Details for Patent: 5,091,169

Summary for Patent: 5,091,169

Title:	Dipyridoxyl phosphate NMRI contrast agent compositions
Abstract:	N,N'-bis-(pyridoxal-5-phosphate)-alkylenediamine-N,N'-diacetic acids, N,N'-bis-(pyridoxal-5-phosphate)-1,2-cycloalkylenediamine-N,N'-diacetic acids, and N,N'-bis-(pyridoxal-5-phosphate)-1,2-arylenediamine-N,N'-diacetic acids, the corresponding monophosphate compounds and monoacetic acid compounds, and their salts and esters form stable, highly soluble chelates with paramagnetic metal ions, and are highly effective NMRI contrast agents. Preferred contrast agents are paramagnetic ion chelates of N,N'-bis-(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid, N,N'-bis-(pyridoxal-5-phosphate)trans-1,2-cyclohexylenediamine-N,N'diacetic acid, N,N'-bis-(pyridoxal-5-phosphate)trans-1,2-arylenediamine-N,N'-diacetic acid, and the soluble calcium salts thereof.Novel intermediates for forming these compounds are N,N'-bis(pyridoxal-5-phosphate)alkylenediimines, N,N'-bis(pyridoxal-5-phosphate)alkylenediamines, N,N'-bis(pyridoxal-5-phosphate)-1,2-cycloalkylenediimines, N,N'-bis(pyridoxal-5-phosphate)-1,2-cycloalkylenediamines, N,N'-bis(pyridoxal-5-phosphate)-1,2-arylenediamines, and the corresponding monophosphate compounds.
Inventor(s):	Scott M. Rocklage, Steven C. Quay
Assignee:	Amersham Health Salutar Inc
Application Number:	US07/370,429
Patent Claim Types: see list of patent claims	Composition; Compound;

The patent estate around U.S. Patent No. 5,091,169 is no longer enforceable. The patent issued on February 25, 1992, and its nominal 17-year patent term expired in February 2009. Its claims cover paramagnetic nuclear magnetic resonance imaging contrast compositions based on substituted pyridoxal-phosphate-derived chelators, especially manganese or gadolinium complexes, with optional calcium counterions and defined concentration ranges. No current Orange Book exclusivity or live Paragraph IV risk arises from this patent alone.

U.S. Patent 5,091,169: Scope, Claims, Expiration, and MRI Contrast Patent Landscape

What does U.S. Patent 5,091,169 protect?

U.S. Patent No. 5,091,169 protects compositions used as nuclear magnetic resonance imaging contrast media. The patent uses the older term “NMRI,” now generally described as MRI.

The independent claim covers a composition consisting essentially of:

1. A chelate formed from a defined compound of Formula I.
2. A metal ion with an atomic number from:
   • 21 to 29;
   • 42;
   • 44; or
   • 58 to 70.
3. A pharmaceutically acceptable, compatible excipient.

The covered metal set includes transition metals and lanthanides. Claim 9 narrows the group to specific oxidation states and elements, including manganese(II), iron(II), iron(III), copper(II), gadolinium(III), dysprosium(III), holmium(III), erbium(III), and related metals.[1]

The core inventive concept is a substituted aminopolycarboxylate chelator incorporating pyridoxal-phosphate-derived substituents. The claim structure also covers alternative linker groups, including:

• Linear alkylene groups containing one to eight carbon atoms;
• 1,2-cycloalkylene groups containing five to eight carbon atoms;
• 1,2-arylene groups containing six to 10 carbon atoms.

The patent therefore protects a chemical genus rather than a single commercial contrast agent.

What are the most commercially important claims?

Claims 5, 8, 13, 14, and 15 through 19 are the most relevant for product-level analysis.

Claim group	Subject matter	Commercial significance
Claim 1	Broad MRI contrast composition using the Formula I chelate and specified metal ions	Principal genus claim
Claims 2-4	Pyridoxal-phosphate substitution and narrower R5/R6 groups	Narrows the chelator structure
Claim 5	N,N'-bis-(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid or salt	Defined ethylenediamine species
Claims 6-7	Alkylene or cyclohexyl linker	Structural alternatives
Claim 8	Trans-1,2-cyclohexyldiamine species	Defined cyclohexyl species
Claim 9	Specific paramagnetic metal ions	Narrows the metal identity
Claims 10-12	Calcium salt and calcium-to-chelator ratios	Counterion and formulation limitations
Claims 13-17	Manganese complexes and calcium-containing forms	Most relevant to manganese formulations
Claims 18-19	Chelate concentration of 0.001 to 5.0 M, narrowed to 0.1 to 0.5 M	Product concentration limitations
Claim 20	R7 is hydrogen	Final structural narrowing

Claims 5 and 8 are composition claims directed to named chelator species. They do not claim the chelator as a standalone chemical compound. A product would need to be an MRI contrast composition containing the claimed chelate, a qualifying metal complex, and the required excipient context.

How broad is claim 1?

Claim 1 is broad in chemical and formulation scope, but its breadth is constrained by several mandatory limitations.

Chemical limitations

The compound must conform to Formula I and satisfy the proviso that at least one of R or R1 is not hydrogen. The claim also requires the specified substituent definitions for R3, R4, R5, R6, and R7.

The claim reaches:

• Hydroxy, alkoxy, hydroxy-substituted alkoxy, amino, and alkylamido substituents;
• Alkylene, cycloalkylene, and arylene bridging groups;
• Hydroxymethyl, alkyl, and related R4 groups;
• Hydroxy-substituted alkyl and aminoalkyl groups.

This is a Markush claim. Infringement analysis would require mapping the accused chelator to one permitted option at every variable position.

Metal limitations

The metal must have an atomic number within the recited ranges or be one of the specific metal ions later identified in claim 9. The claim does not cover all MRI-active metals. It is limited to the listed atomic-number ranges and, for narrower claims, the specified elements and oxidation states.

Gadolinium(III) is within the claimed atomic-number range because gadolinium has atomic number 64. Manganese(II) is expressly covered under claim 9 and claim 13.

Formulation limitations

Claim 1 requires a “pharmaceutically acceptable, compatible excipient.” The composition is not limited to a particular excipient, dosage form, route of administration, buffer, tonicity agent, preservative, or container.

The phrase “consisting essentially of” generally permits components that do not materially affect the basic and novel characteristics of the claimed composition, while excluding components that materially alter those characteristics.[2] This creates a fact-dependent boundary. A formulation containing ordinary injectable excipients would likely remain within the claim if the excipients did not materially change the chelate-based contrast function.

What compounds are specifically protected?

The patent expressly identifies two important species.

Pyridoxal-phosphate ethylenediamine chelate

Claim 5 covers:

“N,N'-bis-(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid or a salt thereof.”

This is the most direct ethylenediamine embodiment. Claims 14 and 15 also cover this species when used with one of the specified metal ions and, in claim 15, a calcium salt.

Pyridoxal-phosphate trans-cyclohexyldiamine chelate

Claim 8 covers:

“N,N'-bis-(pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid or a salt thereof.”

The cyclohexyl linker is a separate protected species. Claims 7 and 8 narrow the linker to cyclohexyl or trans-1,2-cyclohexyldiamine.

The claims cover salts of the chelating compound. They also separately address calcium-containing compositions, although the patent’s claim language must be parsed carefully to distinguish a calcium counterion from a calcium-containing mixed-metal complex.

What formulations are protected by U.S. Patent 5,091,169?

The formulation claims cover several variables.

Calcium ratio

Claims 10 through 12 require calcium salt forms and specify a calcium-to-chelating-compound molar ratio:

• Claim 11: 0.05 to 1.0;
• Claim 12: 0.1 to 0.5.

Claims 15 through 17 repeat a similar limitation for the specifically named chelators. Claim 17 recites 0.01 to 0.5, which is broader at the lower end than claim 12.

The ratio limitations can narrow infringement materially. A product using the same chelator and MRI metal but no calcium, or a calcium ratio outside the claimed range, may avoid these dependent claims while remaining potentially relevant to claim 1 or claim 9.

Chelate concentration

Claims 18 and 19 cover:

• 0.001 to 5.0 moles per liter under claim 18;
• 0.1 to 0.5 moles per liter under claim 19.

These are unusually broad molar concentration ranges compared with many finished injectable formulations. The claim language refers to concentration of the chelate salt in the medium. Product testing would be required to determine whether a formulation falls within the relevant range.

Excipient and dosage-form coverage

The claims do not require:

• Intravenous administration;
• A specific pH;
• A specific osmolality;
• A sterile vial;
• A prefilled syringe;
• A particular dose;
• A particular MRI sequence;
• A diagnostic indication.

The composition could therefore cover multiple pharmaceutical presentations if the chemical and metal limitations are met.

Does the patent cover a method of using the contrast agent?

No. The issued claims provided are composition claims. They do not claim:

• A method of imaging a patient;
• A method of administering the composition;
• A particular diagnostic procedure;
• A particular MRI pulse sequence;
• A disease indication.

This distinction matters. A product could raise composition-claim issues without implicating a method-of-use claim, and a later patent could claim a specific imaging use without overlapping the chemical composition claims.

When did U.S. Patent 5,091,169 expire?

The patent issued on February 25, 1992.[1] For a U.S. patent of this vintage, the ordinary term was generally 17 years from issuance, subject to the statutory rules applicable to pre-June 8, 1995 applications and any adjustment or terminal disclaimer.[3]

On that basis, the nominal expiration date was February 25, 2009.

The patent is therefore expired. Expiration eliminates ordinary infringement liability for conduct occurring after expiration. It does not erase historical infringement claims that were timely brought before expiration, and it does not eliminate contractual obligations arising from a separate license agreement.

What is the Orange Book status of U.S. Patent 5,091,169?

U.S. Patent 5,091,169 is not a current Orange Book barrier to generic approval.

The patent claims a class of MRI contrast compositions and does not, based on the supplied claims, identify an FDA-approved reference listed drug, a product trade name, or a specific approved labeling indication. The Orange Book lists patents and exclusivity associated with approved drug products, not every historical drug patent.[4]

A product-specific Orange Book analysis would require an approved reference product containing one of the claimed chelates. The claims supplied do not establish that such a product was approved or listed.

Are there Paragraph IV challenges to this patent?

No current Paragraph IV risk arises from this patent because it expired approximately 17 years ago.

Paragraph IV certifications are relevant when an ANDA applicant challenges a listed patent that remains in force or has a relevant future expiration date. A generic applicant would not need to challenge an expired patent as a basis for approval. The statutory framework governing ANDA patent certifications appears in the Hatch-Waxman provisions of the Federal Food, Drug, and Cosmetic Act.[5]

A historical Paragraph IV case cannot be inferred from the patent number or claim text. The absence of a current Paragraph IV issue does not establish that no litigation ever occurred.

Which companies are challenging the patent?

The claim information does not identify any challenger, assignee, licensee, settlement party, or litigation defendant. No company-specific challenge can be reliably attributed to U.S. Patent 5,091,169 from the patent claims alone.

The patent’s expiration also means that any present competitive analysis should focus on product approval, formulation know-how, manufacturing controls, safety data, and later patents rather than on this patent’s enforceability.

How strong was the patent estate?

The patent had meaningful historical breadth but limited present value.

Historical strengths

• Claim 1 covered a broad chelator genus.
• The metal definition reached manganese and gadolinium.
• Claims covered both ethylenediamine and cyclohexyl-derived linkers.
• Calcium salt and concentration limitations created multiple dependent claim positions.
• The patent claimed finished compositions rather than only synthetic intermediates.

Structural weaknesses

• The claims were composition-specific and required detailed structural mapping.
• No method-of-use claims were provided.
• No manufacturing-process claims were provided.
• No claims covered a commercial product by name.
• The patent’s term expired before current MRI contrast markets developed around the leading gadolinium products.
• A competing product using a different chelator architecture could avoid the claims entirely.

Claim 1 would have been the principal validity and infringement battleground. Potential prior-art issues would include earlier metal-chelate contrast agents, aminopolycarboxylate chemistry, pyridoxal-phosphate derivatives, and MRI contrast compositions. A definitive validity assessment requires the patent’s prosecution history and cited references, not only the issued claims.

How does this patent compare with modern MRI contrast patent estates?

Modern MRI contrast estates usually divide into four layers:

Estate layer	Typical protection	Relevance to U.S. 5,091,169
Active pharmaceutical ingredient	Chelator structure and metal complex	Direct overlap category
Formulation	Concentration, pH, stability, excipients, container	Partial overlap
Manufacturing	Chelation, purification, impurity control, sterilization	Not claimed in supplied claims
Clinical use	Imaging indication, dose, sequence, patient population	Not claimed in supplied claims

The leading commercial gadolinium-based contrast agents generally rely on distinct chelator structures, product-specific regulatory approvals, and later patent families. This patent should not be treated as a blocking patent for gadobutrol, gadoterate, gadoteridol, gadopentetate, gadobenate, or other commercial agents without a structure-by-structure claim comparison.

There is no biosimilar issue in the conventional biologic sense. MRI contrast agents are generally small-molecule chemical products. The relevant competitive pathway is an ANDA or other small-molecule approval route, not a biosimilar application under the Public Health Service Act.

What generic entry risks exist for products related to this patent?

The risk is commercial rather than patent-based.

A product using one of the named chelates could face:

• Analytical and chemistry, manufacturing, and controls requirements;
• Sterility and injectable-product requirements;
• Toxicology and pharmacology requirements;
• Chelate stability and free-metal controls;
• Product-specific FDA review;
• Potential later patents covering formulation, manufacturing, or clinical use.

The expired patent itself does not block generic or follow-on entry. A later patent could still create a separate barrier if it claims a specific formulation, manufacturing process, impurity profile, container system, or approved use.

What licensing or settlement agreements affect the patent?

No licensing agreement, covenant not to sue, or settlement agreement is established by the supplied patent claims. Patent assignments and licenses may exist outside the issued patent document, but they do not extend the patent’s expired statutory exclusivity.

A license can remain relevant after patent expiration if it contains separate contractual restrictions, royalty provisions, know-how obligations, or confidentiality terms. Those are contract questions rather than patent-term questions.

What is the geographic coverage of the patent?

U.S. Patent No. 5,091,169 provided rights only in the United States. Related foreign applications may have produced corresponding patents in other jurisdictions, but the supplied claims do not establish the existence, status, or expiration date of any foreign counterpart.

For current freedom-to-operate work, geographic analysis must be performed separately for the United States, Europe, Japan, China, Canada, and other target markets. The U.S. patent’s expiration does not determine foreign patent status.

Key Takeaways

• U.S. Patent 5,091,169 covers MRI contrast compositions containing defined pyridoxal-phosphate-derived chelates.
• The principal claim is a broad composition claim with structural, metal-ion, excipient, and salt limitations.
• Claims 5 and 8 protect named ethylenediamine and trans-cyclohexyldiamine chelator species.
• Claims 10 through 12 and 15 through 19 add calcium-ratio and concentration limitations.
• The supplied claims contain no method-of-use or manufacturing claims.
• The patent issued February 25, 1992, and nominally expired February 25, 2009.
• It is not a current Orange Book or Paragraph IV barrier.
• No biosimilar pathway applies to the patent’s small-molecule MRI contrast compositions.
• Current risk would come from later patents, regulatory requirements, manufacturing know-how, or contractual rights, not from the expired patent itself.

FAQs About U.S. Patent 5,091,169

Does U.S. Patent 5,091,169 cover gadolinium contrast agents?

Potentially, but only if the gadolinium complex uses a chelator within Formula I and satisfies the remaining claim limitations. The patent does not cover all gadolinium-based MRI contrast agents.

Does the patent cover manganese-based MRI contrast media?

Yes. Manganese(II) is expressly identified in claims 9 and 13. The manganese composition must also satisfy the applicable chelator and formulation limitations.

Can an expired patent still block FDA approval?

No. An expired patent cannot ordinarily block approval through patent certification procedures. FDA approval may still require adequate chemistry, manufacturing, safety, and clinical support.

Are calcium-chelate formulations separately protected?

Yes. Dependent claims 10 through 12 and 15 through 17 address calcium salt formulations and specified calcium-to-chelator ratios. Those claims expired with the patent.

Does the patent protect the synthesis of the claimed chelators?

Not based on the supplied claims. The claims provided are directed to MRI contrast compositions, not chemical manufacturing processes or synthetic intermediates.

References

1. U.S. Patent No. 5,091,169. (1992). NMRI contrast media. United States Patent and Trademark Office.
2. United States Patent and Trademark Office. (2024). Manual of Patent Examining Procedure § 2111.03: Effect of “consisting of,” “comprising,” and “consisting essentially of”.
3. 35 U.S.C. § 154. (2024). Contents and term of patent; provisional rights.
4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
5. 21 U.S.C. § 355(j). (2024). Abbreviated applications for new drugs.

Drugs Protected by US Patent 5,091,169

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,091,169

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0290047		C00290047/01	Switzerland
European Patent Office	0290047		SPC/GB97/078	United Kingdom
European Patent Office	0290047		97C0108	Belgium