United States Patent 6,143,274: Claim Scope, Patent Expiration, and Gadolinium Contrast-Agent Landscape

U.S. Patent No. 6,143,274 is a broad, expired method-of-use patent covering administration of charge-neutral tetraazacyclo metal complexes for in vivo imaging and radiopharmaceutical therapy. Its most commercially relevant embodiment is the neutral gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, commonly known as gadoteridol, the active agent in ProHance.

The patent’s claim strategy combines five elements: a tetraazacyclo ligand, a metal complex with defined physicochemical properties, charge neutrality in aqueous solution, administration to a mammal, and imaging or radiotherapeutic use. The patent expired in 2017 under the ordinary pre-1995 U.S. patent-term rule, eliminating current U.S. infringement risk from the patent itself. Its historical significance remains relevant for freedom-to-operate analysis, prosecution history, and identification of related continuation, foreign, formulation, and product patents.

What does U.S. Patent 6,143,274 cover?

The patent covers methods of using charge-neutral complexes formed between a metal atom and a tetraazacyclo compound. The independent claims are method claims rather than composition claims.

There are seven principal independent claims:

Claim	Use category	Core subject
1	Brain imaging	Imaging brain tissue in vivo
21	Heart imaging	Imaging heart tissue in vivo
41	Kidney imaging	Imaging kidney tissue in vivo
61	Prostate imaging	Imaging prostate tissue in vivo
81	Breast imaging	Imaging breast tissue in vivo
101	Bladder imaging	Imaging bladder tissue in vivo
121	Spleen imaging	Imaging spleen tissue in vivo
141	Tumor imaging	Imaging tumor tissue in vivo
161	Arthrography	In vivo joint imaging
181	Radiopharmaceutical therapy	Radioactive metal complex therapy
184	Radiopharmaceutical therapy	Therapy using a specified tetraazacyclo ligand
185	Radiopharmaceutical therapy	Therapy using an unsymmetrically substituted tetraazacyclo compound
186	Radiopharmaceutical therapy	Therapy using a specified unsymmetrically substituted ligand

The provided claim set contains 186 claims. Claims 1 through 180 generally use a repeated imaging-claim structure. Claims 181 through 186 address radiopharmaceutical therapy and are materially different in scope.

What is the broadest enforceable claim concept?

The broadest imaging concept is a method that requires:

Administration of an effective amount of a contrast agent to a mammalian host.
A contrast agent containing a complex of a metal atom and a tetraazacyclo compound.
The complex being charge neutral in aqueous solution.
Acquisition of an in vivo image using x-ray, radionuclide, ultrasound, or magnetic resonance imaging equipment.

The claim does not require gadolinium, a specific ligand, intravenous administration, a particular imaging sequence, or a particular tissue unless a dependent claim is used. Claim 1 therefore reaches a wide class of neutral tetraazacyclo metal complexes used for brain imaging.

The same structure is repeated for heart, kidney, prostate, breast, bladder, spleen, and tumor imaging. Claim 161 covers arthrography without specifying a particular anatomical tissue.

The broad claims are limited by the requirement that the complex be charge neutral in aqueous solution. A charged gadolinium chelate, including many conventional ionic extracellular MRI agents, would not satisfy that limitation.

How do the dependent claims narrow the patent scope?

The dependent claims add physicochemical, structural, dosing, formulation, and targeting limitations.

Physicochemical limitations

Claims 3 through 8, and their counterparts in the other tissue groups, impose the following limitations:

Property	Claimed threshold
Equilibrium constant, Keq	Greater than 19 M^-1
Higher Keq limitation	Greater than 23 M^-1
Aqueous conductivity	Less than 10 mho·cm²·mmol^-1
Lower conductivity limitation	Less than 2 mho·cm²·mmol^-1
Osmolality at 0.5 M	Less than 1 Osmol/kg water
Lower osmolality limitation	Less than 0.65 Osmol/kg water
Solubility and stability	At least 0.25 M at 20-37°C
Higher concentration stability	At least 0.5 M at 20-37°C
Highest concentration stability	At least 0.75 M at 20-37°C
Falling-ball viscosity at 0.5 M	Less than 1.5 cP at 25°C

These limitations are important because they distinguish neutral, highly concentrated, low-osmolality injectable solutions from ionic or poorly soluble contrast agents.

The conductivity and osmolality limitations are functional product attributes. A product would need analytical testing under the stated conditions to establish whether it falls within these claims. The claims do not define a specific test protocol beyond the stated temperature, concentration, and measurement units, which could create claim-construction and reproducibility issues in litigation.

Administration and dosage limitations

The patent claims bolus administration and intravenous administration in specified dose ranges.

Anatomical use	Claimed intravenous dose
Brain	0.05-1.0 mmol/kg
Heart	0.25-1.0 mmol/kg
Kidney	0.05-0.25 mmol/kg
Prostate	0.25-1.0 mmol/kg
Breast	0.05-1.0 mmol/kg
Bladder	0.05-1.0 mmol/kg
Spleen	0.05-1.0 mmol/kg
Tumor	0.05-1.0 mmol/kg
Arthrography	At least 0.5 mmol/kg intra-articular in claim 162; claim 180 separately recites 0.1-0.25 mmol/kg intravenous administration

The dose limitations are narrower than the independent claims and could have been relevant to a product using a neutral gadolinium chelate outside the claimed dosing range. They have no current exclusionary effect because the patent has expired.

Ligand and complex limitations

Claims 15 and 35, and corresponding claims in the other groups, refer to tetraazacyclodecane or tetraazacyclo compounds having a broad Markush structure. Claims 19 and 39 narrow the complex to gadolinium and the ligand:

10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

This ligand is generally associated with the gadoteridol complex. The claim language identifies the ligand but does not expressly use the commercial name gadoteridol.

The Markush definition permits extensive substitution at the tetraazacyclo ring and pendant groups. It includes alkyl, arylalkyl, alkoxy, hydroxyalkyl, amino-containing groups, nitrile-containing groups, and other substituted structures. The breadth is reduced by the requirement that the final metal complex be charge neutral in aqueous solution and satisfy any additional dependent-claim property.

Biologically active conjugates

Claims 9 and 10 cover complexes bonded to a biologically active entity, including:

Bile acids
Fatty acids
Lipids
Sugars and other alcohols
Amino acids
Peptides
Monoclonal antibodies
Other proteins

These claims extend beyond conventional extracellular MRI contrast agents. They address targeted or conjugated contrast agents in which the chelate is attached to a biological targeting or functional entity.

What are the radiopharmaceutical therapy claims?

Claims 181 through 186 cover radiopharmaceutical therapy rather than diagnostic imaging.

The central elements are:

A radioactive metal ion.
A tetraazacyclo compound.
Binding of the complex to a disease-specific entity.
Administration of an effective amount.

Claim 182 specifies a monoclonal antibody or antibody fragment as the disease-specific entity. Claim 183 covers administration into a specific body cavity. Claims 185 and 186 focus on an unsymmetrically substituted tetraazacyclo compound.

These claims could encompass targeted radioimmunotherapy constructs in which a radioactive metal is chelated by a tetraazacyclo ligand and attached to an antibody or other targeting molecule. They are structurally broader than a conventional MRI claim in one respect because they do not require the complex to be charge neutral in every claim. Claim 181 does include charge neutrality, while claim 185 does not expressly repeat it.

What product is most closely associated with the patent?

The closest commercial product is ProHance, an MRI contrast agent containing gadoteridol. Gadoteridol is a neutral macrocyclic gadolinium chelate based on the 10-(2-hydroxypropyl)-DO3A ligand identified in claims 19, 39, 59, 79, 99, 119, 139, and 159.

Product	Active ingredient	Charge character	Macrocyclic or linear	Primary use
ProHance	Gadoteridol	Neutral	Macrocyclic	MRI contrast
Dotarem/Clariscan	Gadoterate meglumine	Ionic formulation	Macrocyclic	MRI contrast
Gadavist/Gadovist	Gadobutrol	Neutral	Macrocyclic	MRI contrast
Omniscan	Gadodiamide	Neutral complex with formulation components	Linear	MRI contrast
OptiMARK	Gadoversetamide	Neutral complex with formulation components	Linear	MRI contrast
Magnevist	Gadopentetate dimeglumine	Ionic	Linear	MRI contrast
MultiHance	Gadobenate dimeglumine	Ionic	Linear	MRI contrast
Eovist/Primovist	Gadoxetate disodium	Ionic	Linear	Liver MRI

The patent’s claim language is not limited to MRI. It expressly includes x-ray, radionuclide, ultrasound, and MRI apparatus. In commercial practice, the strongest relevance is to gadolinium-based MRI contrast agents.

What is the patent expiration date for U.S. Patent 6,143,274?

U.S. Patent 6,143,274 issued on November 7, 2000. The patent appears to fall under the pre-June 8, 1995 transition rules, under which the term generally runs for 17 years from issuance rather than 20 years from the earliest effective U.S. nonprovisional filing date.

The ordinary term therefore ended on November 7, 2017, subject to any terminal disclaimer, patent-term adjustment, or other recorded term event. The patent is no longer an enforceable barrier to U.S. commercial use.

Milestone	Date or status
Patent issued	November 7, 2000
Ordinary 17-year term endpoint	November 7, 2017
Current enforceability	Expired
Current Paragraph IV relevance	None for this patent
Current Orange Book exclusivity effect	None

The expiration of this patent does not establish that all related patents have expired. Separate patents may have covered gadoteridol composition, manufacturing processes, formulations, specific indications, delivery systems, or later-developed uses.

What is the Orange Book status of U.S. Patent 6,143,274?

U.S. Patent 6,143,274 is not a current Orange Book patent barrier. The patent’s claims are method claims covering diagnostic imaging and radiopharmaceutical therapy. Orange Book listing depends on whether a patent claims the approved drug substance, drug product, or an approved method of use and whether the patent was submitted and accepted for listing.

The patent’s age and expiration status mean it does not provide current Hatch-Waxman exclusivity. Any historic Orange Book listing would no longer prevent approval or launch based on this patent.

The relevant regulatory distinction is:

FDA approval governs whether a contrast agent may be marketed.
Orange Book listing identifies certain patents associated with approved drug products.
Patent expiration governs whether the patent can exclude conduct.
Regulatory exclusivity and patent term are separate rights.

Were Paragraph IV challenges or litigation associated with this patent?

A Paragraph IV certification would be relevant only while the patent was listed and unexpired against an approved drug product. After November 7, 2017, this patent could not independently support a current Paragraph IV litigation block.

The provided information does not establish a complete litigation history, terminal disclaimer record, patent-term adjustment record, or Orange Book listing history. A definitive case-by-case litigation conclusion cannot be made from the claims alone.

The legal risk analysis is still straightforward:

Any historical challenge would have focused on claim construction, written description, enablement, anticipation, obviousness, or noninfringement.
A competitor could challenge whether its chelate was charge neutral in aqueous solution.
A competitor could dispute whether its ligand fell within the Markush formula.
Physicochemical claims could be challenged based on measurement methodology and reproducibility.
A product using a different imaging indication could avoid tissue-specific claims but potentially remain within a broader claim if the claim covered the relevant imaging method.

How strong was the patent estate?

The patent was broad in subject matter but uneven in practical enforcement strength.

Strengths

Independent claims covered multiple high-value anatomical indications.
Charge neutrality created a meaningful distinction from ionic chelates.
The claims covered multiple imaging modalities.
The Markush structure reached a broad class of tetraazacyclo ligands.
Dependent claims added commercially relevant properties, including low osmolality and high concentration stability.
Claims 181 through 186 extended into targeted radiopharmaceutical therapy.

Weaknesses

The claims were method claims, not direct composition claims.
The tissue categories were broad and potentially vulnerable to written-description or enablement arguments depending on the specification.
Several dependent claims used unusual physicochemical parameters that could create proof and claim-construction disputes.
The claims repeated substantially similar limitations across many tissue indications.
The patent expired in 2017.
Later products may have been protected by separate composition, formulation, manufacturing, or use patents.

The patent’s commercial strength was likely greatest against a neutral macrocyclic gadolinium agent used in the claimed dose range and imaging context. It was weaker against ionic agents, non-tetraazacyclo chelates, products used outside the claimed tissues, and products with materially different administration routes.

What manufacturing and intellectual-property barriers remain?

Although U.S. Patent 6,143,274 is expired, commercial entry into the gadolinium contrast-agent market can still face non-patent and separate patent barriers.

Manufacturing barriers

Manufacturers must control:

Macrocyclic ligand synthesis.
Gadolinium complexation.
Removal of uncomplexed gadolinium.
Residual solvent and elemental impurity levels.
Chelate purity and stereochemical composition.
Injectable formulation stability.
Sterility and endotoxin controls.
Container-closure compatibility.
High-concentration solution behavior.

For gadolinium products, control of free gadolinium is a central quality issue because unchelated gadolinium can create safety and regulatory concerns.

Potential residual IP categories

A current freedom-to-operate review should distinguish the expired patent from:

Composition-of-matter patents for specific chelates.
Process patents for ligand synthesis.
Complexation and purification patents.
Formulation patents.
Container or ready-to-use presentation patents.
Specific indication patents.
Diagnostic workflow or imaging-protocol patents.
Conjugate and targeted radiopharmaceutical patents.
Foreign patents with different expiration dates.

The expiration of a use patent does not authorize use of a separately patented composition or process.

How does this patent compare with competing gadolinium patent estates?

Patent category	Typical claim focus	Relationship to U.S. 6,143,274
Ligand composition patents	Specific macrocyclic or linear chelating compounds	May block manufacture or composition use independently
Gadolinium complex patents	Defined metal-ligand complexes	More direct product coverage than the method claims here
Formulation patents	Concentration, excipients, pH, stability, packaging	May remain relevant after use-patent expiration
Method-of-use patents	MRI, angiography, cardiac, CNS, tumor, or organ-specific use	Closest category to this patent
Targeted-agent patents	Chelate linked to antibodies, peptides, lipids, or sugars	Related to claims 9, 10, and 181-186
Manufacturing patents	Ligand preparation, metalation, purification	Independent entry barrier
Regulatory exclusivity	FDA orphan, pediatric, or other exclusivity	Separate from patent term

Gadoteridol, gadobutrol, gadoterate, and other macrocyclic agents should be analyzed at the product-family level. Similar neutral charge characteristics do not establish infringement because the patent also requires a tetraazacyclo compound and a claimed method of administration and imaging.

What generic launch scenarios existed, and what risks remain?

During the patent term, a generic or follow-on manufacturer could have pursued several strategies:

Use a non-tetraazacyclo chelate.
Use an ionic complex.
Use a different macrocyclic ligand outside the claimed Markush structure.
Avoid a claimed tissue or indication.
Use a dose outside the applicable dependent-claim range.
Challenge the patent through Paragraph IV certification.
Design around the charge-neutrality limitation.
Rely on a separate product whose composition was outside the patent claims.

After expiration, these design-around strategies are no longer needed to avoid this patent. They may still matter against unexpired related patents.

The most commercially important launch scenario is a generic gadoteridol product. Such a product would face FDA requirements for pharmaceutical equivalence, bioequivalence where applicable, manufacturing validation, sterile injectable controls, and clinical or labeling requirements. Patent clearance would need to address the full ProHance-related patent family rather than U.S. 6,143,274 alone.

What is the geographic coverage of the patent?

U.S. Patent 6,143,274 provides rights only in the United States. It does not control:

European Union markets.
United Kingdom markets.
Canada.
Japan.
China.
Australia.
Other jurisdictions.

Related foreign applications may have had different claim scope, prosecution outcomes, term dates, and legal status. Patent families for gadoteridol and related chelates should be reviewed separately by jurisdiction.

The U.S. expiration date cannot be used to infer the status of corresponding foreign patents.

Key Takeaways

U.S. Patent 6,143,274 covers methods using charge-neutral tetraazacyclo metal complexes for in vivo imaging and radiopharmaceutical therapy.
The principal commercial embodiment is the gadoteridol complex used in ProHance.
The patent claims brain, heart, kidney, prostate, breast, bladder, spleen, tumor, and joint imaging.
Dependent claims add bolus dosing, intravenous dose ranges, low osmolality, low conductivity, high stability, low viscosity, and defined ligand structures.
Claims 181 through 186 cover targeted radiopharmaceutical therapy using radioactive metal complexes and disease-specific entities.
The patent issued November 7, 2000, and its ordinary U.S. term ended November 7, 2017.
The patent is expired and does not create a current U.S. Paragraph IV or Orange Book launch block.
Expiration does not resolve separate composition, formulation, manufacturing, foreign, or later-issued method-of-use patents.
The patent was historically strongest against neutral macrocyclic gadolinium agents used within the claimed imaging and dosing framework.

FAQs

Can a company market gadoteridol in the United States after U.S. Patent 6,143,274 expired?

Yes, this patent no longer blocks U.S. marketing. The company must still clear any separate unexpired patents and satisfy FDA requirements.

Does U.S. Patent 6,143,274 claim gadoteridol as a composition?

No. The relevant claims describe methods using a gadolinium complex with the specified HP-DO3A ligand. They are method claims rather than standalone composition claims.

Does the patent cover gadobutrol?

Potentially relevant claim language includes neutral tetraazacyclo complexes, but infringement would depend on whether gadobutrol satisfies the claimed tetraazacyclo structure and every limitation of the asserted method claim. The patent’s expiration makes the issue historical in the United States.

Could the patent cover antibody-linked gadolinium agents?

Claims 9 and 10 expressly contemplate complexes bonded to biologically active entities, including monoclonal antibodies and other proteins. Claims 181 through 186 separately address disease-targeted radioactive metal complexes.

Does patent expiration eliminate FDA approval requirements for a generic MRI contrast agent?

No. Patent expiration removes the patent exclusion right. FDA approval, manufacturing compliance, sterile product controls, labeling, and applicable clinical or bioequivalence requirements remain separate regulatory obligations.

Sources

United States Patent and Trademark Office. (2000). U.S. Patent No. 6,143,274, methods for imaging and radiopharmaceutical therapy using neutral tetraazacyclo metal complexes.
United States Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations.
United States Code, 35 U.S.C. § 154. (2018). Contents and term of patent; provisional rights.
United States Food and Drug Administration. (2017). ProHance prescribing information: Gadoteridol injection.
United States Food and Drug Administration. (2018). Gadolinium-based contrast agents: Drug safety communication.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	1296715	⤷ Start Trial
Germany	3772785	⤷ Start Trial
Germany	3855451	⤷ Start Trial
European Patent Office	0232751	⤷ Start Trial
European Patent Office	0292689	⤷ Start Trial
Japan	2537502	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,143,274

Summary for Patent: 6,143,274