United States Patent 4,957,939: Scope, Claims, Expiration, and Gadolinium Contrast-Agent Patent Landscape

U.S. Patent No. 4,957,939 is an early Schering AG patent covering sterile pharmaceutical compositions containing physiologically compatible gadolinium chelate complexes for NMR, now generally called MRI, imaging. Its most commercially important embodiment is the aqueous, injectable formulation of gadolinium-diethylenetriaminepentaacetic acid, or gadopentetate, particularly the di-N-methylglucamine salt marketed as Magnevist.

The patent’s enforceable life has ended. Based on the patent’s 1990 issue date and the pre-1995 U.S. patent-term rules, the patent expired no later than September 18, 2007, absent an unusual term adjustment or intervening legal event. It cannot now block generic or competing gadolinium-based contrast agents. Its historical importance remains substantial because it covered the basic sterile composition platform used by the first major extracellular gadolinium MRI agents.

What does U.S. Patent 4,957,939 cover?

The patent covers a sterile pharmaceutical composition containing:

A physiologically compatible gadolinium chelate complex; and
A pharmaceutically acceptable carrier.

The independent claim is composition-based rather than method-based. A product must satisfy all limitations of claim 1 to infringe that claim. The patent does not broadly claim every use of gadolinium in imaging, every gadolinium compound, or every MRI procedure.

Core claim elements

Claim element	Scope
Pharmaceutical composition	Requires a drug composition rather than an isolated chemical compound or research reagent
Enhancement of NMR imaging	Ties the composition to imaging contrast functionality
Physiologically compatible	Excludes toxic, unstable, or clinically unsuitable complexes
Gadolinium chelate complex	Requires gadolinium coordinated by a chelating ligand
Pharmaceutically acceptable carrier	Requires a formulation suitable for pharmaceutical administration
Sterile	Requires sterility, a significant limitation for injectable products

The use of “comprising” generally makes the claims open-ended. A product containing the claimed gadolinium chelate and carrier can fall within the claims even if it also contains additional excipients, buffers, stabilizers, or other ingredients.

How broad is claim 1 of Patent 4,957,939?

Claim 1 is broad at the chemical and formulation levels, but narrower than a claim to all gadolinium MRI contrast agents.

A potentially infringing product would generally need to be:

A pharmaceutical composition;
Sterile;
Suitable for physiological administration;
Formulated with a gadolinium chelate;
Intended or suitable for MRI contrast enhancement; and
Combined with a pharmaceutically acceptable carrier.

The claim does not require:

A particular gadolinium oxidation-state formulation beyond the chelate complex concept;
A specific chelating ligand;
A specific salt;
A particular concentration;
A particular administration route;
An injectable route;
An isotonic solution;
A particular pH; or
A specific commercial product.

Those additional limitations appear in dependent claims.

Claim construction issues

“Physiologically compatible” is a functional and suitability-based limitation. It would likely be evaluated using clinical and pharmaceutical facts, including toxicity, stability, tolerability, and suitability for administration.

“Sterile” is a material limitation. A nonsterile laboratory formulation would not satisfy the literal language of claim 1, although a product made and sold as a sterile pharmaceutical composition would present a stronger historical infringement case.

“Enhancement of NMR imaging” is also material. A gadolinium chelate sold solely for an unrelated industrial or analytical purpose would not automatically satisfy this limitation.

The claims are directed to compositions, not merely to the chemical identity of gadolinium complexes. Manufacture, sale, or commercial use of the claimed sterile composition would have been the principal historical infringement risks.

What chelating agents are covered?

Claims 2 through 9 define progressively narrower chelator categories.

Claims	Covered chelator category
2	Open-chain or cyclic ligands containing organic nitrogen, phosphorus, oxygen, or sulfur
3	Open-chain chelating agents
4	Cyclic chelating agents
5	Aminopolycarboxylic acids
6	NTA, EDTA, HEDTA, DTPA, and hydroxyethyliminodiacetic acid
7	A defined amine formula with hydrogen or C1-C4 alkyl substituents
8	Polyethylene polyamines, including ethylenediamine and diethylenetriamine
9	Defined macrocyclic compounds containing nitrogen or phosphorus and oxygen-, sulfur-, or carbonyl-containing donor groups

DTPA and gadopentetate

Claim 15 specifically identifies diethylenetriaminepentaacetic acid, or DTPA. Claim 27 identifies the di-N-methylglucamine salt of gadolinium(III)-DTPA.

That compound is gadopentetate dimeglumine, the active ingredient in Magnevist. The claim therefore reaches the principal commercial embodiment associated with the patent.

The patent does not claim only gadopentetate. Claims 1 through 6 and related dependent claims extend to numerous other gadolinium chelate structures, subject to the claim limitations and any applicable enablement or written-description analysis.

Macrocyclic compounds

Claim 9 reaches certain macrocyclic chelators. This is important because later MRI agents include macrocyclic gadolinium complexes such as:

Gadoteridol, marketed as ProHance;
Gadoterate meglumine, marketed as Dotarem;
Gadobutrol, marketed as Gadavist or Gadovist.

The existence of a chemical overlap at the broad claim-category level would not by itself establish infringement. The product would also need to satisfy the precise structural limitations of claim 9, including the substituted ring framework and donor-atom requirements shown in the patent’s chemical formula.

The supplied claim text does not reproduce the chemical drawings for formulas 9 through 14. Exact mapping of a modern macrocyclic agent to claim 9 therefore cannot be made from the text alone.

What salt and formulation features are protected?

Claims 10 through 14, 16, and 17 address the acid-base and salt state of the gadolinium complex.

The claims cover complexes:

Without free acid or base groups;
With free acid or base groups;
In salt form with inorganic or organic acids or bases;
Existing as both a gadolinium-chelate salt and an additional acid or base salt;
Existing only as a gadolinium-chelate salt; or
Combined with specified acids, bases, amino acids, or amines.

Claim 17 lists hydrochloric acid, sulfuric acid, acetic acid, citric acid, aspartic acid, glutamic acid, sodium hydroxide, glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, ornithine, and arginine.

These claims were designed to capture pharmaceutical salt selection and neutralization states, including the use of meglumine-type bases to improve aqueous formulation properties.

Stabilizers, sodium chloride, pH, and concentration

Claim	Formulation limitation
18	Conventional galenic stabilizer
19	Sodium chloride
20	Chelate dissolved in water
21	5-250 mmol/L chelate concentration
22	pH of 6.5-8.0
26	Isotonic with blood

Claims 20 through 22 describe an aqueous formulation suitable for parenteral administration. Claim 21 is particularly relevant to commercial contrast solutions because it defines a broad concentration interval rather than a single dose or strength.

Claim 26 narrows the formulation to blood isotonicity. A product could fall within claim 1 without being isotonic, but it would need to satisfy the isotonicity limitation to infringe claim 26.

Which administration routes are covered?

Claims 23 through 25 address administration suitability:

Oral administration;
Neural administration; and
Intravascular administration.

The claims do not require a particular injection technique or imaging protocol. “Neural administration” is broader than standard intravenous use and may include administration associated with neural or central nervous system imaging, subject to the patent’s specification and claim-construction record.

The most commercially important route is intravascular administration. FDA-approved gadolinium-based contrast agents are predominantly administered intravenously, while intrathecal use is more restricted and product-specific.

What does claim 27 cover?

Claim 27 covers a composition in which the chelate is the di-N-methylglucamine salt of gadolinium(III)-DTPA.

This is the claim most directly associated with gadopentetate dimeglumine, the active ingredient in Magnevist. The claim narrows the broader platform claims to a specific salt and metal-chelate combination.

A product containing the same active ingredient could historically have presented a strong claim 27 issue if it also met the sterile composition and carrier limitations of claim 1. Since the patent expired, claim 27 no longer creates a current U.S. market-exclusion right.

How do claims 28 through 32 limit the scope?

Claim 28 excludes gadolinium citrate and gadolinium edetate. Claims 29 through 32 require a nonionic chelate and apply that limitation across selected claim branches.

These claims have two effects:

They narrow the covered subject matter to nonionic complexes; and
They expressly remove at least two compounds from the claim scope.

The proviso in claim 28 is important in infringement analysis. A gadolinium citrate or gadolinium edetate composition would not fall within claim 28 merely because it otherwise satisfies claim 1.

The nonionic limitation also separates the claimed formulations from ionic gadolinium salts and from compositions whose charge state depends on the particular chelate and counterion.

When did U.S. Patent 4,957,939 expire?

Event	Date or status
Patent issued	September 18, 1990
Original statutory framework	Pre-1995 patent term rules
Expected term based on 17 years from issue	September 18, 2007
Current status	Expired
Current blocking effect	None for new U.S. manufacture, sale, or launch

The patent was issued before the change to the standard 20-year term measured from the earliest effective nonprovisional filing date. For a pre-June 8, 1995 application, the applicable term generally used the longer of 17 years from issue or 20 years from the relevant filing date. On the available dates, the 17-year-from-issue period controls.

No current product launch can be blocked by Patent 4,957,939 alone. Any surviving risk would have to arise from a different patent, regulatory exclusivity, trade secret, contract, or product-specific intellectual-property right.

What is the Orange Book status of Patent 4,957,939?

Patent 4,957,939 does not provide a current Orange Book barrier.

The Orange Book concerns FDA-approved drug products and patent information submitted by sponsors. Historical product approval does not keep an expired patent enforceable. Magnevist and other gadolinium contrast agents also do not create a current right to exclude competitors based on the expired patent.

For generic-drug strategy, the relevant question is whether a currently approved reference product has unexpired listed patents or other applicable exclusivity. Patent 4,957,939 is not a live patent obstacle to an abbreviated new drug application or to a competing gadolinium contrast product.

What FDA regulatory status applies to gadolinium contrast agents?

Gadolinium-based contrast agents are FDA-approved prescription drugs regulated as imaging agents. Approved products include:

Active ingredient	Representative product	Structural class
Gadopentetate dimeglumine	Magnevist	Linear ionic DTPA derivative
Gadobenate dimeglumine	MultiHance	Linear ionic
Gadoxetate disodium	Eovist	Linear ionic, hepatobiliary
Gadodiamide	Omniscan	Linear nonionic
Gadoversetamide	OptiMARK	Linear nonionic
Gadoteridol	ProHance	Macrocyclic nonionic
Gadoterate meglumine	Dotarem	Macrocyclic ionic
Gadobutrol	Gadavist	Macrocyclic nonionic

FDA labeling requires warnings concerning gadolinium retention and nephrogenic systemic fibrosis in at-risk patients. The FDA has required class-wide labeling changes and has distinguished agents by retention characteristics and clinical risk profiles [U.S. Food and Drug Administration, 2018].

Regulatory approval does not determine patent infringement. A product can be FDA-approved and still require freedom-to-operate review for active patents covering formulation, manufacturing, delivery, or a particular diagnostic use.

How strong was the historical patent estate?

Historically, the estate was strong as a platform patent because it combined:

A broad gadolinium-chelate composition concept;
Multiple ligand classes;
Specific DTPA coverage;
Salt and counterion claims;
Aqueous pharmaceutical formulations;
Sterility;
Concentration and pH ranges;
Isotonicity; and
Intravascular administration suitability.

Its strongest commercial position was against early competitors seeking to market sterile gadolinium chelate solutions before the expiration of the core patent family.

Its weaknesses included:

Broad functional language such as “physiologically compatible”;
Potential enablement and written-description questions for the full range of open-chain, cyclic, macrocyclic, and heteroatom-containing chelators;
The need to prove sterility and pharmaceutical composition status;
The exclusion of gadolinium citrate and gadolinium edetate in claim 28;
Dependence on exact chemical structures for claim 9; and
The absence of a direct claim to every MRI use or every gadolinium compound.

Current patent strength is zero in terms of exclusionary force because the patent has expired.

Which companies and products are relevant to the competitive landscape?

The principal historical and commercial participants include:

Schering AG, the original patent owner and developer associated with Magnevist;
Bayer AG, which acquired Schering AG and commercialized multiple contrast agents;
Bracco, associated with MultiHance and ProHance in various markets;
Guerbet, associated with Dotarem;
GE HealthCare, associated with Omniscan and related imaging products;
Covidien and Mallinckrodt, historically associated with OptiMARK and contrast-agent commercialization; and
Generic manufacturers supplying gadopentetate and other gadolinium agents after patent expiry.

The commercial competition has shifted from basic composition patent control to product safety, macrocyclic versus linear chemistry, hepatobiliary imaging, manufacturing quality, regulatory approvals, hospital contracting, and supply reliability.

What patent litigation and settlement risks remain?

Patent 4,957,939 cannot support a new infringement injunction or exclusionary claim against a current U.S. competitor because it is expired.

No current Paragraph IV challenge is legally necessary for this patent. A Paragraph IV certification addresses an unexpired patent listed for an FDA reference product. An applicant would not need to certify against an expired patent as a basis for blocking approval.

No current settlement agreement is required to launch a product solely because of this patent. Historical settlements involving gadolinium contrast agents, if any, would not revive the patent or extend its term.

The relevant litigation risks now arise from later patents, including possible claims directed to:

Improved macrocyclic complexes;
Specific impurity profiles;
Manufacturing and purification processes;
Stable injectable formulations;
Container-closure systems;
Reduced free-gadolinium content;
Hepatobiliary targeting;
New imaging indications;
Pediatric dosing;
Combination diagnostic protocols; and
Delivery systems.

A manufacturer must evaluate those later rights separately. Patent 4,957,939 is not a substitute for a current freedom-to-operate search.

What geographic coverage did the patent provide?

The patent provided U.S. rights only. Foreign counterparts may have existed in Europe and other jurisdictions, but expiration dates and legal status depended on each national filing, grant, renewal, and transitional-term rule.

The U.S. patent could not directly block:

Manufacture outside the United States with no U.S. importation or sale;
Purely foreign sales;
Foreign clinical use; or
Foreign regulatory filings, except through applicable local rights.

International launches required separate analysis of corresponding Schering family members, national-phase patents, supplementary protection certificates, and local regulatory exclusivities.

What manufacturing and intellectual-property barriers remain?

The expired patent removed the central composition barrier for gadopentetate-type formulations. Manufacturing remains technically demanding because a commercial product must control:

Chelation completeness;
Free gadolinium;
Residual chelating agent;
Counterion content;
Osmolality;
pH;
Sterility;
Endotoxins;
Particulate matter;
Stability; and
Container compatibility.

Those requirements are regulatory and manufacturing barriers, not continuing rights under Patent 4,957,939. Process patents or confidential know-how may still affect a competitor’s ability to manufacture efficiently.

Key Takeaways

U.S. Patent 4,957,939 covers sterile pharmaceutical compositions containing physiologically compatible gadolinium chelates for MRI enhancement.
The central commercial embodiment is gadopentetate dimeglumine, the active ingredient in Magnevist.
Claims cover broad chelator classes, DTPA, macrocyclic compounds, salt forms, aqueous solutions, pH, concentration, isotonicity, sterility, and administration routes.
Claim 27 specifically targets the di-N-methylglucamine salt of gadolinium-DTPA.
Claim 28 excludes gadolinium citrate and gadolinium edetate.
The patent expired no later than September 18, 2007.
It has no current Orange Book or Paragraph IV blocking effect.
Current competitive risk must be assessed against later formulation, manufacturing, use, and product-specific patents.
The patent’s historical strength was high as a foundational gadolinium contrast-composition patent; its present exclusionary strength is zero.

FAQs About U.S. Patent 4,957,939

Does Patent 4,957,939 cover Magnevist?

Yes. Claim 27 specifically covers the di-N-methylglucamine salt of gadolinium(III)-DTPA, corresponding to gadopentetate dimeglumine, the active ingredient in Magnevist.

Can an applicant still receive FDA approval for a gadopentetate product?

Yes. The expired patent does not prevent FDA approval. The applicant must satisfy applicable drug-quality, clinical, labeling, manufacturing, and regulatory requirements and must evaluate any later unexpired patents.

Does the patent cover all macrocyclic gadolinium agents?

No. Claim 9 reaches a defined macrocyclic structural genus, but not every macrocyclic gadolinium complex automatically falls within it. Exact structural comparison is required.

Is a sterile formulation required for infringement?

For claim 1, yes. Sterility is an express limitation. A nonsterile composition would not literally satisfy that limitation, although other patent claims or legal theories could apply in a different case.

Does expiration eliminate manufacturing barriers for gadolinium contrast agents?

No. Expiration eliminates the patent’s exclusionary effect, but manufacturers must still control free gadolinium, impurities, sterility, endotoxins, osmolality, stability, and other attributes required for an approved injectable drug.

References

Bayer AG. (n.d.). Magnevist (gadopentetate dimeglumine) injection prescribing information. U.S. Food and Drug Administration.

U.S. Food and Drug Administration. (2018). Drug safety communication: FDA warns that gadolinium-based contrast agents are retained in the body; requires new class warnings. https://www.fda.gov/

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

U.S. Patent and Trademark Office. (1990). U.S. Patent No. 4,957,939: NMR contrast agents. Washington, DC.

U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent term information. https://www.uspto.gov/partnerships/patent-term-adjustment

35 U.S.C. §§ 154, 271, 286.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	3129906	Jul 24, 1981
Germany	3302410	Jan 21, 1983
Germany	3401052	Jan 11, 1984

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0071564	⤷ Start Trial	SPC/GB93/060	United Kingdom	⤷ Start Trial
Austria	18719	⤷ Start Trial
Austria	397465	⤷ Start Trial
Austria	52247	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,957,939

Summary for Patent: 4,957,939