinated contrast-media market. Relevant products include:

Active ingredient	Representative brand	Competitive position
Iopamidol	Isovue	Broad radiographic and CT use
Iohexol	Omnipaque	Major nonionic contrast competitor
Iopromide	Ultravist	Competes in CT and angiography
Ioversol	Optiray	Competes in vascular and CT imaging
Iodixanol	Visipaque	Iso-osmolar alternative
Diatrizoate	Multiple legacy products	Ionic, higher-osmolality alternative

The primary competitive comparison is not based on the expired patent. It depends on:

iodine concentration;
osmolality;
viscosity;
renal and cardiovascular tolerability;
approved indications;
hospital formulary status;
supply reliability;
contract pricing; and
device and packaging compatibility.

What generic entry risks exist for iopamidol?

The patent risk from U.S. Patent 4,001,323 is zero because the patent expired in 1994. Generic entry risks instead arise from regulatory and commercial execution.

Key risks include:

Manufacturing complexity. Iopamidol is a highly iodinated, multifunctional molecule requiring control of regioisomers, stereoisomers, residual iodine-related impurities, and degradation products.
Sterile injectable production. ANDA applicants must demonstrate validated aseptic processing, container-closure integrity, particulate control, and stability.
Supply-chain exposure. Iodinated intermediates and high-purity active pharmaceutical ingredient supply can affect continuity.
Reference-product comparability. Concentration, viscosity, pH, osmolality, labeling, and presentation must align with the reference product.
Hospital contracting. Contrast media are often purchased through group purchasing organizations and integrated hospital contracts, creating pricing pressure.
Later patent rights. Any unexpired formulation, device, process, or use patent must be screened separately.

What licensing deals and litigation affect iopamidol?

The supplied claims do not establish a licensing arrangement or litigation event. U.S. Patent 4,001,323 itself is expired, so it has no current litigation value.

The commercial history of iopamidol includes development and commercialization by Bracco-related entities and the Isovue product franchise. A current freedom-to-operate review should separate:

ownership of the original compound patent;
historical commercialization rights;
later process patents;
formulation patents;
regulatory exclusivities; and
contractual supply or distribution arrangements.

No active biosimilar litigation applies because iopamidol is a small molecule. No current Paragraph IV risk attaches to the expired 1977 patent.

How does iopamidol compare with competing contrast agents?

Iopamidol has the same broad commercial category as iohexol, iopromide, and ioversol: nonionic, low-osmolality iodinated contrast media. Iodixanol differs because it is generally classified as iso-osmolar.

The patent landscape is fragmented by molecule. Expiration of U.S. Patent 4,001,323 affects iopamidol only. It does not establish freedom to operate for competing active ingredients, and patents covering another contrast agent cannot ordinarily be used to extend protection over iopamidol.

Key Takeaways

U.S. Patent 4,001,323 covers a class of tri-iodinated isophthalamide compounds associated with iopamidol.
Claim 1 is the broadest claim and covers specified combinations of 1,3-dihydroxyisopropyl and 2,3-dihydroxypropyl substituents.
Claim 2 narrows coverage to the symmetric 1,3-dihydroxyisopropyl compound.
Claim 3 adds an optical-activity limitation.
The patent issued January 4, 1977, and expired January 4, 1994.
The patent has no current Orange Book blocking value, Paragraph IV value, or generic-entry value.
The claims supplied are compound claims, not formulation or method-of-use claims.
Iopamidol is regulated as a small-molecule injectable contrast agent through the FDA NDA/ANDA framework.
Current freedom-to-operate analysis must focus on later formulation, process, device, use, and manufacturing patents, not U.S. Patent 4,001,323.
The main commercial competitors are iohexol, iopromide, ioversol, and iodixanol products.

FAQs

Is iopamidol still patent protected in the United States?

No. The principal compound patent, U.S. Patent 4,001,323, expired on January 4, 1994.

Can a company manufacture generic iopamidol?

Yes, subject to FDA approval, current regulatory requirements, manufacturing controls, and clearance of any later unexpired patents.

Does U.S. Patent 4,001,323 cover Isovue formulations?

It covers the chemical compound class, not necessarily every Isovue formulation, concentration, package, or administration device.

Is iopamidol subject to biosimilar competition?

No. Iopamidol is a chemically synthesized small-molecule drug. Competition proceeds through generic-drug pathways rather than the biosimilar pathway.

What is the main remaining IP risk for a generic iopamidol manufacturer?

The principal risks are later formulation, manufacturing-process, device, or method-of-use patents, together with FDA requirements for sterile injectable manufacturing and product equivalence.

References

U.S. Patent and Trademark Office. (1977). U.S. Patent No. 4,001,323: N,N'-bis(2,3-dihydroxypropyl)-5-[(2-hydroxyacetyl)amino]-2,4,6-triiodoisophthalamide compounds.
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
U.S. Food and Drug Administration. (n.d.). Isovue-200, Isovue-250, Isovue-300, and Isovue-370 prescribing information. Bracco Diagnostics Inc.
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application submissions and patent certifications.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	16588/74	Dec 13, 1974

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	211853	⤷ Start Trial
Austria	340582	⤷ Start Trial
Austria	342579	⤷ Start Trial
Austria	349449	⤷ Start Trial
Austria	349450	⤷ Start Trial
Austria	A481277	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,001,323

Summary for Patent: 4,001,323