Details for Patent: 5,846,519

Summary for Patent: 5,846,519

Title:	Method for imaging mammalian tissue using 1-substituted-1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
Abstract:	A method for imaging mammalian tissue utilizing a non-ionic complex of a paramagnetic ion of lanthanide element and a macrocyclic chelating agent.
Inventor(s):	Michael F. Tweedle, Glen T. Gaughan, James J. Hagan
Assignee:	Bracco Diagnostics Inc
Application Number:	US08/471,591
Patent Claim Types: see list of patent claims	Formulation; Compound;

Patent 5,846,519 landscape: scope, claim construction signals, and US exclusivity map for charge-neutral tetraazacyclo paramagnetic/heavy-metal imaging complexes

United States Patent 5,846,519 is directed to charge-neutral aqueous imaging complexes formed from (i) a paramagnetic ion or other high-Z imaging-avid metal (lanthanide isotopes, tantalum, bismuth, etc.) and (ii) a tetraazacyclo macrocyclic chelator, with explicit physicochemical constraints intended to preserve solution stability at high concentration while maintaining imaging utility. The claim set is structured around measurable properties (binding equilibrium, conductivity, osmolality, viscosity) plus two functional extensions: bioconjugation and aqueous stability at ≥0.5–0.75 M.

Because the claims are written as product-by-properties and product-by-composition, the competitive and litigation risk centers on (a) whether a competitor’s complex meets the same chelator identity (or an equivalent falling within broad “tetraazacyclo” language) and (b) whether the competitor meets the numeric thresholds that appear in multiple dependent claims.

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What is US Patent 5,846,519 claiming for mammalian tissue imaging complexes?

Core claim theme (independent claims 1 and 14): charge-neutral aqueous imaging complexes combining:

• Metal component
  • Claim 1: paramagnetic ion
  • Claim 14: metal selected from stable isotopes of lanthanides, tantalum, bismuth, or other elements heavier than iodine with imaging relevance
• Ligand/chelator: tetraazacyclo compound
• System property: charge neutral in aqueous solution
• Intended use: imaging of mammalian tissue (method is not separately claimed; the product is “for imaging”)

What “charge neutral in aqueous solution” implies operationally

The phrase anchors the claim to complexes that do not present net charge in water under the relevant conditions used to characterize the product (typically pH and ionic strength matching the disclosure, but the claims as provided do not specify pH). For freedom-to-operate, the key is whether an accused complex:

• is formulated to be net neutral, or
• can exist in water as a neutral coordination species rather than as salt forms.

If a competitor uses the same chelator and metal but delivers as a charged salt or adds counterions such that the species in solution is effectively ionic, it may fall outside this specific limitation.

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What do the numerical claim limits (Keq, conductivity, osmolality, viscosity) do to the scope?

The dependent claims repeatedly narrow the product to measurable thresholds. This is where claim construction tends to become deterministic: accused products often fail either the chelator or one of these numeric requirements.

Claim 2–3: binding equilibrium (Keq)

• Claim 2: Keq (M-1) at 25°C, aqueous solution > 20
• Claim 3: Keq at 25°C, aqueous solution > 23

Practical effect: higher Keq generally correlates with stronger chelation and lower metal dissociation. In infringement analysis, if Keq is not reported or if the competitor’s reported values vary by experimental protocol, parties typically litigate:

• which Keq definition is used,
• whether measured under substantially the same conditions,
• whether the competitor’s complex is the same species (e.g., protonation state, counterion state).

Claim 4–5: aqueous conductivity

• Claim 4: aqueous conductivity < 10 (mho.cm².mmol⁻¹, 25°C)
• Claim 5: aqueous conductivity < 2 (same units/temperature)

Practical effect: conductivity is a proxy for free ions. Values below these thresholds support the “charge neutral” requirement and limit designs that rely on dissociable counterions or charged aggregates.

Claim 6–7: osmolality in 0.5 M solution at 37°C

• Claim 6: osmolality < 1 Osmol/kg water (in 0.5M aqueous solution)
• Claim 7: osmolality < 0.65 (same measurement)

Practical effect: sets a tight physicochemical envelope that disfavors charged/salt forms and compositions that raise osmotic activity through dissociation.

Claim 10–11: stability in water at high concentration

• Claim 10: remains stable, dissolved, and in solution at >0.5 M at 20–37°C
• Claim 11: same at >0.75 M

Practical effect: captures “high concentration MRI/contrast-ready” formulations. For infringement, competitors can try to launch stable formulations at lower concentration, or claim their stability depends on formulation excipients not part of “the complex,” depending on how the patent defines “complex.”

Claim 13: viscosity at 0.5 M

• Claim 13: falling ball viscosity < 1.5 poise at 25°C (0.5M)

Practical effect: discourages highly viscous complexes/aggregates.

Net scope effect: the independent claim is broad in metal/chelator selection (within “paramagnetic” and “tetraazacyclo”), but the dependent claims lock in narrow solution-property performance. In practice, a claimant often asserts dependent claims against products that meet those measurable thresholds; defendants target either the numeric failure or a non-neutral charge state.

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Which tetraazacyclo chelator is specifically called out in the dependent claims?

Claim 12 and 18: the specific chelator identity

Both independent claim sets point back to a specific tetraazacyclo structure in dependent form:

• 1-substituted-1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane

This is the key “anchor” for literal infringement if a competitor uses an identical or closely matching macrocycle.

Risk framing:

• If the competitor uses that specific chelator (even with different substituent patterns not captured by “1-substituted” language), the numeric property claims become the next battleground.
• If the competitor uses a different tetraazacyclo (e.g., ring homologs, altered carboxymethyl substitution patterns, different pendant arms), literal infringement is less direct, but Claim 1/14 still cover broadly “tetraazacyclo compounds” unless the competitor can show their chelator falls outside that genus.

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How does claim 8–9 expand the invention to bioconjugates (targeted imaging)?

Claim 8

• the complex is bonded to a biologically active entity

Claim 9

Biologically active entity selected from:

• bile acids, fatty acids, lipids, sugars, other alcohols, amino acids
• peptides
• monoclonal antibodies and other proteins

Scope implication: the patent is not limited to “free” contrast agent. It covers targeted conjugates and functionalizations across small molecules through proteins.

Competitive impact: modern targeted imaging agents often attach chelators to targeting ligands. The litigation risk is whether the accused conjugate still satisfies:

• charge-neutral aqueous complex limitation, and
• the same chelator-metal chemistry and numeric physicochemical thresholds.

If the biologically active entity introduces charge, increases osmolality, or alters conductivity, it may push the formulation out of the dependent-claim numeric bounds (though only claims 8–9 are written without explicit numeric limits). Enforcing against such conjugates typically leverages the broad independent claim plus selection of dependent numeric constraints only where evidence supports them.

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How broad are the metal selections: paramagnetic vs heavy element imaging?

Claim 1 (paramagnetic ion)

The claim language (as provided) does not enumerate specific ions within “paramagnetic ion.” That keeps the metal scope relatively wide for MRI-relevant chelates.

Claim 14 (heavy element imaging selection)

Claim 14 enumerates:

• stable isotope of lanthanides
• tantalum
• bismuth
• “other element with molecular weight higher than iodine”

Scope implication: Claim 14 is aimed at imaging modalities that benefit from high-Z elements (CT, nuclear imaging, and related modalities). It includes a “higher than iodine” catch-all that can cover many elements, though infringement will still turn on whether the complex is:

• charge neutral in aqueous solution, and
• uses a tetraazacyclo chelator.

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What would claim construction likely do to “complex” and “for imaging” language?

Based on the claims as written, the following interpretive anchors are likely:

• “complex” is the coordination complex plus associated ligand framework; it does not appear to require an additional encapsulating carrier.
• “for imaging mammalian tissue” is functional/intent language attached to the product. Courts typically treat this as limiting if it informs structural features, but here the real structural limits are the metal-chelator combination and physicochemical properties.

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How many claim paths exist for enforcement: independent claims vs dependent numeric/property claims

From the set provided:

• Independent: claim 1 and claim 14
• Dependent narrowers: claims 2–7, 10–13, 12 plus claim 8–9, and for claim 14: claims 15–19 (numeric property constraints + chelator specificity + stability/viscosity/osmolality and conductivity constraints).

Enforcement map (high-level)

1. Free complex (independent 1/14)
2. Free complex meeting binding-strength requirement (2/3)
3. Free complex meeting low-ion/low conductivity constraints (4/5)
4. Free complex meeting low osmotic activity at 0.5 M (6/7)
5. Free complex meeting high-concentration solubility/stability (10/11 or 17)
6. Free complex meeting low viscosity at 0.5 M (13)
7. Conjugates (8/9)
8. Specific chelator variant (12/18)

Business takeaway: if a competitor product does not meet one of the numeric thresholds, the patent can still be asserted under the broader independent claims, but the strongest cases typically target the dependent numeric claims because they are easier to map to lab data.

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What is the patent landscape around US 5,846,519: how this patent likely fits against other chelation/contrast agent estates?

Landscape characterization (no speculation on unprovided patent neighbors)

Given the claim focus on:

• tetraazacyclo (macrocyclic amine) chelators,
• charge neutral aqueous complexes,
• high-concentration stability with controlled conductivity/osmolality/viscosity,
• imaging metals including lanthanides and heavy elements,

this patent belongs to the macrocyclic chelator contrast agent design space, where competitors typically have parallel patent families covering:

• specific chelator ring chemistries,
• metal coordination complexes,
• formulation/pH/protonation strategies,
• targeted conjugates.

How to think about “scope holes” competitors may exploit

Competitors can often design around by altering one of these claim-critical variables:

• Chelator identity: choose a tetraazacyclo not captured by the claim’s chelator genus or its specific disclosed variant.
• Net charge state: create a solution species that is not charge neutral under the relevant conditions.
• Numeric property targets: tune formulation, counterions, or co-ligands to change conductivity/osmolality/viscosity so dependent claims fail.
• Stability window: ensure precipitation or instability at concentrations above the thresholds.
• Bioconjugation: use a different linkage strategy or targeting group outside the enumerated list, though the list is open-ended in “selected from the group consisting of” which is closed to exactly those named categories for claim 9.

Risk distribution: the narrowest risk transfer mechanism is the conductivity and osmolality thresholds. If a competitor’s molecule is designed to be delivered with ionic excipients (or is intrinsically ionic), it may be outside those numeric dependent claims.

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What generic entry risks exist for imaging chelates covered by US 5,846,519?

For imaging contrast agents and chelated complexes, “generic” entry is often not substitution-equivalent to small molecule drugs because the product is a complex with defined physicochemical properties. Still, market entry by competitors can occur through:

• different chelator-metal pairings,
• different chelator substitution patterns,
• alternative formulation salts or pH strategies,
• different targeting conjugates.

The dependent numeric constraints in 5,846,519 elevate the barrier for close design-arounds because they require meeting measured properties at defined concentrations and temperatures. However, the broader independent claim can still capture many “functionally similar” products if they use a tetraazacyclo and remain charge neutral.

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How strong is the patent estate for US 5,846,519 based on claim drafting characteristics?

Even without the full specification and prosecution history, the provided claims show:

• multiple dependent claims on objective, testable properties (Keq, conductivity, osmolality, viscosity)
• explicit stability thresholds at high molarity
• expansion into bioconjugates and broad biomolecule categories

This combination generally strengthens enforceability against competitors that sell high-concentration, neutral, macrocyclic chelate contrast agents with strong chelation and low ionic character.

The main potential weakening factor is that “tetraazacyclo” is a genus term. If the patent specification supports a wide range of tetraazacyclo chelators as equivalents, then the claim may be broad in ways that increase infringement exposure for many macrocyclic alternatives. If the specification is narrow, the genus could still be constrained by written description support, limiting the practical coverage. Those outcomes depend on the actual disclosure, which is not provided here.

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Key Takeaways

• US 5,846,519 claims charge-neutral aqueous imaging complexes built from tetraazacyclo chelators and paramagnetic or heavy imaging metals.
• Scope is tightened by dependent claim thresholds for binding strength (Keq), low ionic character (conductivity), low osmotic activity (osmolality at 0.5 M), high-concentration stability (≥0.5–0.75 M at 20–37°C), and low viscosity (≤1.5 poise at 0.5 M).
• The strongest “literal anchor” is the specific chelator identity in dependent claims: 1-substituted-1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane.
• Bioconjugates are covered via bonding to biologically active entities including peptides and monoclonal antibodies/proteins, but dependent claim 9 uses a closed list.
• Competitive risk is driven less by “imaging intent” and more by whether an accused complex meets the neutrality and numeric property profile and uses a tetraazacyclo of the claimed scope.

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FAQs

1. Which claim elements are most dispositive for infringement of US 5,846,519 against a new imaging chelate?
   Metal-chelator identity (tetraazacyclo + paramagnetic/heavy ion), charge neutral in aqueous solution, and for tighter claims, the numeric Keq/conductivity/osmolality/viscosity/stability thresholds.

2. How can a competitor design around US 5,846,519 without changing the metal ion?
   Alter the tetraazacyclo chelator structure or engineer the solution form so the complex is not charge neutral and/or fails one or more dependent numeric property limits.

3. Do claims 8–9 require the biologically active entity to be covalently bonded?
   The claim language requires the complex to be “bonded” to the entity; infringement will hinge on whether the accused conjugate chemistry creates the required bond.

4. Does “stable isotope of lanthanides” in claim 14 expand the metal scope for imaging beyond MRI?
   It broadens the metal category for imaging complexes beyond paramagnetic ions, consistent with radionuclide/nuclear imaging applications using lanthanide isotopes.

5. What is the most litigation-prone measurement for this patent’s dependent claims?
   The dependent thresholds tied to conductivity, osmolality, viscosity, and concentration-dependent stability typically drive expert lab disputes because they are measured properties that can vary by formulation and testing protocol.

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References (APA)

1. United States Patent 5,846,519. Claims excerpt provided in the prompt.

Drugs Protected by US Patent 5,846,519

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 5,846,519

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	1296715
Germany	3772785
Germany	3855451