Details for Patent: 4,916,246

Summary for Patent: 4,916,246

Title:	Paramagnetic chelates useful for NMR imaging
Abstract:	Compounds suitable for NMR imaging having the formula: ##STR1## wherein a is 2 or 3;b is an integer from 0 to 4;Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ;E.sup.(b+) is an ion of an alkali metal, alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyalkyl ammonium, or basic protonated amino acid, said ions representing a total charge of b;m is an integer from 1 to 5;R is H, alkyl with from 1 to 8 carbon atoms, alkyl with from 1 to 8 carbon atoms wherein from 1 to 5 carbons are substituted with OH; aralkyl with 1 to 4 aliphatic carbon atoms; phenyl or phenyl substituted by halogen, hydroxyl, carboxyl, carboxamide, ester, SO3 H, sulfonamide, lower alkyl, lower hydroxy alkyl, amino, acylamino; (poly)oxa-alkyl with 1 to 50 oxygen atoms and from 3 to 150 carbon atoms, wherein 1 to 5 hydrogen atoms may be substituted by OH;R1 is the same as R2 oris --CH2 COOZ, --CH(CH3)COOZ, CH2 CH2 --N(CH2 COOZ)2, a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)alkyl or hydroxy pyridyl-(carboxy)alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO3 H;R2 is --CH2 COOZ, --CH(CH3)COOZ, ##STR2## wherein R3 is --CH2 COOZ, --CH(CH3)COOZ or a monovalent radical having the structure ##STR3## X is a direct chemical bond, --O--, --S--, --NH--, ##STR4## n is the integer 2 or 3, with the proviso that when X represents a direct bond, n is 1, 2 or 3;Z is hydrogen or a unit of negative charge, and --(CH2)m -- may also be --CH2 --C(CH3)2 --.
Inventor(s):	Ernst Felder, Fulvio Uggeri, Luciano Fumagalli, Giorgio Vittadini
Assignee:	Bracco International BV
Application Number:	US07/002,115
Patent Claim Types: see list of patent claims	Compound;

United States Drug Patent 4,916,246: Claim Scope, Gadobenate Landscape, Exclusivity and Generic Risk

US Patent 4,916,246 is a foundational patent for substituted amino-acid metal chelates used as magnetic resonance imaging contrast agents. Its broadest claims cover gadolinium, iron and manganese complexes, physiologically acceptable salts, and their use in NMR contrast media. The patent is expired. Its effective U.S. term ended on December 22, 2007, leaving no enforceable exclusivity under the patent today.[1][2]

The patent is most closely associated with gadobenate, the active chelate in gadobenate dimeglumine, marketed in the United States as MultiHance by Bracco Diagnostics. The commercial product is a gadolinium complex of BOPTA, or benzyloxypropionyl-tetraazacyclododecanetetraacetic acid-related chemistry. The patent itself covers a substantially broader chemical genus than the marketed product.[1][3]

What does US Patent 4,916,246 cover?

US 4,916,246 covers metal complexes of substituted alpha-amino propionic acids containing multiple carboxymethyl-substituted nitrogen atoms. The principal technical concept is a paramagnetic metal ion coordinated by a polyaminocarboxylate ligand that also contains a substituted side chain.

The claimed metal centers are:

Metal in the claims	Charge identified in the patent	Commercial relevance
Gadolinium	+3	Primary MRI contrast-agent relevance
Iron	+2 or +3	Covered, but not the basis of MultiHance
Manganese	+2	Covered, but not the basis of MultiHance

The claims also cover physiologically compatible salts formed with inorganic bases, organic bases and amino acids. The salt-forming cation may contribute a total positive charge of zero to four units, depending on the degree of deprotonation and the metal complex charge.[1]

The patent has three principal claim groups:

1. Broad compound claims.
2. Specific compound and salt claims.
3. Use claims directed to NMR contrast media containing the claimed compound as a relaxation-time agent.

How broad is claim 1 of US 4,916,246?

Claim 1 is the broadest compound claim. It covers a metal complex having a substituted alpha-amino propionic acid framework with highly variable side chains and nitrogen substituents.

Metal limitation

Claim 1 requires Me(a+) to be Fe(2+), Fe(3+), Gd(3+) or Mn(2+). This limitation excludes other paramagnetic metals, such as dysprosium, chromium and cobalt, from the literal scope of the claim.

Claim 2 narrows claim 1 to gadolinium complexes. That limitation is commercially significant because approved extracellular and partially protein-binding MRI agents predominantly use gadolinium rather than iron or manganese.

Side-chain limitation

The S substituent in claim 1 is broadly defined as:

• Hydroxyalkoxy;
• Alkoxy;
• Branched alkoxy;
• Aralkoxy;
• Phenoxy;
• Alkoxy chains containing multiple ether oxygens;
• Substituents with hydroxy, phenyl or polyether functionality.

The permitted R groups include hydrogen, C1-C8 alkyl, hydroxy-substituted alkyl, aralkyl, phenyl, substituted phenyl and polyoxa-alkyl structures containing up to 10 oxygen atoms and up to 30 carbon atoms.

This creates a broad chemical perimeter around the side chain. The claim is not limited to a single commercial ligand, a single salt, a particular osmolality, a particular concentration, or a particular imaging sequence.

Polyaminocarboxylate coordination structure

The R1, R2 and R3 definitions permit multiple arrangements of:

• Acetic acid substituents;
• Propionic acid substituents;
• Ethylenediamine-derived linkages;
• Ether linkers;
• Thioether linkers;
• Secondary amine linkers;
• Additional nitrogen atoms bearing carboxymethyl groups.

The functional result is a multidentate ligand designed to bind a paramagnetic metal ion and produce a stable, water-compatible complex.

Which claims cover gadobenate and MultiHance chemistry?

Claims 7 through 22 identify individual gadolinium complexes. Claim 7 is the most commercially relevant species claim because it covers the gadolinium complex of the 3-phenylmethoxy-substituted ligand corresponding to the BOPTA family.

Claims 7 through 11 focus on different salts of that gadolinium complex, including:

Claim	Claimed subject matter
7	Gadolinium complex of the 3-phenylmethoxy ligand
8	Sodium salt
9	Tris(hydroxymethyl)aminomethane salt
10	Serinol salt
11	L-ornithine salt

Commercial gadobenate dimeglumine uses a meglumine salt rather than the sodium, tris(hydroxymethyl)aminomethane, serinol or L-ornithine salts expressly listed in claims 8 through 11. The broader salt language in claim 6 could have been relevant to a meglumine salt, provided the claimed structural and charge limitations were met.[1]

Claims 12 through 22 cover additional gadolinium species with:

• Ether-linked polyaminocarboxylate structures;
• Hydroxy-substituted side chains;
• Octyloxy substituents;
• Methoxy substituents;
• Dihydroxypropoxy groups;
• Phenoxy groups;
• Polyether side chains;
• A dimethyl-substituted aminobutyric acid structure.

The commercial assessment is therefore:

Product or structure	Relationship to US 4,916,246
Gadobenate dimeglumine	Closely aligned with the claimed gadolinium BOPTA species and salt genus
Gd-DTPA, gadopentetate dimeglumine	Different ligand architecture
Gadodiamide	Different nonionic ligand architecture
Gadoterate meglumine	Macrocyclic DOTA derivative, structurally different
Gadobutrol	Macrocyclic, nonionic gadolinium complex, structurally different
Gadoxetate disodium	Different hepatobiliary ligand architecture
Gadoxetic acid products	Outside the specific claimed BOPTA structure

What do claims 3, 23, 25, 28 and 30 protect?

These are method or composition-of-use claims directed to NMR contrast media.

Each claim requires a medium that contains an agent influencing relaxation time, where the agent is a compound covered by the associated compound claim. In modern terminology, these claims would be analyzed as imaging-composition or method-of-use claims, although the claim language uses the older expression “media for NMR contrast imaging.”

The claims do not expressly require:

• Intravenous administration;
• A human patient;
• A specific MRI field strength;
• A particular dose;
• A particular gadolinium concentration;
• A specific imaging indication;
• A specific formulation excipient;
• A commercial vial or presentation.

The claims could therefore have had meaningful breadth against use of a covered chelate in an MRI contrast composition. Their practical enforcement value would have depended on proving that the accused compound satisfied the structural limitations of the corresponding compound claim.

What formulation patents are protected by US 4,916,246?

US 4,916,246 is primarily a compound and salt patent, not a detailed pharmaceutical formulation patent.

The patent covers salts with physiologically compatible cations, including salts associated with inorganic bases, organic bases and amino acids. This provides some salt-form coverage. It does not, based on the supplied claims, specifically claim:

• A defined pH range;
• A specific buffer system;
• A prescribed osmolality;
• A particular vial or syringe;
• A specified concentration of gadobenate dimeglumine;
• A particular stabilizer;
• A manufacturing sterilization cycle;
• A ready-to-use multidose formulation;
• A branded formulation presentation.

Accordingly, a product could avoid the patent by using a non-covered ligand, even if the dosage form and excipients were similar. Conversely, changing the salt alone would not necessarily avoid infringement if a broader salt or compound claim covered the resulting composition.

When did US Patent 4,916,246 lose exclusivity?

The patent issued on April 17, 1990. Because it originated from a pre-June 8, 1995 application, its term was governed by the transitional patent-term rule. The effective term was the longer of 17 years from grant or 20 years from the relevant U.S. filing date.[2]

The resulting term ended on December 22, 2007. The patent is therefore expired and cannot presently block manufacture, sale, importation or use of a compound solely because it falls within claims 1 through 30.

Milestone	Date
Earliest identified priority date	December 22, 1986
U.S. filing date relevant to transitional term	December 22, 1987
U.S. patent grant	April 17, 1990
17 years from grant	April 17, 2007
20 years from relevant filing date	December 22, 2007
Effective U.S. expiration	December 22, 2007

The expiration date is the central freedom-to-operate conclusion. Historical infringement exposure before that date is a separate issue from current enforceability.

What is the FDA regulatory status of gadobenate dimeglumine?

FDA approved MultiHance, gadobenate dimeglumine injection, for MRI of the central nervous system in adults in 2004. The approved product is a gadolinium-based extracellular MRI contrast agent with additional transient albumin interaction that can increase relaxivity relative to some conventional extracellular agents.[3]

The product’s regulatory status does not extend the expired patent. FDA approval, labeling protection and patent rights are separate forms of exclusivity.

The FDA label identifies gadobenate dimeglumine as a gadolinium complex administered by intravenous injection. Its clinical labeling has expanded over time beyond the original central-nervous-system indication, including use in MRI of the breast in adults and other labeled settings depending on the applicable label version.[3]

What is the Orange Book status of US 4,916,246?

US 4,916,246 is an expired patent and should not provide current Orange Book exclusivity for MultiHance.

The Orange Book records patents submitted by sponsors for approved drug products and tracks patent expiration, regulatory exclusivity and certain generic certification events. A historical patent may appear in Orange Book-related records even though it no longer blocks approval or launch. Current Orange Book relevance must therefore be assessed by the listed product, patent status and expiration date, rather than by the existence of the original patent alone.[4]

For gadobenate dimeglumine, the commercial risk analysis should distinguish:

• The expired foundational chelate patent;
• Any later unexpired formulation or manufacturing patents;
• Any later method-of-use patents;
• FDA exclusivity periods;
• Patent certifications submitted by an ANDA applicant.

The supplied patent claims do not establish the existence or expiration of later Bracco patents. US 4,916,246 itself is not a current blocking right.

Which companies are challenging MultiHance exclusivity?

No active Paragraph IV dispute can be inferred from US 4,916,246. The patent expired more than 15 years ago, eliminating the commercial purpose of a present Paragraph IV challenge to that patent.

A generic applicant could pursue an ANDA for gadobenate dimeglumine if the reference product and regulatory requirements support an abbreviated pathway. A Paragraph IV certification would be relevant only to a later unexpired patent listed for the reference product. The expired patent would generally be addressed through an expired-patent certification or would have no remaining blocking effect.

The competitive field includes:

• Bracco Diagnostics, the U.S. marketer of MultiHance;
• Generic injectable manufacturers capable of producing gadolinium chelates;
• Contract manufacturers with sterile injectable and metal-chelation capabilities;
• Suppliers with validated analytical methods for chelate identity, free gadolinium, impurities and stability.

The absence of a current dispute involving this patent does not establish that no later patent dispute exists. It establishes that US 4,916,246 cannot support a current Paragraph IV injunction.

What generic entry risks exist for gadobenate dimeglumine?

The primary present risk is not infringement of US 4,916,246. It is the technical and regulatory difficulty of developing a substitutable sterile gadolinium complex.

Regulatory barriers

An ANDA applicant would need to address:

• Pharmaceutical equivalence;
• Active-moiety and chelate identity;
• Strength and dosage form;
• Sterility;
• Elemental impurities;
• Free gadolinium control;
• Stability and degradation products;
• Container closure integrity;
• Labeling;
• Bioequivalence or other applicable equivalence requirements.

Complexed gadolinium products can create analytical and regulatory issues that are less straightforward than conventional small-molecule tablets. The relevant product is an injectable coordination complex, so chemical identity, chelation state and impurity controls are commercially material.

Manufacturing and intellectual-property barriers

Manufacturing barriers may include:

• Reproducible ligand synthesis;
• Control of stereochemical and regioisomeric impurities;
• Complete metal incorporation;
• Removal of unchelated gadolinium;
• Control of residual solvents and trace metals;
• Sterile fill-finish capacity;
• Validation of long-term stability.

These are technical barriers, not extensions of the expired patent. A manufacturer may face process know-how, trade-secret and quality-system challenges without facing an enforceable claim under US 4,916,246.

How strong was the patent estate for gadobenate?

The foundational estate was structurally broad but commercially concentrated.

Dimension	Assessment
Chemical genus	Broad
Covered metals	Gadolinium, iron and manganese
Salt coverage	Broad, subject to claim limitations
Specific gadobenate species	Expressly addressed by dependent claims
Use coverage	NMR contrast media
Formulation specificity	Limited in the supplied claims
Current enforceability	None, due to expiration
Biosimilar relevance	None
Generic relevance	Historical blocking right; no current patent barrier

The strongest historical position came from the combination of broad genus claims, specific gadolinium species claims and salt claims. The commercial product could potentially have been protected through multiple claim paths rather than through a single narrow claim.

The estate’s current strength is zero as an enforceable U.S. patent right. Any present exclusivity would have to come from later patents, regulatory exclusivity, trade secrets, supply arrangements or product differentiation.

What patent litigation or settlement agreements affect this patent?

The supplied claims do not identify litigation, settlements or licensing agreements. The patent number alone does not establish a litigation history.

No current litigation or settlement can be attributed to US 4,916,246 based solely on the claim text. Because the patent expired in 2007, any historic litigation would now have primarily evidentiary or damages significance, not an ability to prevent a new entrant.

No biosimilar litigation framework applies. Gadobenate dimeglumine is a nonbiologic drug product, so competition would generally be evaluated through generic-drug pathways rather than the Biologics Price Competition and Innovation Act.

How does US 4,916,246 compare with competing MRI contrast-agent patents?

US 4,916,246 differs from patents covering later MRI contrast agents in both ligand architecture and commercialization.

Agent	Core structural category	Relationship to US 4,916,246
Gadobenate dimeglumine	Substituted DTPA-type gadolinium chelate with benzyloxypropionic functionality	Directly aligned with the patent’s most relevant species
Gadopentetate dimeglumine	Linear DTPA-type gadolinium chelate	Different side-chain and ligand structure
Gadodiamide	Linear nonionic gadolinium chelate	Different ligand and charge profile
Gadoterate meglumine	Macrocyclic DOTA-type chelate	Outside the claimed linear substituted alpha-amino-acid framework
Gadobutrol	Macrocyclic nonionic chelate	Structurally distinct
Gadoxetate disodium	Hepatobiliary gadolinium chelate	Structurally distinct and separately developed
Gadopiclenol	Newer high-relaxivity gadolinium chelate	Requires separate patent and regulatory analysis

The patent should not be treated as a generic patent for all gadolinium MRI agents. Its scope is limited by the specified metal ions, ligand architecture, side chains, nitrogen substitution patterns and salt limitations.

What is the revenue exposure from this patent?

US 4,916,246 no longer creates direct revenue exposure because it expired in 2007. The historical value of the patent was linked to the commercial life of gadobenate and the ability to prevent competing products using the claimed chelate chemistry.

Bracco does not generally report MultiHance revenue as a standalone public financial line item in the same detail as consolidated business segments. A defensible product-specific revenue figure cannot be derived from the patent record. The current commercial exposure should instead be modeled through:

• MultiHance U.S. sales;
• Price erosion after generic entry;
• Hospital and radiology purchasing contracts;
• Formulary position;
• Supply continuity;
• Any unexpired later patents;
• Manufacturing cost and sterile capacity.

What is the likely generic launch scenario?

The most plausible legal scenario is:

1. A competitor identifies the approved gadobenate dimeglumine product as a reference product.
2. The competitor evaluates an ANDA or another abbreviated regulatory pathway.
3. The competitor certifies against any currently listed unexpired patents.
4. US 4,916,246 is treated as expired and nonblocking.
5. Launch timing depends on later patents, FDA review, product quality, manufacturing readiness and commercial contracting.

The expired foundational patent lowers legal entry risk. It does not eliminate technical development risk. A generic product that uses the same active chelate may still require extensive process development and analytical comparability work.

Key Takeaways

• US Patent 4,916,246 covers broad substituted amino-acid complexes of gadolinium, iron and manganese.
• Claims 7 through 11 are particularly relevant to gadobenate-type gadolinium complexes and their salts.
• Claims 3, 23, 25, 28 and 30 cover use in NMR contrast media.
• The patent expired on December 22, 2007.
• It has no current enforceable U.S. patent term.
• It is not a biosimilar patent and does not create biologic-style exclusivity.
• A current generic challenge would focus on later listed patents, FDA requirements and manufacturing execution.
• The patent is a historical foundational right, not a present barrier to gadobenate competition.
• Formulation, process and later method-of-use patents must be reviewed separately from US 4,916,246.
• Product-level MultiHance revenue is not separately disclosed in the patent record.

FAQs

Does US 4,916,246 cover all gadolinium MRI contrast agents?

No. It covers a defined class of substituted alpha-amino propionic acid metal complexes. Macrocyclic and structurally unrelated gadolinium agents fall outside the claims unless they independently satisfy every limitation.

Is gadobenate dimeglumine still protected by US 4,916,246?

No. The patent expired in 2007. Any current protection would have to arise from later patents, regulatory exclusivity, trade secrets or commercial agreements.

Can a generic manufacturer use the gadobenate chelate after patent expiration?

In principle, yes, subject to FDA approval requirements and any later unexpired patents. The expired patent does not prevent manufacture or sale based on the claimed chemistry.

Does changing gadobenate dimeglumine from one salt to another avoid every claim?

No. The patent includes broad salt language and specific salt claims. Salt substitution must be evaluated against the complete compound and salt limitations, although the patent’s term has expired.

Is a Paragraph IV certification required against US 4,916,246?

Not as a current blocking patent. Because the patent expired in 2007, an applicant would generally address it as expired or nonblocking. Paragraph IV analysis would focus on any later unexpired patents listed for the reference product.

References

1. U.S. Patent No. 4,916,246. (1990). NMR contrast media. U.S. Patent and Trademark Office.

2. U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. https://www.uspto.gov

3. U.S. Food and Drug Administration. (n.d.). MultiHance (gadobenate dimeglumine) injection prescribing information. https://www.accessdata.fda.gov

4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

Drugs Protected by US Patent 4,916,246

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: 4,916,246

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Italy	19236 A/86	Jan 30, 1986

International Family Members for US Patent 4,916,246

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0230893		SPC/GB97/081	United Kingdom
European Patent Office	0230893		99C0013	Belgium
European Patent Office	0230893		C980024	Netherlands
European Patent Office	0230893		33/1998	Austria