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Patent landscape, scope, and claims: |
US Patent 5,798,092 Scope, Claim Construction, and U.S. Patent Landscape for Metal-Based NMR/Imaging Contrast Agents
US 5,798,092 is a U.S.-granted composition- and method-linked patent estate centered on substituted macrocycle-adjacent chelators (a defined “Z1/Z2” scaffold) complexed with one or more charge-balancing metal ions (“X”). The claims are broad at the genus level (metal-ion class + wide parameter ranges for chain lengths and substituents), then narrow into enumerated complexes and imaging-use limitations (notably NMR contrast with renal and extrarenal excretion and enhanced signal in kidney, gastrointestinal tract, liver, gallbladder, and bile ducts). The estate also sweeps into pharmaceutical compositions and into radiation therapy combinations by using the same chelator-metal scaffold for delivery of radioactive metal ions.
What is the core claim scope of US 5,798,092 (Z1/Z2 scaffold, X metal ions, and key provisos)?
Independent claim structure (Claim 1)
Claim 1 recites a compound of Formula (structural variables not fully transcribed in the provided text), defined by:
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Chelator scaffold variables
One of Z1 and Z2 is H, the other is a poly-aryl ether/linked-alkyl motif of the form:
–(CH2)m–(C6H4)q–(O)k–(CH2)n–(C6H4)l–(O)r–R
with:
- m, n ∈ [0,20]
- k, l, q, r ∈ {0,1} (each independently)
- R ∈ {H, C1–C6 alkyl, OR1-substituted C1–C6 alkyl, CH2COOR1}
- R1 ∈ {H, C1–C6 alkyl, benzyl}
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Metal-ion occupancy variable “X”
X is either:
- H, or
- a metal ion equivalent of an element with atomic number in:
- 21–29, 42, 44, 57–83
This is a wide periodic-table inclusion covering common paramagnetic MRI-relevant and other transition/lanthanide metals.
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Charge/binding provisos that materially narrow genus
- At least two X groups represent a metal ion equivalent (prevents fully protonated forms).
- If n = 0 and l = 0 then k and r are not simultaneously 1 (structural constraint preventing a specific ring/ether pattern).
- “–(O)r–R is not OH” (excludes a specific hydroxyl-containing R pattern).
- Enumerated exclusions on Z1/Z2 substituent identity: Z1 and Z2 are not combinations corresponding to:
- –CH2–C6H4–O–CH2–COOCH2C6H5
- –CH2–C6H5
- –CH2–C6H4–OCH3
- –CH2–C6H4–O–(CH2)5–COOCH2C6H5
- Z1 is not phenyl when Z2 is H.
- At least one of q and l is 1 (forces presence of at least one aryl/linked-alkyl segment in the prescribed pattern).
Functional linkage to use
- Claim 1 itself is a compound genus with exclusions and occupancy rules.
- Claims 10–11 and 32–34 move into pharmaceutical compositions and NMR imaging method dosing/admin.
Which downstream claims narrow the compound space to specific metals, compositions, and embodiments?
Metal-count and metal-class narrowing (Claims 6–8, 12–13, 20, 28)
These provisions define sub-genuses based on how many X sites are occupied by specific metal ions.
- Claim 6: at least three X groups represent Gd
- Claims 7–8: at least three X groups represent Gd for certain Z1/Z2 embodiments.
- Claim 12: at least two X groups represent metal of atomic number 21–29, 42, 44, or 58–70
- Claim 13: either:
- two X = Mn(II), Fe(II), Co(II), Cu(II); or
- three X = Cr(III), Pr(III), Nd(III), Sm(III), Yb(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Fe(III)
- Claim 20: remaining non-qualifying X groups can be Li, K, Na, or if two such are present then Ca or Mg
- Claim 21: remaining non-qualifying X groups can be ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, N-methylglucamine, lysine, arginine, ornithine, lysine methylamide, glycine ethylamide, serine methylamide
These narrowings are critical for designing around: the claim language is “X groups,” so any alternative salt form or counter-ion arrangement can push outside coverage if it fails the explicit “X” definitions.
Explicit enumerated complexes (Claim 9 and Claim 15–16)
Claim 9 enumerates multiple named complexes, including gadolinium/ europium/ iron complexes of a defined 3,6,9-triaza-3,6,9-tris(carboxymethyl) scaffold substituted with benzyl ether substituents (methoxy/ethoxy/butoxy/benzyloxy variants), paired with “undecanedioic acid” derivatives.
Claim 15 and Claim 16 further lock in specific members:
- Claim 15: a gadolinium complex of a specified benzyl/ethoxybenzyl undecanedioic acid derivative
- Claim 16: complexes of the same class with a metal of atomic-number range (21–29, 42, 44, 57–83)
Practical impact: If a product is one of these enumerated complexes, design-around is limited because the claim reads directly on the named embodiments. If a product is in the genus but not the enumerated embodiments, the exclusions in Claim 1 (notably Z1/Z2 exclusion sets) and the metal-occupancy constraints become the main infringement levers.
Which claims cover pharmaceutical compositions and what are the concentration ranges?
- Claim 10: pharmaceutical composition = compound of Claim 1 + pharmaceutically acceptable carrier
- Claims 22–23: concentration ranges:
- 50 μmol/L to 2 mol/L (Claim 22)
- 100 mmol/L to 1 mol/L (Claim 23)
- Claims 29–31: optional formulation support:
- buffer, complexing agent, electrolyte, antioxidant
- aqueous medium
- matching the concentration ranges above
Practical impact: Infringement risk is often tied to whether the marketed product’s concentration falls within these ranges and whether the formulation is in an “aqueous medium” and includes a carrier as contemplated. The “carrier” wording in Claim 10 is broad; the concentration claims add measurable constraints.
What NMR imaging method and dose claims exist, and what do they require about excretion?
Core NMR method claim (Claim 11)
Claim 11 is a method claim with an “improvement” clause:
- administering an NMR contrast agent to a patient, where:
- the contrast agent has both renal and extrarenal excretion, and
- the agent provides enhanced contrast of:
- renal system
- gastrointestinal tract
- liver, gallbladder, bile ducts
Administration and dosing (Claims 32–34)
- Claim 32: intravenous administration
- Claim 33: 1 μmol/kg to 5 mmol/kg
- Claim 34: 10 μmol/kg to 0.5 mmol/kg
Practical impact: A product marketed purely for vascular imaging with primarily renal excretion could argue non-infringement of the “renal and extrarenal” improvement limitation. Conversely, agents used for hepatobiliary imaging or with significant GI/liver-biliary excretion are positioned closer to the claim’s functional requirement.
How does the patent attempt to capture radiation therapy delivery (Claim 35)?
- Claim 35: radiation therapy method = administering a radioactive metal ion in the form of a compound of Claim 1.
This claim links the chelator scaffold to radiotherapeutic radionuclide delivery. If a chelator-metal platform is reused for theranostics, the claim becomes a litigation hook even if the NMR indication is not used.
What is the likely practical breadth of Claim 1, and where are the main “hard walls” (exclusions and occupancy)?
Breadth drivers
- Wide m,n ranges (0–20) and boolean k,l,q,r (0/1) create a large structural genus.
- Broad atomic-number metal inclusion (21–29, 42, 44, 57–83) covers many paramagnetic/lanthanide/transition metals.
- R and R1 variability expands side-chain substitution.
Hard-wall narrowing features
- At least two X are metal equivalents
- Z1/Z2 structural exclusions block specific known members that match the excluded patterns.
- Z1 not phenyl when Z2 is H
- At least one of q and l = 1
- “–(O)r–R is not OH”
- “when n and l each are 0, then k and r are not simultaneously 1”
- Metal counter-ion and salt embodiments are explicitly controlled in dependent claims (20–21), which can constrain what “physiologically acceptable salt” means in practice for certain designs.
What is the U.S. claim ecosystem: how do independent and dependent claims map to infringement theories?
| Claim cluster |
Coverage theme |
What an accused product must match |
| Claim 1 |
Compound genus + scaffold and metal-occupancy + exclusion set |
Exact chelator scaffold family + X metal occupancy rules + Z1/Z2 exclusions + R/R1 constraints |
| Claims 6–8, 12–13 |
Sub-genus by metal count/class |
Product must use required number of Gd or specific other metals in X slots |
| Claim 9 |
Enumerated complexes |
Product is one of the listed named Gd/Eu/Fe complexes with specified benzyl ether substituents |
| Claims 10, 22–23, 29–31 |
Pharmaceutical composition |
Same compound + carrier + aqueous medium + concentration windows (where relevant) |
| Claim 11, 32–34 |
NMR imaging method |
Product is used for renal plus extrarenal excretion with enhanced kidney + GI + liver/gallbladder/bile ducts contrast; IV and dose windows reinforce |
| Claim 35 |
Radiation therapy method |
Radioactive metal delivered via Claim 1 compound (theranostic reuse) |
What generic or biosimilar design-around routes exist based on the claim language?
Because this is a small-molecule chemical patent (not biologics), there is no “biosimilar” pathway. The realistic routes are chemical design and use/design.
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Chemical design-around
- Avoid the exact Z1/Z2 excluded substituent combinations.
- Change the R/R1 patterns so that excluded “–(O)r–R is not OH” and enumerated Z1/Z2 exclusions are not met.
- Use different chelator architecture so “Z1 and Z2” cannot be mapped into the Claim 1 motif under construction.
- Adjust metal occupancy: if the product uses fewer than two metal-equivalent X positions, it may fall outside Claim 1.
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Salt/counter-ion design
- If a product relies on counter-ions outside those expressly permitted for the “not a metal ion equivalent” X groups in dependent claims 20–21, it may support design-around at those dependent-claim layers. Claim 1 itself allows “physiologically acceptable salts,” but dependent constraints can still matter if the asserted claim is a dependent one.
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Use-based design-around
- Avoid indications framed around renal plus extrarenal excretion with enhanced GI and hepatobiliary contrast.
- Avoid IV dosing in ranges argued to map to Claims 33–34.
- If a competitor’s label and clinical protocol keep use outside the “improvement” clause, infringement theories become narrower.
What is the strength profile of the patent estate given the claim design?
Even with only the claims provided, the structure suggests strong coverage where:
- the same chelator-metal platform is used for hepatobiliary or GI-enhanced renal-extrarenal imaging, and
- the product includes multiple Gd or specified lanthanide/transition metals in ways that map to X occupancy and enumerated complexes.
Design-around is strongest where:
- the product uses a materially different chelator scaffold not mapping to the Z1/Z2 family, or
- it avoids the specific Z1/Z2 excluded patterns and does not include the enumerated complexes of Claim 9.
Key Takeaways
- Claim 1 is a genus compound claim defined by a constrained Z1/Z2 scaffold family, R/R1 substitution space, and a wide metal inclusion list for X, narrowed by occupancy and multiple explicit exclusions.
- Dependent claims tighten coverage around Gd occupancy (≥3 X), specific metal class combinations, and explicitly listed gadolinium/europium/iron complexes (Claim 9) that function as direct infringement targets for those exact members.
- Formulation claims (Claims 10, 22–23, 29–31) cover aqueous pharmaceutical compositions in defined concentration windows.
- Method claims (Claims 11, 32–34) require an NMR contrast use with both renal and extrarenal excretion and enhanced signal in the renal system plus GI and hepatobiliary targets; IV and dosing windows further condition coverage.
- Theranostic sweep exists via radiation therapy use of the same Claim 1 compound (Claim 35), potentially extending leverage beyond MRI indications.
FAQs
- Does US 5,798,092 read on a gadolinium chelate used only for vascular/urography imaging with minimal extrarenal excretion?
- How do the “Z1/Z2 excluded substituent combinations” limit infringement for close structural analogs of the claimed chelator scaffold?
- If a formulation falls outside the Claim 22–23 concentration windows, does it avoid infringement of Claim 10’s composition coverage?
- Can a product with different counter-ions still fall within the “X” metal-equivalent occupancy constraints of Claim 1 if it uses alternative physiologically acceptable salts?
- How does Claim 35 affect theranostic competitors using the same chelator to deliver radioactive metal ions?
References
- United States Patent No. 5,798,092.
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