US Patent 4,396,598: Ioversol Claims, Scope, Expiration, and Patent Landscape

US Patent 4,396,598 covers ioversol, a nonionic, water-soluble iodinated X-ray contrast agent, together with compositions containing ioversol and its use in X-ray visualization. The patent issued on August 2, 1983, and its ordinary 17-year patent term expired on August 2, 2000. The claims therefore have no current exclusionary force in the United States.[1]

Ioversol is marketed primarily as Optiray and is used for angiography, computed tomography, intravenous urography, and other radiographic procedures. The patent protects the active chemical entity and two use categories, but it does not create current barriers to generic ioversol manufacture or sale.

What drug does US Patent 4,396,598 protect?

The compound claimed in claim 1 is ioversol. Its systematic chemical description is:

N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide.

Ioversol is a triiodinated benzene derivative. Its structural characteristics are:

Structural element	Relevance
2,4,6-triiodoisophthalamide nucleus	Provides the high iodine content required for X-ray attenuation
Two 2,3-dihydroxypropyl substituents	Increase water solubility
N-(2-hydroxyethyl)glycolamido substituent	Contributes to the nonionic and hydrophilic profile
Nonionic structure	Reduces ionic dissociation in solution
Three iodine atoms	Produces radiopacity for diagnostic imaging

The compound is also identified by the generic name ioversol and by the CAS Registry Number 87771-40-2. Optiray is an injectable, nonionic, low-osmolar contrast medium containing ioversol.[2]

What are the claims of US Patent 4,396,598?

The patent has three claims directed to different legal categories.

Claim	Claim category	Principal subject
1	Composition of matter	Ioversol itself
2	Pharmaceutical composition	A radiological composition containing ioversol
3	Method of use	X-ray visualization using an ioversol composition

Claim 1: What is the scope of the ioversol compound claim?

Claim 1 is a product claim directed to the chemical compound itself:

N,N'-Bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide.

This is the strongest claim type in the patent because it does not depend on a particular formulation, concentration, route of administration, imaging indication, or manufacturing process. During the patent term, a party that made, used, sold, offered for sale, or imported the claimed compound could have faced direct infringement exposure under 35 U.S.C. § 271.

The claim does not expressly recite:

A specific dosage form;
A specific solvent or excipient;
A particular concentration;
A particular route of administration;
A specific imaging indication;
A manufacturing process;
A salt, hydrate, polymorph, or crystalline form;
A stereochemical configuration.

The claim is therefore chemically focused. Its scope would generally turn on whether the accused molecule has the claimed substitution pattern and chemical identity, not on whether the molecule is sold under the Optiray brand or used for a particular diagnostic procedure.

Does claim 1 cover ioversol salts or formulations?

Claim 1 directly covers the named neutral chemical entity. It does not expressly recite a salt, ester, prodrug, hydrate, solvate, or formulation.

A formulation containing ioversol would not escape claim 1 merely because the compound is mixed with water or excipients. A formulation claim is analyzed separately under claim 2, but making or selling the formulation during the patent term could also implicate the compound claim if the formulation contains the claimed ioversol molecule.

The claim does not, on its face, extend to a structurally different iodinated contrast agent such as iohexol, iopamidol, iopromide, iomeprol, or iodixanol. Those compounds have related triiodinated aromatic cores but different substituent arrangements.

What does claim 2 protect?

Claim 2 covers:

Ioversol;
A sufficient amount to provide satisfactory X-ray visualization; and
A pharmaceutically acceptable radiological vehicle.

This is a composition claim. It is narrower in category than claim 1 because it requires a radiological vehicle and an amount suitable for imaging. It is broader in formulation detail because it does not identify a particular vehicle, concentration, osmolality, pH, buffer, container, or preservative.

What formulations fall within claim 2?

During the patent term, formulations containing ioversol in a pharmaceutically acceptable radiological vehicle would have been candidates for claim 2 coverage. The claim language does not limit the vehicle to a named excipient. Water for injection would ordinarily be the principal vehicle for an injectable ioversol product.

Commercial Optiray products are aqueous injectable solutions. FDA labeling identifies ioversol as the active ingredient and specifies different concentrations for particular imaging applications, including products containing approximately 240, ಮಾಡಿದ 320, and 350 mg of organically bound iodine per milliliter, depending on the product presentation.[2]

The claim does not appear limited to:

Optiray packaging;
A particular ioversol concentration;
A specific indication;
A particular administration device;
A single-dose vial;
A prefilled syringe;
A specific osmolality range.

The functional phrase requiring a sufficient amount for satisfactory visualization establishes a utility requirement, but it does not supply a precise concentration threshold. In practice, the intended-use context and product composition would be relevant to determining whether the requirement is met.

What does claim 3 protect?

Claim 3 is an improvement method claim. It requires:

A method for X-ray visualization;
Injection of a radiological composition containing an X-ray contrast agent;
A pharmaceutically acceptable radiological vehicle;
An amount sufficient for adequate visualization;
Subsequent X-ray visualization; and
Use of ioversol as the radiological composition.

Claim 3 does not claim every use of ioversol in the abstract. It requires the procedural sequence described in the claim. The injection step and subsequent X-ray visualization are material limitations.

How broad is the method-of-use claim?

The method claim is not limited to one named diagnostic procedure. It can potentially encompass different X-ray visualization procedures if the claimed elements are present. The wording does not identify:

Angiography;
Computed tomography;
Intravenous urography;
Cardiac imaging;
Peripheral vascular imaging;
A particular anatomical site;
A specified dose;
A specified injection rate.

The claim's practical scope is therefore broader than a method claim limited to one indication, but narrower than a claim covering any administration of ioversol. An administration for a non-X-ray imaging modality would not satisfy the express X-ray visualization limitation.

The phrase "comprising or utilizing" is open-ended in character. It does not ordinarily exclude the presence of additional ingredients or procedural steps. A composition containing ioversol and another contrast agent could raise a claim issue if the remaining limitations were met, although the patent's disclosure and claim construction would be relevant to any mixed-agent analysis.

When did US Patent 4,396,598 expire?

Event	Date
Patent issued	August 2, 1983
Ordinary term under pre-1995 law	17 years from issue
Ordinary expiration	August 2, 2000
Current enforceability	Expired
Current Paragraph IV significance	None for this patent

US Patent 4,396,598 was granted under the pre-Uruguay Round patent-term regime, under which the term was generally 17 years from the grant date. The patent therefore expired in 2000, subject to any term adjustment or terminal-disclaimer information appearing in the official prosecution record. The patent is too old to provide an active U.S. exclusionary right today.[1][3]

No current infringement action can be based on an expired patent. Historical infringement claims may be subject to separate limitation, laches, settlement, and damages issues, but the patent cannot block present-day manufacture, importation, or sale of ioversol.

What is the FDA regulatory status of ioversol?

Ioversol is an FDA-approved small-molecule radiographic contrast agent. Optiray is the principal reference product associated with the active ingredient.

Regulatory item	Status
Active ingredient	Ioversol
Product type	Nonionic iodinated X-ray contrast agent
FDA pathway	New drug application and abbreviated new drug application framework
Dosage form	Sterile injectable solution
Primary use	X-ray and CT contrast enhancement
Biologic status	Not a biologic
Biosimilar pathway	Not applicable
Generic pathway	ANDA pathway may apply, subject to FDA requirements
Patent 4,396,598	Expired

FDA labeling identifies Optiray for intra-arterial and intravenous procedures, including cerebral, peripheral, visceral, renal, and coronary angiography, contrast-enhanced CT, and intravenous excretory urography, subject to product-specific labeling.[2]

Because ioversol is a chemically defined small molecule, competitors do not need to pursue a biosimilar application. The relevant regulatory route is generally a generic-drug application, although contrast media can present product-specific analytical, physicochemical, sterility, packaging, and clinical-bridging requirements.

What is the Orange Book status of US Patent 4,396,598?

US Patent 4,396,598 is not an active Orange Book barrier. Its 2000 expiration date removes it as a current basis for:

A 30-month stay triggered by a Paragraph IV certification;
A current patent listing challenge;
A current generic launch prohibition;
A current patent-based ANDA delay.

The FDA Orange Book distinguishes active listed patents from patents that have expired or are no longer relevant to approval timing.[3] A historical patent may explain the original development and exclusivity position for ioversol, but it does not create present-day regulatory exclusivity.

Were Paragraph IV challenges relevant to this patent?

Paragraph IV litigation is relevant only while an applicable listed patent remains active or has a legally operative term. Since US Patent 4,396,598 expired in 2000, a current ANDA applicant would not need to defeat this patent to launch a generic ioversol product.

Any historical Paragraph IV filing would need to be assessed against the patent's then-current term and Orange Book listing status. The supplied claim text does not establish that such a challenge occurred, and the expired patent cannot support a current Paragraph IV delay.

What other patents may protect ioversol products?

The relevant ioversol patent estate can be divided into four categories:

Category	Potential subject matter	Status of US 4,396,598
Active ingredient	Ioversol molecule	Covered directly; expired
Formulation	Concentration, osmolality, pH, excipients, stability, container system	Not expressly claimed
Method of use	Imaging procedures and administration protocols	Covered broadly by claim 3; expired
Manufacturing	Synthesis, purification, crystallization, impurity control	Not claimed in the three supplied claims

The patent does not claim a specific manufacturing method. A later process patent could have protected a particular route to ioversol without extending the life of the compound patent. Process claims also would not necessarily prevent manufacture through a non-infringing alternative route.

Similarly, a later formulation patent could have covered a specific concentration, pH range, excipient combination, container, or stability profile. Such a patent would need to be analyzed independently. It would not revive the expired compound claim or extend the statutory term of US Patent 4,396,598.

What manufacturing barriers remain after compound-patent expiration?

The principal barriers are likely regulatory and operational rather than compound-patent barriers:

Establishing identity and purity of ioversol;
Controlling iodine content and related impurities;
Demonstrating sterility and endotoxin compliance;
Validating injectable manufacturing;
Matching the reference product's physicochemical characteristics;
Establishing stability through the proposed shelf life;
Qualifying containers and closure systems;
Meeting FDA facility and current good manufacturing practice requirements.

These barriers can increase development cost and launch timing without creating patent exclusivity.

How does ioversol compare with competing iodinated contrast agents?

Ioversol competes with other nonionic, low-osmolar iodinated contrast agents. The competing molecules are chemically related but are not covered by claim 1 merely because they contain a triiodinated benzene nucleus.

Agent	Common brand	Representative manufacturer or marketer	Relationship to claim 1
Ioversol	Optiray	Guerbet and regional commercial partners	Claimed compound
Iohexol	Omnipaque	GE HealthCare	Different compound
Iopamidol	Isovue	Bracco	Different compound
Iopromide	Ultravist	Bayer	Different compound
Iodixanol	Visipaque	GE HealthCare	Different dimeric compound
Iomeprol	Iomeron	Bracco and regional partners	Different compound

The key patent distinction is molecular identity. Patent 4,396,598 does not create a genus claim covering all nonionic iodinated contrast media. A competitor using iohexol or iopamidol would not normally fall within claim 1 solely because those products share a diagnostic function or general chemical class.

Which companies are challenging the ioversol patent estate?

No current challenge to US Patent 4,396,598 is commercially material because the patent expired more than two decades ago. Generic manufacturers may compete against Optiray through ANDA filings or other regulatory routes, but they do not need to litigate this patent to enter the U.S. market.

Potential competitors include manufacturers of generic ioversol and established contrast-media companies with competing agents. The commercial issue is product approval, manufacturing scale, supply reliability, and contracting rather than freedom to operate under this expired patent.

The supplied information does not establish a current infringement action, inter partes review, post-grant proceeding, or settlement agreement involving US Patent 4,396,598.

What is the patent strength of US Patent 4,396,598?

The patent was strong in historical terms because it combined a compound claim with composition and method claims.

Strength factor	Assessment
Compound claim	Strongest historical protection
Formulation coverage	Functional and relatively general
Method coverage	Broad across X-ray visualization procedures
Manufacturing coverage	None in the supplied claims
Indication specificity	Limited
Current enforceability	None because the patent expired
Design-around potential during term	Lower for the exact molecule; higher through alternative contrast agents
Present commercial value	Historical and freedom-to-operate relevance only

Claim 1 would have been difficult to avoid while using ioversol itself. Claims 2 and 3 added protection against commercial formulations and clinical use, but they did not cover competing contrast agents with different structures.

The patent's present value is primarily analytical. It identifies the original compound protection and helps establish that ioversol is long beyond its original U.S. compound-patent term.

What generic launch risks exist for ioversol?

A generic ioversol launch is not blocked by US Patent 4,396,598. The principal launch risks are:

FDA approval requirements for a sterile injectable contrast agent;
Manufacturing validation and inspection readiness;
Product quality and impurity specifications;
Supply of iodine-containing starting materials;
Contracting and hospital procurement;
Product liability and medication-error controls;
Any later unexpired formulation, process, or device patents;
Commercial scale and distribution economics.

A generic applicant would also need to evaluate the current Orange Book for any later-listed patents associated with the relevant reference-listed drug. Those patents, if any, would need separate claim and term analysis. Patent 4,396,598 itself does not create a launch risk.

What is the geographic coverage of this patent?

US Patent 4,396,598 has U.S. territorial scope. It does not independently confer rights in Europe, Japan, Canada, or other jurisdictions.

The original ioversol program may have included foreign counterparts, national-phase applications, or related patents. Those rights would have had separate filing dates, prosecution histories, expiration dates, maintenance requirements, and claim scope. The U.S. expiration date cannot be applied automatically to foreign patents, although older counterparts would also be expected to have expired in most jurisdictions.

What licensing or settlement deals affect US Patent 4,396,598?

The supplied claim information does not identify a licensing agreement, covenant not to sue, patent settlement, or authorized generic arrangement involving this patent. Because the patent expired in 2000, any historical license or settlement would have no current ability to restrict ordinary U.S. ioversol commercialization unless separate contractual or patent rights remain operative.

Key Takeaways

US Patent 4,396,598 claims ioversol, the ioversol-containing radiological composition, and X-ray visualization using ioversol.
Claim 1 is a direct chemical compound claim and was the principal historical protection.
Claim 2 covers ioversol in a pharmaceutically acceptable radiological vehicle.
Claim 3 covers injection of an ioversol composition followed by X-ray visualization.
The patent issued August 2, 1983, and its ordinary U.S. term expired August 2, 2000.
The patent is not a current Orange Book or Paragraph IV barrier.
Ioversol is a small molecule, so biosimilar analysis does not apply.
Generic competition is governed primarily by FDA approval, sterile injectable manufacturing, quality controls, and commercial contracting.
The patent does not claim iohexol, iopamidol, iopromide, iodixanol, or other structurally different iodinated contrast agents.
No current litigation, settlement, or licensing restriction is established by the supplied patent and claim information.

FAQs About US Patent 4,396,598 and Ioversol

Is US Patent 4,396,598 still enforceable?

No. Its ordinary U.S. patent term expired on August 2, 2000.

Does US Patent 4,396,598 cover Optiray?

Historically, yes. Optiray contains ioversol, the compound claimed in claim 1. The patent is now expired.

Can a generic manufacturer make ioversol without a license to this patent?

Yes, this patent no longer prevents manufacture, importation, or sale of ioversol in the United States.

Does the patent cover iohexol or iopamidol?

No. Those are different chemical compounds and are not covered by the specific compound claim quoted from US Patent 4,396,598.

Is ioversol subject to biosimilar competition?

No. Ioversol is a chemically synthesized small molecule, so competition proceeds through the generic-drug framework rather than the biosimilar pathway.

References

United States Patent and Trademark Office. (1983). U.S. Patent No. 4,396,598: N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide.
U.S. Food and Drug Administration. (n.d.). Optiray (ioversol injection) prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0083964	⤷ Start Trial	SPC/GB93/089	United Kingdom	⤷ Start Trial
European Patent Office	0083964	⤷ Start Trial	93C0142	Belgium	⤷ Start Trial
Australia	552188	⤷ Start Trial
Australia	9151182	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,396,598

Summary for Patent: 4,396,598