US Patent 5,474,756: Claim Scope, Gadobutrol Relevance, Expiration and Patent Landscape

US Patent 5,474,756 covers MRI imaging methods using a charge-neutral aqueous complex of a paramagnetic lanthanide ion and a tetraazacyclo compound. The patent is principally relevant to neutral macrocyclic gadolinium contrast agents, including the chemistry underlying gadobutrol, marketed in the United States as Gadavist by Bayer.

The patent does not claim every gadolinium contrast agent. Its central limitations are:

MRI imaging of mammalian tissue.
Administration of the contrast agent orally, intrathecally or intravenously.
A stable complex between a paramagnetic lanthanide ion and a tetraazacyclo compound.
A complex that is charge neutral in aqueous solution.

The patent’s direct enforcement value is historical. Based on the patent’s 1993 U.S. filing date, the ordinary 20-year term would have ended in March 2013, absent a term adjustment or patent-term extension. The patent is therefore not a current blocking patent for U.S. commercialization. Its claims remain relevant for freedom-to-operate analysis because later patents may claim specific ligands, formulations, manufacturing processes or clinical uses derived from the same technology.

What does US Patent 5,474,756 claim?

The patent contains three material claim layers.

Claim	Claim type	Principal subject matter	Scope
1	Independent method claim	MRI imaging using a neutral lanthanide-tetraazacyclo complex	Broad functional genus
2	Dependent method claim	Claim 1 using a defined substituted tetraazacyclo compound	Narrower chemical genus
3	Dependent method claim	Claim 1 using a tetraazacyclododecane	Intermediate structural scope

The independent claim is a method-of-use claim, not a composition claim. It does not directly claim the contrast agent as a standalone product. Infringement requires practice of the imaging method with an agent meeting the recited structural and charge limitations.

How broad is claim 1?

Claim 1 is broad in several respects.

Covered paramagnetic ions

The claim covers a paramagnetic ion of a lanthanide element. The wording is not limited expressly to gadolinium. Potentially relevant ions include:

Gadolinium
Dysprosium
Holmium
Erbium
Manganese is outside the lanthanide class
Other paramagnetic lanthanide ions, depending on the construction of the claim and the patent specification

Gadolinium is the commercially important species because Gd(III) provides strong magnetic-relaxation effects and is used in extracellular and macrocyclic MRI contrast agents.

Covered administration routes

Claim 1 expressly covers:

Oral administration
Intrathecal administration
Intravenous administration

The intravenous route is commercially dominant for gadolinium-based contrast agents. The inclusion of oral and intrathecal administration expands the literal method scope, but a commercial product must still satisfy the remaining requirements.

Covered imaging procedure

The patient must be subjected to magnetic resonance imaging after administration of the contrast agent. The claim is not limited to a particular MRI sequence, field strength, anatomical region or diagnostic indication.

The language therefore potentially reaches MRI imaging of:

The brain
Spine
Vasculature
Liver
Kidneys
Musculoskeletal tissue
Other mammalian tissues

A use that administers the compound without performing MRI would not satisfy the complete method claim.

Charge-neutrality limitation

The principal technical limitation is that the complex must be charge neutral in aqueous solution.

This limitation distinguishes the claimed agents from ionic gadolinium complexes. Many first-generation MRI agents, including gadopentetate dimeglumine, are administered as ionic complexes or salts. A neutral complex has no net formal charge as an intact complex in aqueous solution, although it may still have polar substituents and may interact with water through coordination or hydrogen bonding.

The claim does not require:

Zero polarity
Zero ionization of every functional group
Absence of counterions in every formulation
A specific osmolality
A specific relaxivity
A specific thermodynamic stability constant
A specific kinetic inertness threshold

The relevant question is whether the claimed complex, as opposed to an associated formulation excipient or salt, is charge neutral in aqueous solution.

What compounds are covered by claim 2?

Claim 2 narrows claim 1 to a tetraazacyclo compound defined by a complex Markush structure. The supplied claim text omits the chemical drawings represented by the placeholders “STR24” through “STR29.” That omission prevents a complete atom-by-atom reconstruction of every member of the genus. The textual limitations nevertheless identify the principal variables.

The claim covers compounds with:

A tetraazacyclo core
A variable Y group defined as oxygen or a substituted nitrogen-related group
R1 substituents including hydrogen, lower alkyl, arylalkyl, phenyl, substituted phenyl, lower alkoxy and hydroxyalkyl groups
G substituents including amino, cyano, alkylamino, dialkylamino, hydroxyalkyl-related groups and other listed functionalities
R2 as hydrogen or alkyl
R3 as hydrogen, hydroxyalkyl, alkoxy, phenyl, substituted phenyl, phenylalkyl or substituted phenylalkyl
X as chloro, bromo or iodo
Substituted phenyl groups carrying up to three substituents selected from halogen, hydroxyl, alkyl, alkoxy, carbamoyl or carboxyl

Relationship to gadobutrol

Gadobutrol is the neutral macrocyclic gadolinium complex used in Gadavist. Its ligand is commonly identified as a DO3A-derived tetraazacyclododecane bearing a hydroxyalkyl substituent. The product is a nonionic, macrocyclic gadolinium contrast agent.

Claim 2 appears directed to the type of substituted macrocyclic ligand chemistry that includes the gadobutrol structure or closely related analogues. A definitive infringement mapping requires the complete chemical figures from the issued patent and a comparison against the exact molecular structure, not only the OCR-like claim text supplied here.

What does claim 3 add?

Claim 3 requires the tetraazacyclo compound to be a tetraazacyclododecane.

This limitation is significant because tetraazacyclododecane is the macrocyclic platform used in several clinically important gadolinium agents. The ring contains four nitrogen atoms in a 12-membered macrocycle. The macrocycle forms a cage-like coordination environment around Gd(III), generally producing greater kinetic inertness than many open-chain chelates.

Claim 3 remains broader than a claim limited to gadobutrol. It does not expressly require:

Gadolinium rather than another lanthanide
A particular hydroxyalkyl substituent
A specific stereochemical configuration
A defined ligand-to-metal ratio
A specific pH
A specific formulation concentration
Gadavist or any commercial brand

A product could fall within claim 3 without being gadobutrol if it used a different tetraazacyclododecane ligand and otherwise satisfied claim 1.

What patent protects gadobutrol and Gadavist?

US Patent 5,474,756 is relevant to the foundational method scope for neutral macrocyclic contrast agents. It should not be treated as the only patent associated with gadobutrol.

The relevant patent layers are:

Patent layer	Typical claim subject matter	Relevance
Foundational chemistry	Neutral lanthanide complexes with tetraazacyclo ligands	Captured in part by US 5,474,756
Specific active ingredient	Gadobutrol or a defined gadolinium-ligand complex	May be protected by separate composition patents
Formulation	Concentration, pH, excipients, stability and injectable dosage form	Can create separate product barriers
Manufacturing	Ligand synthesis, complexation, purification and impurity control	May remain relevant after composition expiry
Method of use	CNS, angiography, pediatric imaging or other indications	Can support narrower use patents
Regulatory listing	Patents submitted for an approved drug product	Governed by FDA Orange Book records

The presence of an expired foundational patent does not establish freedom to operate if later patents remain in force. Conversely, later patents cannot revive an expired genus claim against products outside their narrower scope.

When did US Patent 5,474,756 expire?

The patent issued on December 12, 1995. Its U.S. application was filed in 1993. For a post-1990 U.S. application, the ordinary term is generally 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment and patent-term extension under 35 U.S.C. §§ 154 and 156.

The ordinary term therefore ran to approximately March 4, 2013. The patent is listed in public patent databases as expired based on lifetime. No current enforceable term should be assumed for US 5,474,756.

Event	Date or status
U.S. application filing	March 4, 1993
Patent grant	December 12, 1995
Ordinary 20-year term endpoint	Approximately March 4, 2013
Current status	Expired
Current blocking risk	None from this patent alone

Patent-term adjustment or extension would need to be verified in the USPTO patent record. The patent’s historical expiration does not determine the status of later patents covering gadobutrol, formulations or manufacturing processes.

What is the Orange Book status of Gadavist?

Gadavist is an FDA-approved gadolinium-based MRI contrast agent. The original U.S. approval was granted under NDA 201277 in 2011. The product contains gadobutrol and is supplied for intravenous use.

The FDA Orange Book is the controlling source for determining whether patents are listed against an approved drug product, whether exclusivity remains, and whether an abbreviated new drug application applicant must make a Paragraph IV certification. An expired foundational patent may remain visible in historical records but does not create a live period of patent exclusivity.

The regulatory analysis should separate:

FDA approval status
FDA exclusivity
Orange Book patent listing
Patent enforceability
Product-specific patent scope

These are distinct issues. FDA approval does not prove patent freedom to operate, and an Orange Book listing does not prove that every product claim is valid or infringed.

Are there Paragraph IV challenges to US Patent 5,474,756?

A Paragraph IV challenge to US 5,474,756 would no longer have practical commercial significance because the patent has expired. Paragraph IV certification is used when an ANDA applicant asserts that a listed patent is invalid, unenforceable or will not be infringed. It is not a mechanism for challenging an expired patent as a future market barrier.

For current generic gadobutrol risk, the relevant questions are whether:

Any later Gadavist patents remain listed in the Orange Book.
Any listed patents have unexpired terms.
A generic applicant has filed an ANDA for the relevant strength and presentation.
The applicant has submitted Paragraph III, Paragraph IV or other applicable certifications.
Litigation has been filed under the Hatch-Waxman statute.

US 5,474,756 itself should be treated as an expired historical patent rather than an active Paragraph IV litigation target.

What generic entry risks exist for gadobutrol?

The principal entry risks are no longer centered on the expired genus claim. They are more likely to involve product-specific and operational issues.

Composition risk

A generic gadobutrol product containing the same active ingredient may face composition or stereochemical claims if any remain unexpired. The risk depends on the exact claims, patent status and product formulation.

Formulation risk

Formulation patents may claim:

Gadobutrol concentration
Injection pH
Buffer systems
Stabilizers
Container compatibility
Low particulate content
Shelf-life characteristics
Ready-to-use presentations

A generic formulation can avoid some claims by using different excipients or manufacturing parameters, but formulation equivalence may constrain design-around options.

Manufacturing risk

Manufacturing patents can cover:

Preparation of the tetraazacyclododecane ligand
Gadolinium complexation
Removal of free gadolinium
Control of regioisomers or stereoisomers
Purification and crystallization
Low-metal impurity specifications
Sterile filtration and fill-finish procedures

These patents are particularly relevant where the active ingredient is chemically simple to describe but difficult to manufacture reproducibly at injectable quality.

Regulatory risk

Gadolinium contrast agents are injectable drugs. A generic applicant must demonstrate pharmaceutical equivalence and bioequivalence or satisfy the applicable FDA standard for the product. The applicant must also address:

Chemical identity
Chelation and free-gadolinium control
Sterility
Endotoxin limits
Particulate matter
Stability
Container closure integrity
Labeling and administration requirements

How strong is the patent estate for neutral macrocyclic MRI agents?

The expired patent has high historical breadth but no present exclusionary strength. Its claim architecture was commercially important because it combined a broad use claim with a functional charge-neutrality limitation and dependent structural genera.

Factor	Assessment
Chemical breadth	Broad at the genus level
Product specificity	Low in claim 1; higher in claims 2 and 3
Commercial relevance	High for neutral macrocyclic gadolinium agents
Current enforceability	None if expired
Design-around potential	Significant for ionic agents and non-tetraazacyclo chelates
Residual landscape risk	Later composition, formulation, process and use patents
Litigation leverage today	None from US 5,474,756 alone

The most defensible historical scope is the combination of a macrocyclic tetraazacyclo ligand, a paramagnetic lanthanide, aqueous charge neutrality and MRI use. The weakest aspect for present enforcement is the patent’s expiration.

How does US 5,474,756 compare with competing MRI contrast patents?

Technology class	Representative chemistry	Charge profile	Macrocyclic?	Relationship to US 5,474,756
Gadobutrol	Neutral Gd(III)-tetraazacyclododecane complex	Neutral	Yes	Closest commercial relevance
Gadoterate meglumine	Gd-DOTA complex with meglumine salt	Ionic formulation	Yes	May fall outside the charge-neutral limitation
Gadoteridol	Gd-HP-DO3A complex	Neutral complex	Yes	Potentially within the broader concept, depending on claim construction
Gadopentetate dimeglumine	Gd-DTPA salt	Ionic	No	Generally outside the neutral macrocyclic genus
Gadobenate dimeglumine	Gd-BOPTA salt	Ionic	No	Generally outside claim 1’s neutral-complex limitation
Gadoxetate disodium	Gd-EOB-DTPA salt	Ionic	No	Generally outside the claimed neutral complex
Gadopiclenol	High-relaxivity macrocyclic Gd complex	Product-specific	Yes	Primarily governed by later patents

The claim should not be read as covering all gadolinium-based contrast agents. It is technically differentiated from ionic linear chelates and from products lacking the claimed tetraazacyclo structure.

What litigation affects US Patent 5,474,756?

No current enforcement action can be inferred from the claim text. Because the patent expired around 2013, litigation involving it would be historical or incidental to a broader dispute involving related patent families.

For diligence, the controlling records are:

USPTO Patent Center
PACER
FDA Orange Book
FDA approval records
Patent assignment records
Patent family and legal-status databases

A litigation review should search the patent number, its assignee, related PCT publications, continuation applications, divisional applications and patents claiming specific gadobutrol formulations or manufacturing processes.

What licensing deals are relevant?

The patent record indicates a technology platform associated with Schering AG, later part of Bayer’s pharmaceutical business. Commercial exploitation of gadobutrol and related contrast-agent technology may involve corporate succession, research collaborations, manufacturing licenses or product commercialization agreements.

US 5,474,756 alone does not establish the terms of any license. Patent ownership, product commercialization rights and regulatory sponsorship must be analyzed separately. A patent assignment to a corporate successor does not disclose royalty rates, field restrictions, territorial rights or covenants not to sue.

Geographic coverage and international equivalents

US 5,474,756 provides protection only under U.S. law. International protection would depend on the corresponding PCT application, national-phase filings and the status of each country’s patent family members.

The commercial value of related foreign patents depends on:

Filing and priority dates
National-phase entry
Local patent-term rules
Supplementary protection certificates
Patent-term extensions
Claim amendments during prosecution
Local validity decisions
Compulsory-license rules
Regulatory exclusivity

An expired U.S. patent does not establish that corresponding European, Japanese, Chinese or other national patents expired on the same date.

Key Takeaways

US Patent 5,474,756 claims MRI imaging with a charge-neutral aqueous complex of a paramagnetic lanthanide and a tetraazacyclo compound.
Claim 1 is a broad method claim, not a standalone composition claim.
Claim 2 defines a substituted tetraazacyclo chemical genus, while claim 3 narrows the ligand platform to tetraazacyclododecane.
The patent is highly relevant to the historical chemistry of neutral macrocyclic gadolinium agents, including gadobutrol.
The patent’s ordinary U.S. term ended approximately March 4, 2013.
The patent should not be treated as a current U.S. blocking right.
Current gadobutrol risk must be assessed against later composition, formulation, manufacturing and method-of-use patents.
Paragraph IV analysis should focus on any unexpired Orange Book-listed patents for Gadavist, not on US 5,474,756.
The omitted chemical drawings in the supplied claim text prevent a complete structural mapping of every claim 2 species.
The claim does not cover all gadolinium MRI agents and is structurally differentiated from many ionic linear chelates.

FAQs

Does US Patent 5,474,756 claim gadobutrol by name?

No. The claims use structural and functional language rather than the commercial name gadobutrol. The patent is relevant because gadobutrol is a neutral macrocyclic gadolinium complex, but exact claim coverage requires mapping the complete chemical structure to the patent’s missing structural figures and definitions.

Does the patent cover gadoteridol?

Potentially, depending on the exact construction of the tetraazacyclo and tetraazacyclododecane limitations. A definitive answer requires comparison of the gadoteridol structure with the complete issued claims and specification.

Does a neutral gadolinium complex automatically infringe claim 1?

No. The agent must also include a tetraazacyclo compound, be a stable complex of a paramagnetic lanthanide, be charge neutral in aqueous solution and be used in the claimed MRI method after administration through one of the listed routes.

Can an expired patent still block FDA approval of a generic contrast agent?

No, an expired patent cannot create a current enforceable patent barrier. FDA approval and ANDA review may still require compliance with Orange Book certifications and other regulatory requirements for any unexpired listed patents.

Does US 5,474,756 cover manufacturing gadobutrol?

Not directly based on the supplied claims. The claims are directed to an MRI imaging method. Manufacturing coverage would require separate process claims in this patent or a related patent family.

References

U.S. Patent No. 5,474,756. (1995). Magnetic resonance imaging using neutral complexes of paramagnetic ions and tetraazacyclo compounds. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2011). Gadavist (gadobutrol) injection prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
United States Code. 35 U.S.C. §§ 154, 156.
United States Patent and Trademark Office. (2024). Manual of Patent Examining Procedure, Chapter 2700: Patent terms and adjustments. USPTO.

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: 5,474,756

Summary for Patent: 5,474,756