Details for Patent: 4,364,921

Summary for Patent: 4,364,921

Title:	Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media
Abstract:	New triiodinated isophthalic acid diamides of the formula ##STR1## wherein the amide residues --CO--N.R1 R2 and --CO--N.R3 R4 are different from each other andR1 is hydrogen or C1-6 alkyl,R2 is mono- or polyhydroxyalkyl,R3 is hydrogen or C1-6 alkyl,R4 is mono- or polyhydroxylalkyl,R5 is C1-6 alkyl or mono- or polyhydroxy-C1-6 -alkyl or C1-3 -alkoxy-C1-3 -alkyl, andR6 is hydrogen, C1-6 alkyl or mono- or polyhydroxyalkyl provide superior nonionic X-ray contrast media.
Inventor(s):	Ulrich Speck, Peter Blaszkiewicz, Dieter Seidelmann, Erich Klieger
Assignee:	Bayer Pharma AG
Application Number:	US06/127,613
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 4,364,921: Claim Scope, Expiration, Orange Book Status, and Nonionic X-Ray Contrast Patent Landscape

US Patent 4,364,921 covers a class of nonionic, water-soluble, triiodinated isophthalic acid diamides used as X-ray contrast agents. Its claims include a broad chemical genus, selected named compounds, pharmaceutical compositions, and radiological examination methods, including angiography. The patent issued in the early 1980s and is expired. It no longer blocks manufacture, sale, or use of compounds that fall within its claims, although its claim structure remains relevant to historical freedom-to-operate analysis, validity review, and lineage analysis for later contrast-media patents.

What does US Patent 4,364,921 cover?

The patent covers triiodinated isophthalic acid diamides with two different amide substituents and hydroxyalkyl-containing side chains. The claimed compounds are designed to provide radiopacity and water solubility while avoiding the high ionic load associated with older ionic contrast media.

The central structure is a 2,4,6-triiodoisophthalic acid core bearing:

• Two carboxamide groups;
• A 5-position amino or acylamino substituent;
• Hydroxyalkyl or polyhydroxyalkyl groups on the amide nitrogen atoms;
• Optional methyl, alkyl, hydroxyalkyl, alkoxyalkyl, or related substituents.

The claims target the chemical characteristics that became common in second-generation nonionic contrast agents:

1. A heavily iodinated aromatic nucleus for X-ray attenuation.
2. Multiple hydroxyl groups for aqueous solubility.
3. Nonionic amide functionality to reduce osmolality relative to ionic contrast agents.
4. Substitution patterns that influence viscosity, pharmacokinetics, tolerability, and formulation concentration.

The claim set supplied for analysis contains an incomplete ending in claim 1: "R6 is hydrogen or C1-6 alkyl or mono-." That truncation affects the precise outer boundary of the Markush genus. Claims 2 through 15 still permit a substantial analysis of the patent's operative scope.

What are the independent claims in US Patent 4,364,921?

The patent has three principal categories of protection.

Chemical compound claims

Claim 1 is the principal genus claim. It covers a triiodinated isophthalic acid diamide of a defined formula in which the two amide residues are different. The variables regulate:

• Whether the amide nitrogens are unsubstituted or methylated;
• The length and hydroxylation of alkyl substituents;
• The identity of the 5-position acylamino group;
• The substitution of the acyl side chain.

Claims 2, 3, 4, and 10 identify specific compounds. Claims 5 through 7 and 11, 12, and 15 narrow the genus through additional substituent restrictions.

Composition claim

Claim 8 covers a pharmaceutical composition containing:

• A radiopaque amount of a claim 1 compound; and
• A pharmaceutically acceptable carrier.

Claim 13 narrows the composition to a carrier acceptable for angiography.

This type of claim can cover a finished injectable formulation if the active ingredient and carrier satisfy the limitations. It does not necessarily cover every formulation containing a related nonionic contrast agent because the compound must first fall within claim 1 or a dependent claim.

Method claims

Claim 9 covers administering a radiopaque amount of a claim 1 compound to a patient for radiological examination. Claim 14 narrows the method to angiography.

The method claims are broader in clinical purpose than the composition claims. They do not appear limited to a particular imaging protocol, injection rate, concentration, anatomical site, or imaging instrument. Their practical scope depends on the construction of "radiological examination," "radiopaque amount," and the incorporated compound limitations.

How broad is claim 1?

Claim 1 is a Markush claim directed to a chemical genus. Its scope is materially broader than the named compounds in claims 2, 3, 4, and 10.

A compound generally would need to satisfy all of the following conditions to fall within claim 1:

Limitation	Scope indicated by the supplied claim
Core	Triiodinated isophthalic acid
Iodine placement	2,4,6-triiodo substitution
Amide pattern	Two carboxamides with different amide residues
R1 and R3	Hydrogen or C1-C6 alkyl
R2 and R4	Mono- or polyhydroxyalkyl
R5	C1-C6 alkyl, monohydroxy-C1-C6 alkyl, or certain alkoxyalkyl groups
R6	Hydrogen or alkyl-related substituent; supplied text is truncated
Use	No use limitation in the compound claim

The phrase requiring the two amide residues to be "different from each other" is a meaningful limitation. A symmetrical diamide in which both amide residues are identical may fall outside claim 1 even if all other structural elements are present.

The claim also uses nested variable definitions. A molecule may fall within the genus even if it does not match any one of the specifically named compounds, provided every substituent satisfies the Markush definitions.

What compounds are specifically claimed?

Claims 2, 3, 4, and 10 provide narrower species claims.

Claim	Compound description	Claim function
2	5-Methoxyacetylamino derivative with one 2,3-dihydroxy-N-methylpropyl amide residue and one 2,3-dihydroxypropyl residue	Named species
3	S-2-Hydroxypropionylamino derivative with the same dihydroxypropyl and N-methyl-dihydroxypropyl pattern	Named stereochemical species
4	5-Methoxyacetylamino derivative with an alternative dihydroxy side-chain arrangement	Named species
10	5-Acetylamino derivative with 2,3-dihydroxypropyl and 2,3-dihydroxy-N-methylpropyl residues	Named species

Claim 3 is particularly significant because it expressly identifies the S configuration of the 2-hydroxypropionyl group. A racemic compound, the R enantiomer, or an unspecified stereochemical mixture may raise separate claim-construction and anticipation questions.

The species claims provide narrower fallback positions if the broad genus claim is attacked for anticipation, obviousness, written description, or enablement.

What formulations are protected by US Patent 4,364,921?

Claim 8 protects compositions containing a qualifying claim 1 compound in a pharmaceutical carrier. The claim does not, on the supplied text, require a particular:

• Iodine concentration;
• Osmolality;
• pH;
• Buffer;
• Preservative;
• Container;
• Injection volume;
• Route of administration;
• Excipient identity.

Claim 13 adds angiography as the formulation context but does not identify a specific formulation recipe.

The formulation claims therefore appear to be compound-centered rather than formulation-optimization claims. A later formulation patent directed to concentration, viscosity control, pH adjustment, packaging, sterilization, or a particular excipient system could have had a distinct claim scope, even if it used a compound falling within the 1981 patent.

What methods of use are protected?

Claims 9 and 14 cover administration for radiological examination, with claim 14 limited to angiography.

The method claims are potentially broad because they do not specify:

• Computed tomography;
• Digital subtraction angiography;
• Coronary angiography;
• Cerebral angiography;
• Peripheral angiography;
• Intravenous or intra-arterial administration;
• A particular dose or iodine concentration.

The compound limitation remains central. A method using a structurally different contrast agent would not infringe merely because it was used for the same imaging purpose.

The claims also predate modern divided-infringement and induced-infringement case law that often affects method-of-use enforcement. Any historical enforcement analysis would require review of the patent's prosecution history, accused product labeling, prescribing instructions, and conduct of the relevant parties.

When did US Patent 4,364,921 expire?

US Patent 4,364,921 issued on January 18, 1983, according to the USPTO patent record. It was subject to the pre-URAA patent term generally calculated as 17 years from issuance. On that basis, the patent expired on January 18, 2000, subject to any patent-term adjustment, terminal disclaimer, or other term-specific record entry.[1]

Because the patent expired more than two decades ago:

• It cannot support a current patent infringement action.
• It cannot block an ANDA applicant from commercial launch.
• It cannot create a current patent-based injunction risk.
• It does not create a current patent-term extension opportunity.
• Its claims remain relevant only as prior-art and patent-history evidence.

The relevant commercial question is therefore not whether the patent remains enforceable. It does not. The question is whether later, unexpired patents covered the same active ingredient, formulation, manufacturing process, or use.

What is the Orange Book status of US Patent 4,364,921?

US Patent 4,364,921 has no current Orange Book blocking effect because it is expired. Historical Orange Book listing, if any, would not restore enforceability after expiration.

For small-molecule contrast agents, the Orange Book may identify patents associated with approved new drug applications, including:

• Drug substance patents;
• Drug product or formulation patents;
• Method-of-use patents.

An expired patent can remain visible in historical regulatory records while having no current ability to delay ANDA approval or prevent generic launch. The FDA's patent-listing framework distinguishes regulatory listing from enforceable patent term.[2]

No biosimilar pathway applies to these products. Nonionic iodinated contrast agents are chemically synthesized small molecules regulated through the NDA/ANDA framework, not biologic products regulated through section 351(k) of the Public Health Service Act.

Which companies competed in the nonionic contrast-agent market?

The patent sits within the broader development of nonionic monomeric and dimeric iodinated contrast agents. Key commercial products included the following:

Active ingredient	Representative brand	Major historical sponsor or commercial company	Product type
Iopamidol	Isovue	Bracco	Nonionic monomer
Iohexol	Omnipaque	GE Healthcare and predecessors	Nonionic monomer
Iopromide	Ultravist	Bayer and predecessors	Nonionic monomer
Ioversol	Optiray	Mallinckrodt and predecessors	Nonionic monomer
Ioxilan	Oxilan	Guerbet and predecessors	Nonionic monomer
Iodixanol	Visipaque	GE Healthcare and predecessors	Nonionic dimer

These products do not necessarily fall within US Patent 4,364,921. Structural differences at the 5-position, amide nitrogen atoms, hydroxylated side chains, stereocenters, and dimeric architecture can place a product outside the claim genus.

The key comparison is between a patent claim and the exact active ingredient, not between commercial products that share the same therapeutic category.

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

US Patent 4,364,921 is primarily an early composition-of-matter and use patent. Later estates in the contrast-media sector generally added protection in four areas:

Active-ingredient patents

Later patents claimed distinct substitution patterns, stereoisomers, or different triiodinated structures. These patents could cover products outside the 4,364,921 genus.

Formulation patents

Formulation patents often address high-concentration injectable products, reduced viscosity, osmolality, stability, pH, container compatibility, and ready-to-use presentations. A later formulation patent could create a separate barrier after expiration of the original compound patent.

Manufacturing patents

Manufacturing claims can cover:

• Selective amidation;
• Protection and deprotection of polyols;
• Iodination conditions;
• Purification;
• Control of regioisomers;
• Control of stereoisomer content;
• Crystallization or isolation;
• Removal of residual solvents and impurities.

These claims may matter even when the compound itself is off-patent. Their commercial significance depends on whether a noninfringing process is available at acceptable cost and scale.

Method-of-use patents

Later method patents may target specific imaging procedures, dosing regimens, organ systems, or patient populations. Such patents must be assessed separately from the broad radiological-examination method in claim 9.

What patent litigation and Paragraph IV risks exist?

US Patent 4,364,921 cannot support a current Paragraph IV challenge because its term has expired. A Paragraph IV certification is relevant only where an ANDA applicant addresses an unexpired listed patent.

Historical challenges involving related nonionic contrast agents would have focused on:

• Whether the generic active ingredient was within the claimed chemical genus;
• Whether a named species was anticipated;
• Whether the genus was obvious in view of earlier iodinated contrast compounds;
• Whether the patent adequately described and enabled the full Markush scope;
• Whether the formulation or labeling infringed a method claim;
• Whether later patents, rather than 4,364,921, controlled market entry.

No current litigation risk can arise from the expired patent itself. A current generic entrant would need to review later patents listed for the relevant reference product, as well as unlisted formulation, process, and use patents that could create separate litigation exposure.

How strong is the patent estate for current commercial purposes?

The current estate strength of US Patent 4,364,921 is zero as an exclusionary right because the patent is expired. Its historical claim breadth was substantial, but breadth does not translate into current commercial value after expiration.

Issue	Assessment
Compound claim breadth	Broad genus, narrowed by different-amide-residue requirement
Species protection	Meaningful fallback claims for named compounds
Formulation protection	Broad carrier-based claim, limited technical detail
Method protection	Broad radiological-examination and angiography claims
Current enforceability	None
Current Orange Book blocking value	None
Biosimilar relevance	None
Generic launch impact	No current barrier
Manufacturing barrier	Only through later unexpired process patents
Geographic reach	United States only; foreign family members required separate review

The patent may still have analytical value in determining whether later patents represent genuine technical advances or claim strategies built around the same chemical platform.

What generic launch scenarios exist today?

For a product covered only by US Patent 4,364,921, the principal launch scenario is an ordinary generic pathway without a patent-based delay from this patent.

A current entrant would typically evaluate:

1. FDA approval requirements for the relevant contrast agent;
2. Reference-product exclusivity, if any;
3. Current Orange Book-listed patents;
4. Non-Orange Book formulation and process patents;
5. Manufacturing know-how and supplier qualification;
6. Sterility, container, and injectable-product requirements;
7. Clinical labeling and method-of-use exposure.

The major practical barriers are likely regulatory comparability, sterile manufacturing, iodine-containing raw-material control, impurity specifications, and commercial scale rather than this expired patent.

Key Takeaways

• US Patent 4,364,921 covers triiodinated isophthalic acid diamides, related pharmaceutical compositions, and radiological-examination methods.
• Claim 1 is a broad Markush genus, subject to the requirement that the two amide residues differ.
• Claims 2, 3, 4, and 10 identify narrower chemical species.
• Claims 8 and 13 cover pharmaceutical compositions, including angiography formulations.
• Claims 9 and 14 cover radiological examination and angiography methods.
• The supplied version of claim 1 is textually truncated at the R6 definition, limiting exact construction of the complete genus.
• The patent issued on January 18, 1983 and expired, on the ordinary pre-URAA term calculation, on January 18, 2000.
• It has no current blocking Orange Book effect and cannot support a current Paragraph IV enforcement action.
• These are small-molecule contrast agents, so biosimilar analysis is not applicable.
• Current market-entry risk must be assessed against later active-ingredient, formulation, process, and method-of-use patents.
• The relevant competitive products include iopamidol, iohexol, iopromide, ioversol, ioxilan, and iodixanol.

FAQs about US Patent 4,364,921 and iodinated contrast agents

Does US Patent 4,364,921 cover iopamidol?

The supplied claims cover a genus of triiodinated isophthalic acid diamides that may overlap structurally with certain nonionic contrast agents. Product-specific coverage requires mapping the complete molecular structure against every limitation of claim 1 and the narrower species claims.

Can an ANDA applicant receive a stay based on this patent?

No. An expired patent cannot provide the patent basis for a current 30-month stay under the Hatch-Waxman framework.

Does claim 8 cover every injectable contrast formulation?

No. The formulation must contain a compound within claim 1 and a pharmaceutically acceptable carrier. A formulation using a structurally different active ingredient falls outside the claim even if it is used for the same imaging purpose.

Are foreign equivalents of US Patent 4,364,921 still enforceable?

Not automatically. Each national patent has its own filing history, term, maintenance requirements, and expiration date. A US expiration date does not establish the status of foreign family members.

Can later process patents block manufacture of a compound covered by this expired patent?

Yes. Expiration of the compound patent does not eliminate separately enforceable process patents, formulation patents, impurity-control patents, or method-of-use patents that remain in force.

References

1. United States Patent and Trademark Office. (1983). US Patent No. 4,364,921, triiodinated isophthalic acid diamides, pharmaceutical compositions, and radiological examination methods. U.S. Department of Commerce.

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

3. U.S. Food and Drug Administration. (2022). Listing of patent information in the Orange Book. Center for Drug Evaluation and Research.

4. U.S. Food and Drug Administration. (2015). Abbreviated new drug application submissions: Refuse-to-receive standards. Center for Drug Evaluation and Research.

Drugs Protected by US Patent 4,364,921

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 4,364,921

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	2909439	Mar 08, 1979

International Family Members for US Patent 4,364,921

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	1061
Australia	529565
Australia	5627280
Canada	1130316
Czechoslovakia	226408