United States Patent 4,396,597: Claim Scope, Expiration, Litigation, and X-Ray Contrast Patent Landscape

U.S. Patent No. 4,396,597 protects a buffered, high-concentration injectable formulation of certain nonionic iodinated X-ray contrast agents. Its central invention is not the broad discovery of iodinated contrast media, but the use of a low-concentration amine buffer whose pH decreases as temperature rises and whose pKa is no greater than 9.5 at 15°C. The patent issued on August 2, 1983, and expired on August 2, 2000, under the pre-1995 patent-term rule. It has no current enforceable patent term in the United States. [1]

The patent could have been relevant to sterile injectable formulations containing the claimed contrast-agent class, particularly formulations using meglumine or tromethamine at 5 to 25 mM. It does not create a current barrier to generic or competing contrast-agent products.

What does U.S. Patent 4,396,597 protect?

The patent claims a pharmaceutical solution containing four principal elements:

A nonionic iodinated X-ray contrast agent within a specified chemical class.
An iodine concentration of 100 to 450 mg I/mL.
A physiologically acceptable buffer system containing a qualifying amine buffer.
A temperature-dependent pH profile in which pH falls as temperature rises.

The patent also claims selected buffers, selected contrast-agent structures, a specified example compound, sterile injectable solutions, and an autoclaved product.

Claim	Principal subject matter	Relative scope
1	Broad buffered solution with nonionic iodinated contrast agent, 100-450 mg I/mL, qualifying amine buffer, pKa ≤9.5 at 15°C, and pH falling with temperature	Broadest composition claim
2	Claim 1 where the amine is the sole buffer	Narrower
3	Claim 1 where the buffer is meglumine or tris(hydroxymethyl)methylamine	Narrower
4	Claim 1 with buffer concentration no greater than 50 mM	Redundant limitation because claim 1 already contains it
5	Claim 4 with buffer concentration of 5-25 mM	Narrower
6	Claim 1 limited to a defined iodinated isophthalamide structure	Narrower chemical genus
7	Claim 6 limited to the specified triiodoisophthalamide compound	Species claim
8	Claim 1 where the solution is sterile and injectable	Product-use and dosage-form limitation
9	Sterile injectable solution prepared by autoclaving in the presence of ammonia or a qualifying water-soluble amine	Separate process-defined product claim

How broad is claim 1 of U.S. Patent 4,396,597?

Claim 1 is a combination claim. A product must satisfy every material limitation to fall within its literal scope.

Contrast-agent limitation

The claimed contrast agent must be a nonionic m-carboxamido-o-iodo-N-(beta-hydroxyalkyl)aniline X-ray contrast agent. The wording identifies a class of highly iodinated aromatic compounds having:

Nonionic character;
Carboxamido substitution;
Ortho iodine substitution;
A beta-hydroxyalkyl group attached to nitrogen; and
Utility as an X-ray contrast agent.

A commercially used nonionic iodinated contrast agent would not automatically infringe. The product must also fall within the structural class described in the claim and meet the formulation limitations.

Concentration limitation

The solution must contain 100 to 450 mg iodine per milliliter. This is a substantial limitation because many injectable iodinated contrast products are sold in concentrations within or near this range.

A product below 100 mg I/mL or above 450 mg I/mL would fall outside claim 1 based on the express concentration range. A concentration exactly at either endpoint is included unless a different construction applies.

Buffer limitation

The buffer system must contain an amine conforming to the extensive Markush definition in claim 1. The definition covers:

Ammonia;
Primary, secondary, and tertiary amines;
Hydroxyalkyl, carboxyl, carboxamido, mercapto, and heterocyclic substituents;
Amino-substituted alkyl groups;
Sugar residues;
Pyrrolidine and piperidine rings bearing selected substituents.

Claims 3 and 9 identify two commercially and formulation-relevant examples: meglumine and tromethamine, also known as tris(hydroxymethyl)aminomethane or TRIS.

pKa and temperature-dependent pH limitations

The buffer system must have a pKa of no greater than 9.5 at 15°C. The solution's pH must decrease as temperature increases.

These limitations are technically important. A conventional buffer with a suitable pKa but a different temperature coefficient may not satisfy the claim. Conversely, a formulation that uses a listed amine but has a pKa above 9.5 at the specified temperature would not meet claim 1.

The claim requires assessment of the buffer system, not merely the isolated amine. Ionic strength, formulation composition, concentration, and measurement conditions can affect measured pH and apparent pKa. The patent therefore presents potential claim-construction and analytical issues that would have mattered during the patent term.

What formulations are protected by claims 2 through 5?

Claims 2 through 5 progressively narrow the buffer formulation.

Meglumine and tromethamine formulations

Claim 3 expressly covers formulations using:

Meglumine; or
Tris(hydroxymethyl)methylamine, commonly called tromethamine or TRIS.

Claim 3 remains subject to all limitations of claim 1. Naming the buffer does not remove the required iodine concentration, pH behavior, pKa threshold, and contrast-agent structure.

Low-buffer formulations

Claim 5 covers a buffer concentration between 5 and 25 mM. This is narrower than claim 1's maximum concentration of 50 mM.

Claim 4 is substantively duplicative of claim 1 because claim 1 already requires the buffer concentration to be no greater than 50 mM. The additional claim may have been included for drafting or prosecution reasons, but it does not materially expand the claim set.

Sole-buffer formulations

Claim 2 applies where the amine is the sole buffer. A formulation containing a second buffer system may avoid claim 2 while remaining potentially relevant to claim 1, depending on whether the overall system still satisfies claim 1.

What compound is covered by claims 6 and 7?

Claim 6 narrows the broad contrast-agent class to a substituted triiodoisophthalamide structure. It defines substituents through multiple alternatives covering hydroxyalkyl, acyloxyalkyl, sugar, alkylcarbonyl, and alkylsulfonyl groups.

Claim 7 narrows further to:

5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide.

This is a species claim. It remains dependent on claim 6 and, through claim 6, on claim 1. A formulation containing the claim 7 compound would therefore still need to meet the concentration, buffer, pKa, and temperature-dependent pH limitations inherited from the earlier claims.

The patent does not claim the compound in every possible dosage form or formulation. It claims the compound as an ingredient of the specified buffered solution.

What does claim 9 cover?

Claim 9 is an independent claim directed to a sterile injectable solution prepared by autoclaving.

Its key elements are:

A sterile injectable solution;
A nonionic m-carboxamido-o-iodo-N-(beta-hydroxyalkyl)aniline contrast agent;
Autoclaving;
A physiologically acceptable buffer;
Ammonia or a water-soluble amine;
A pKa of no greater than 9.5 at 15°C; and
A pH that decreases with increasing temperature.

Claim 9 does not expressly repeat the 100 to 450 mg I/mL concentration range found in claim 1. That makes it potentially broader in concentration, although it remains limited by the specified chemical class, buffer properties, sterilization process, and injectable sterile product requirements.

Because claim 9 is written as a product "when prepared by" a process, its interpretation would depend on whether the process language is treated as limiting the claimed product and how the product's characteristics are established. During the patent term, a product manufactured by a different sterilization process could have raised a noninfringement argument, but the claim's practical application would have depended on the applicable product-by-process doctrine and evidence of product identity.

When did U.S. Patent 4,396,597 lose exclusivity?

The patent issued on August 2, 1983. For a U.S. patent filed before June 8, 1995, the governing term was generally 17 years from issuance, subject to terminal disclaimers and other adjustments. On that basis, U.S. Patent 4,396,597 expired on August 2, 2000. [1,2]

Event	Date
U.S. patent grant	August 2, 1983
Original statutory term	17 years from grant
Expected expiration	August 2, 2000
Current enforceability	Expired
Current Paragraph IV significance	None as an enforceable patent barrier

The patent cannot currently support an infringement action based on products made, used, or sold after expiration. Patent expiration does not remove historical relevance to freedom-to-operate reviews, prosecution history, technical prior-art analysis, or validity investigations.

What is the FDA and Orange Book status of the patent?

The patent is not a current U.S. regulatory exclusivity asset. Its expiration removes it as a live patent barrier regardless of whether a corresponding contrast-agent product remains FDA-approved.

Iodinated contrast agents are regulated as drugs and may be approved through new drug applications. Commercial products historically associated with nonionic iodinated contrast media include products containing iopamidol, iohexol, iopromide, ioversol, and related agents. The FDA Orange Book is primarily relevant to approved drug products and listed patents submitted by NDA holders. [3]

No current Paragraph IV risk follows from U.S. Patent 4,396,597 because the patent expired more than two decades ago. A modern generic applicant would not need to certify Paragraph IV against this patent. If the patent had remained unexpired and had been listed for an applicable NDA, the relevant challenge would have involved claims directed to the formulation, not merely the existence of the active iodine-containing molecule.

FDA approval and patent status are separate questions. A product may remain approved after the patent expires, and a patent may expire without affecting the product's regulatory approval.

What patent litigation affects U.S. Patent 4,396,597?

The provided claim set establishes the patent's technical scope but does not establish a current infringement action, settlement, or Paragraph IV proceeding involving this patent.

Because the patent expired in 2000, it has no present-term enforcement value. Any historical litigation would require review of federal court dockets, Patent and Trademark Office records, and relevant settlement documents. The expiration date is sufficient to resolve the current exclusivity question: the patent cannot block present-day entry.

No live biosimilar issue arises from this patent. The claimed products are small-molecule iodinated contrast agents, not biologics. A generic contrast-agent applicant would generally use an ANDA pathway where the reference product and active ingredient satisfy applicable FDA requirements. Biosimilar approval under the Public Health Service Act is not the relevant pathway.

How strong was the patent estate?

The patent's estate was technically focused rather than broad across the entire contrast-media field.

Strength factor	Assessment
Chemical composition coverage	Moderate to broad in claim 1; narrower in claims 6 and 7
Formulation coverage	Strong for the claimed low-buffer, temperature-responsive systems
Specific buffer coverage	Clear coverage for meglumine and tromethamine
Sterile injectable coverage	Present through claim 8
Process coverage	Present through autoclaving claim 9
Coverage of all nonionic contrast agents	No
Coverage of unbuffered products	No
Coverage of unrelated buffers	Generally no
Current enforceability	None because the patent expired

The strongest commercial position would have been a sterile injectable product containing a covered triiodoisophthalamide at 100 to 450 mg I/mL, buffered with meglumine or tromethamine at 5 to 25 mM, and exhibiting the required pH-temperature relationship.

The patent would have been weaker against:

A contrast agent outside the claimed chemical class;
A formulation outside the iodine concentration range;
A buffer with a pKa above the threshold;
A system whose pH did not decline with increasing temperature;
An unbuffered solution;
A product using a materially different formulation architecture; or
A product manufactured without the claimed autoclaving process, where claim 9's process limitation was material.

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

Modern risk is more likely to arise from later patents covering:

New contrast-agent molecules;
Specific injectable concentrations;
Premixed containers and delivery systems;
Pharmaceutical stability improvements;
Manufacturing and impurity-control processes;
Combination products and injector systems;
New diagnostic uses; and
Formulation excipients or container-closure systems.

U.S. Patent 4,396,597 is an expired formulation patent. It should be treated as historical prior art and a technical reference, not as a current freedom-to-operate obstacle.

Issue	U.S. Patent 4,396,597	Current commercial risk
Active ingredient	Defined nonionic iodinated contrast-agent class	Depends on later composition patents
Formulation	Amine-buffered injectable solution	Depends on later formulation patents
Manufacturing	Autoclaving covered in claim 9	Later process patents may remain relevant
Method of use	No distinct diagnostic method-of-use claim in the provided claims	Later use patents may apply
Biosimilar exposure	None	Not applicable to small molecules
Paragraph IV exposure	None from this patent	Depends on later unexpired Orange Book patents
Geographic coverage	United States only for this patent	Foreign family members must be reviewed separately
Current blocking effect	None	Must be assessed against later patents

Does the patent have geographic coverage outside the United States?

U.S. Patent 4,396,597 provides rights only in the United States. Any corresponding protection in Europe, Japan, Canada, or other jurisdictions would depend on separate national patents or regional applications.

Foreign patent terms, prosecution outcomes, claim amendments, and expiration dates may differ. A U.S. expiration date does not establish that every family member expired on the same date. For a global launch, the patent family and national registers would need to be reviewed separately. The U.S. patent itself cannot support an injunction outside the United States.

What generic launch risks exist?

There is no current launch risk from U.S. Patent 4,396,597. The patent expired in 2000, and its claims cannot prevent present manufacture, regulatory submission, sale, or use.

The remaining commercial risks would arise from other rights, including:

Later patents covering a specific active ingredient;
Unexpired patents covering a formulation or concentration;
Orange Book-listed patents associated with a reference product;
Manufacturing patents;
Device or injector patents;
Regulatory exclusivity independent of patent rights; and
Trade-secret or know-how barriers involving sterile manufacture.

A generic launch analysis should distinguish the expired patent from any later patent family that claims the same marketed product or manufacturing route.

What licensing deals are associated with the patent?

The supplied patent information does not establish a current license, assignment, settlement, or commercial agreement associated with U.S. Patent 4,396,597. Any historical license would not revive the expired patent or create a present patent exclusion right.

Assignments and ownership changes affect title during the patent term. They do not extend the statutory expiration date.

Key Takeaways

U.S. Patent 4,396,597 claims buffered injectable solutions containing selected nonionic iodinated X-ray contrast agents.
The core formulation limits are 100 to 450 mg I/mL, an amine buffer, pKa of no greater than 9.5 at 15°C, and pH that decreases as temperature increases.
Meglumine and tromethamine are expressly covered examples.
Claims 6 and 7 narrow the invention to defined triiodoisophthalamide structures and a specific compound.
Claim 9 separately addresses autoclaved sterile injectable solutions.
The patent issued on August 2, 1983, and expired on August 2, 2000.
It presents no current Paragraph IV, Orange Book, generic-launch, biosimilar, or infringement barrier.
Any present commercial risk must come from later patents, regulatory exclusivity, manufacturing rights, devices, or foreign family members.

FAQs

Is U.S. Patent 4,396,597 still enforceable?

No. The patent expired on August 2, 2000, under the pre-1995 17-year patent-term rule.

Does the patent claim iopamidol, iohexol, or iopromide broadly?

No. The claims do not cover every nonionic iodinated contrast agent. They require the claimed chemical class and formulation limitations. Claim 7 covers the specifically recited triiodoisophthalamide compound.

Can a product avoid claim 1 by using a buffer concentration above 50 mM?

Yes, based on the express concentration limitation, a formulation above 50 mM would not meet that limitation. The patent has no current enforceability in any event.

Does claim 9 cover a non-autoclaved sterile injectable product?

Claim 9 expressly requires preparation by autoclaving. A non-autoclaved product would present a noninfringement position under the claim's process language, although the patent is expired.

Is a Paragraph IV certification required for this patent?

No. An expired patent cannot create a current Paragraph IV challenge requirement or delay generic approval based on patent term.

Sources:

U.S. Patent No. 4,396,597, “X-ray contrast media,” issued August 2, 1983. United States Patent and Trademark Office. https://patents.google.com/patent/US4396597
35 U.S.C. § 154. Patent term provisions for patents subject to the pre-1995 term rules. United States Code. https://www.law.cornell.edu/uscode/text/35/154
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	28764/78	Jul 4, 1978

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	222337	⤷ Start Trial
Austria	371998	⤷ Start Trial
Austria	A464479	⤷ Start Trial
Australia	4861579	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,396,597

Summary for Patent: 4,396,597