Details for Patent: 6,039,931

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Summary for Patent: 6,039,931

Title:	Derivatized DTPA complexes, pharmaceutical agents containing these compounds, their use, and processes for their production
Abstract:	Compounds of general Formula I ##STR1## wherein Z1 and Z2 in each case independently mean the residue --(C6 H4)l --(O)r --R, whereinm and n means the numbers 0-20,k, l, q and r means the numbers 0 and 1, andR means a hydrogen atom, an optionally OR1 -substituted C1 -C6 -alkyl residue, or a CH2 COOR1 group with R1 meaning it hydrogen atom, a C1 -C6 -alkyl residue, or a benzyl group,X means a hydrogen atom and/or a metal ion equivalent of an element of atomic number 21-29, 42, 44 or 57-83,with the provisos that at least two the substituents X stand for a metal ion equivalent; that one of the substituents Z1 and Z2 stands for a hydrogen and the other is not H; that--if n and l each mean the number 0--k and r do not simultaneously mean the number 1; that --(O)r --R is not --OH; and that Z1 and Z2 are not --CH2 --C6 H4 --O--CH2 --COOCH2 C6 H5 or --CH2 --C6 H4 --O--(CH2)5 --COOCH2 C6 H5, as well as their salts with inorganic and/or organic bases, amino acids or amino acid amides, are valuable pharmaceutical agents, e.g., for NMR.
Inventor(s):	Heribert Schmitt-Willich, Johannes Platzek, Heinz Gries, Gabrielle Schumann-Giampieri, Hanns-Joachim Weinmann, Hubert Vogler, Julius Deutsch, Juergen Conrad
Assignee:	Bayer Intellectual Property GmbH
Application Number:	US08/319,357
Patent Claim Types: see list of patent claims	Use; Composition; Delivery;

United States Drug Patent 6,039,931: Claim Scope, Exclusivity, and NMR Contrast-Agent Patent Landscape

U.S. Patent No. 6,039,931 covers methods of enhancing NMR images with multimetal complexes of substituted 3,6,9-triaza-3,6,9-tris(carboxymethyl)undecanedioic acids. The claims focus on compounds containing at least two paramagnetic metal equivalents, including gadolinium, linked to a lipophilic aromatic substituent. The patent has broad method-of-use coverage for general NMR imaging, renal imaging, hepatobiliary imaging, gastrointestinal imaging, and imaging in patients with renal insufficiency.

The patent is a small-molecule contrast-agent patent, not a biologic patent. Biosimilar analysis is therefore inapplicable. Its commercial relevance depends on whether an approved contrast agent contains a claimed complex and whether the compound was administered for a claimed imaging use during the patent term.

What does U.S. Patent 6,039,931 protect?

The patent protects a method, not a compound per se. An infringement theory generally requires:

1. Administration of a qualifying metal complex to a patient.
2. Use of that complex to enhance an NMR image.
3. Satisfaction of the structural limitations in the relevant claim.
4. For narrower claims, performance of the specified imaging application, dose, route, or formulation limitation.

The core independent claim is claim 1. It requires a compound with the following characteristics:

Claim limitation	Scope
Therapeutic use	Enhancing an NMR image
Core ligand	A 3,6,9-triaza-3,6,9-tris(carboxymethyl)undecanedioic-acid-type structure shown in the patent formula
Substitution	One of Z1 and Z2 is hydrogen; the other is an aromatic, ether-containing or related substituent
Aromatic requirement	At least one of q and l must equal 1
Metal loading	At least two X groups must be metal-ion equivalents
Covered metals	Atomic numbers 21-29, 42, 44, or 58-70
Salt forms	Inorganic or organic base salts, amino-acid salts, and amino-acid-amide salts
Exclusions	Several specified benzyl, phenyl, ester, and hydroxyl arrangements are excluded

The claim is structurally broad but chemically constrained. It does not cover every gadolinium contrast agent. A candidate product must satisfy the ligand architecture, substitution pattern, metal-loading requirement, and express exclusions.

How broad is claim 1 of Patent 6,039,931?

Claim 1 has three principal breadth drivers.

First, the linker variables m and n independently range from 0 to 20. This permits substantial variation in the distance between the ligand and the aromatic substituent.

Second, the variables k, l, q, and r independently equal 0 or 1. These variables control the presence of ether linkages and aromatic rings. The requirement that at least one of q and l equal 1 prevents the claim from reaching purely aliphatic analogues.

Third, R may be hydrogen, C1-C6 alkyl, an OR1-substituted C1-C6 alkyl group, or CH2COOR1. R1 may be hydrogen, C1-C6 alkyl, or benzyl.

The claim is narrowed by several negative limitations:

• The terminal group -(O)r-R cannot be hydroxyl.
• Certain phenyl and benzyl substituents are excluded.
• Particular benzyl ester and pentoxybenzyl ester arrangements are excluded.
• When n and l are both zero, k and r cannot both be one.

These exclusions likely reflect prosecution amendments directed to prior-art compounds. They also create potential claim-construction disputes because infringement may depend on whether a marketed compound falls inside or outside one of the expressly excluded structures.

Which dependent claims add the most commercial value?

Claims 8 through 10, 14, 16, and 17 narrow the metal identity. Claims 8-10 require at least three gadolinium ions. These claims are commercially more relevant to gadolinium-based MRI products than claim 1, but they are materially narrower.

Claims 11 and 16 identify specific compounds. Claim 11 lists complexes incorporating methoxybenzyl, ethoxybenzyl, butoxybenzyl, benzyloxybenzyl, carboxymethoxybenzyl, and related substituents. Claim 16 specifically identifies the gadolinium complex of 4-(4-ethoxyphenyl)undecanedioic acid.

Claims 24-27 cover administration conditions:

• Claim 24: 1 micromole/kg to 5 millimole/kg.
• Claim 25: 10 micromole/kg to 0.5 millimole/kg.
• Claim 26: intravenous administration.
• Claim 27: oral administration.

Claim 29 covers administration as a pharmaceutical composition with a pharmaceutically acceptable carrier.

Claims 12 and 13 cover renal-system and hepatobiliary-system imaging. Claims 31-33 cover gastrointestinal imaging. Claim 34 covers imaging a patient with renal insufficiency.

What are the independent claims?

The patent contains four principal independent method claims.

Claim	Independent subject matter	Practical significance
1	General method of enhancing an NMR image	Broadest general-use claim
31	Enhancing an NMR image of the GI tract	Organ-specific use claim
34	Enhancing an NMR image in a patient with renal insufficiency	Patient-population claim
35	Improvement to an NMR-imaging method using the claimed compound as contrast agent	Jepson-style improvement claim

Claim 35 is particularly important because it frames the invention as an improvement over a preexisting NMR method involving administration of a contrast agent. The novelty resides in replacing the prior contrast agent with the claimed multimetal complex.

Claims 31 and 34 have narrower factual requirements. A product may satisfy claim 1 while avoiding claim 31 because the imaging target is not the GI tract. Conversely, a renal-insufficiency indication could create exposure under claim 34 even if the product is not labeled for that population, provided the relevant use is induced or otherwise attributable to the accused party.

What structures are covered by the Markush formula?

The principal chemical class includes substituted derivatives of a triaza polycarboxylic acid ligand. The ligand has three nitrogen atoms bearing carboxymethyl substituents and two additional carboxylic-acid-derived termini. The patent examples place a substituted aromatic group on one of the carbon-chain positions.

Representative claimed substituents include:

• 4-methoxybenzyl;
• 4-ethoxybenzyl;
• 4-butoxybenzyl;
• 4-benzyloxybenzyl;
• 4-carboxymethoxybenzyl;
• 4-(4-methoxybenzyloxy)benzyl;
• benzyloxymethyl;
• 4-ethoxyphenyl;
• 4-ethoxyphenylethyl.

The claim permits several metal classes, including gadolinium, europium, iron, manganese, cobalt, copper, chromium, and other listed elements. Claims 8-10 narrow the invention to compounds containing at least three gadolinium ions.

The use of “metal ion equivalent” indicates that X may represent a coordinated metal species or, where not occupied by a metal, a counterion or proton-compatible form. Claims 21 and 22 expressly identify lithium, potassium, sodium, calcium, magnesium, ethanolamine, lysine, arginine, glucamine, and related salt forms.

How should the claim inconsistencies be interpreted?

Several textual irregularities affect enforcement analysis.

Claim 17 refers to metals with atomic numbers 21-29, 42, 44, or 57-83, while claim 1 refers to 21-29, 42, 44, or 58-70. Because claim 17 depends on claim 1, it cannot ordinarily expand the scope of the parent claim. The broader atomic-number range in claim 17 may be a drafting or transcription error. The dependent claim should be analyzed together with all limitations inherited from claim 1.

Claim 31 contains an apparent variable inconsistency. The substituent definition repeats “l” where claim 1 uses both q and l. This may create an antecedent-basis and definiteness issue, although courts generally interpret claims in light of the specification and prosecution history where the intended meaning is clear.

Claim 23 depends on claim 11 but introduces a Z2 definition that does not align cleanly with the listed compounds in claim 11. Its scope may depend heavily on the issued patent file history and any correction certificate.

These defects do not automatically invalidate the claims. They increase the importance of the prosecution record, claim-construction history, and technical mapping of a proposed accused compound.

When did Patent 6,039,931 lose exclusivity?

U.S. Patent No. 6,039,931 issued in 2000. A patent filed after the 1995 patent-term transition generally receives a term of 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and any applicable extension under 35 U.S.C. §§ 154 and 156.[1]

The patent’s ordinary term therefore would have fallen in the 2016-2018 period, depending on the effective filing date and any adjustment. A patent-number record alone does not establish the precise expiration date, PTA, PTE, or terminal-disclaimer status. The commercial exclusivity analysis should use the USPTO patent-term record rather than the issue date.

No patent-term extension should be assumed merely because the claimed subject matter relates to an FDA-regulated imaging agent. A regulatory extension requires a qualifying approved product and satisfaction of the statutory requirements under 35 U.S.C. § 156.[1]

What is the Orange Book status of U.S. Patent 6,039,931?

The patent claims methods of using chemical contrast agents. It is not automatically an Orange Book-listed patent.

Orange Book listing depends on submission by the approved-product sponsor and FDA acceptance of the patent as meeting the applicable listing criteria. A patent may be relevant to an approved product without appearing in the Orange Book. Conversely, an Orange Book listing does not establish that every claim is valid or infringed.[2]

The claims supplied here do not identify:

• an approved active ingredient;
• a U.S. New Drug Application;
• a proprietary product name;
• an approved dosage form;
• an Orange Book patent-use code; or
• a listed sponsor.

The patent should therefore be treated as a composition-specific and method-of-use patent unless an FDA listing links it to a particular approved contrast agent.

Does the patent cover gadolinium contrast agents such as MultiHance, Magnevist, or Gadavist?

Not automatically. The patent does not claim “gadolinium contrast agents” generically. It claims a defined ligand class with particular aromatic substitutions and at least two qualifying metal equivalents.

A product-by-product analysis requires comparison of:

1. The active ligand structure.
2. The number and identity of coordinated metals.
3. The position of the aromatic substituent.
4. The presence or absence of ether linkages.
5. The terminal R group.
6. The salt or counterion form.
7. The approved or promoted imaging use.

The principal commercial gadolinium agents include gadobenate dimeglumine, gadopentetate dimeglumine, gadodiamide, gadoterate meglumine, gadobutrol, gadoxetate disodium, and gadoteridol. These agents have different ligand structures. A product cannot be placed inside the '931 patent solely because it contains gadolinium or is used for MRI.

What patent landscape surrounds the claimed technology?

The relevant landscape has four layers.

Earlier gadolinium chelation patents

The closest prior-art field includes DTPA, EDTA, macrocyclic chelator, and acyclic polyaminopolycarboxylate complexes. These patents generally address metal chelation, water solubility, kinetic stability, relaxivity, biodistribution, and diagnostic imaging.

The '931 patent distinguishes itself through the combination of:

• a multicarboxylate triaza ligand;
• at least two paramagnetic metal equivalents;
• an aromatic ether-containing substituent; and
• use in NMR imaging, including specified organ systems.

Product patents for approved MRI agents

Commercial products typically have separate patent families covering:

• the active chelate;
• specific salt forms;
• pharmaceutical formulations;
• manufacturing processes;
• purification;
• polymorphs or hydrates;
• diagnostic uses;
• organ-specific imaging indications.

The existence of a later product patent does not eliminate an earlier method patent. A marketed product may require freedom to operate under both the product patent estate and any still-enforceable use patent.

Formulation and manufacturing patents

The '931 claims do not materially protect manufacturing operations, sterile filling, vial configuration, concentration, excipient selection, or container systems. Claim 29 reaches a pharmaceutical composition only as a dependent method claim. It does not create a standalone composition claim.

The most relevant manufacturing barriers would likely arise from separate patents covering:

• preparation of the triaza ligand;
• selective alkylation;
• metal-complex formation;
• removal of unchelated metal;
• control of regioisomers;
• salt conversion;
• sterile formulation and stabilization.

Regulatory and clinical-use patents

Claims 12, 13, 31, and 34 create potential use-case coverage for renal, hepatobiliary, GI, and renal-insufficiency imaging. These claims are narrower than claim 1 but may be commercially relevant if a sponsor promotes a product for one of those uses.

Which companies could face generic-entry or Paragraph IV risk?

The patent is not directed to a conventional oral small-molecule drug. Generic-entry risk would arise only if an ANDA applicant sought approval for a product containing a compound that falls within the claimed chemical class and relied on an approved reference product associated with the patent.

Potential challengers would include manufacturers of generic MRI contrast agents, such as large injectable-generic companies. A Paragraph IV certification would be relevant only if the patent were listed in the Orange Book for the reference product. If the patent were not listed, a generic applicant could still face ordinary patent litigation, but not necessarily an Orange Book-triggered Paragraph IV dispute.

No Paragraph IV challenge, settlement agreement, or litigation outcome can be inferred from the claim text itself.

Is there biosimilar risk?

No. U.S. Patent 6,039,931 covers chemically defined metal complexes and methods of NMR imaging. It does not cover a biologic, recombinant protein, monoclonal antibody, or other product eligible for the biosimilar pathway under the Public Health Service Act.

The relevant competitive pathway is an ANDA or, for a structurally distinct contrast agent with a different clinical development strategy, a 505(b)(2) application. FDA approval status and patent certification consequences depend on the reference product and listed patents.[3]

How strong is the patent estate?

The patent has moderate structural breadth but limited practical breadth.

Strength factor	Assessment
Independent claim breadth	Broad within a defined ligand class
Product coverage	No standalone composition claim
Gadolinium relevance	Strong for covered three-gadolinium complexes
Organ-specific coverage	Narrow but commercially targeted
Formulation protection	Limited to a dependent method claim
Manufacturing protection	Not apparent from the supplied claims
Regulatory linkage	Not established
Claim clarity	Reduced by apparent variable and atomic-number inconsistencies
Biosimilar relevance	None
Generic exposure	Depends on exact active structure and Orange Book linkage

The strongest enforcement position would involve a product that is one of the named or closely corresponding compounds in claims 11 or 16, contains at least three gadolinium ions, and is administered intravenously for a claimed imaging purpose.

The weakest position would involve a structurally different gadolinium chelate, an unlisted use, or a product that lacks the required aromatic substitution or multimetal configuration.

What generic launch scenarios exist?

Three scenarios are commercially relevant.

Scenario 1: Exact claimed compound

An ANDA or competing injectable product using a named compound could face direct method-claim exposure if the patent remained enforceable and the product label or promotional activity encouraged a claimed use.

Scenario 2: Structurally related analogue

A close analogue may avoid literal infringement by changing the aromatic substituent, linker length, terminal R group, or metal count. The doctrine of equivalents could still be considered, but the express exclusions and prosecution history may restrict that argument.

Scenario 3: Different approved gadolinium chelate

A product based on a different chelator, such as a macrocyclic agent or a conventional single-gadolinium DTPA derivative, would likely require a separate structural analysis and may fall outside the '931 claims.

Key Takeaways

• U.S. Patent 6,039,931 is a method-of-use patent for multimetal NMR contrast complexes.
• Claim 1 requires a specific triaza-polycarboxylate ligand architecture, aromatic substitution, and at least two qualifying metal equivalents.
• Claims 8-10 and 16 are particularly relevant to three-gadolinium compounds.
• Claims 12, 13, 31, and 34 target renal, hepatobiliary, GI, and renal-insufficiency imaging.
• Claim 29 does not create a broad standalone formulation claim.
• The patent does not generically cover all gadolinium MRI contrast agents.
• Exact patent expiration requires the USPTO term record, including PTA, PTE, and terminal-disclaimer data.
• Orange Book listing, Paragraph IV activity, litigation, licensing, and settlement status cannot be established from the supplied claims.
• Biosimilar risk is irrelevant because the claimed products are chemical metal complexes.
• The key freedom-to-operate question is whether a marketed product’s exact ligand, metal count, salt form, and labeled use fall within an issued claim.

FAQs

Could a gadolinium product infringe without being chemically identical to a named example?

Yes. Claim 1 is a Markush claim and reaches compounds within the defined structural variables, not only the examples listed in claim 11. Literal infringement depends on satisfying every limitation.

Does claim 27 create a broad right to market oral MRI contrast agents?

No. Claim 27 depends on claim 1. An oral product must first satisfy the full structural and metal-complex limitations of claim 1.

Can a company avoid the patent by using one gadolinium ion?

Potentially, if the accused compound does not satisfy the claim’s requirement that at least two X groups represent qualifying metal-ion equivalents. The complete structure must be evaluated because other claims may impose different metal requirements.

Are renal-insufficiency claims especially important after FDA concerns about gadolinium?

They can be commercially relevant, but claim 34 still requires the claimed compound structure and administration for NMR imaging in a patient with renal insufficiency. Regulatory warnings do not expand the patent claim.

Would a later formulation patent eliminate risk under Patent 6,039,931?

No. A later formulation patent may protect a different aspect of the product. It does not negate an earlier enforceable method claim covering administration of the active contrast complex.

References

1. United States Patent and Trademark Office. (2024). Patent term adjustment and patent term extension provisions under 35 U.S.C. §§ 154 and 156. U.S. Department of Commerce.

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.

3. U.S. Food and Drug Administration. (2024). Abbreviated new drug application process and 505(b)(2) applications. U.S. Department of Health and Human Services.

4. U.S. Patent No. 6,039,931. (2000). NMR contrast agents. United States Patent and Trademark Office.

Drugs Protected by US Patent 6,039,931

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: 6,039,931

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	39 22 005	Jun 30, 1989

International Family Members for US Patent 6,039,931

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0405704		300182	Netherlands
European Patent Office	0405704		SPC/GB05/021	United Kingdom
European Patent Office	0405704		C00405704/01	Switzerland
European Patent Office	0405704		16/2005	Austria
European Patent Office	0405704		C300182	Netherlands