| 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)ethylene-diamine-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. |
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Patent landscape, scope, and claims: |
Scope, Claims, and Patent Landscape for US Patent 4,933,456
US 4,933,456 covers a class of metal-ion chelates in which a defined chelating scaffold (a substituted aminopolyphosphate/aminodicarboxylate-type compound with “formula” variables) is coordinated to paramagnetic metal ions within specific atomic-number ranges, including late-transition metals (Mn, Fe, Co, Ni, Cu, Cr) and select lanthanides (Pr, Nd, Sm, Yb, Gd, Tb, Dy, Ho, Er), as well as physiologically biocompatible salts. The claims also narrow to manganese(II) complexes and to specific named chelates built from pyridoxal-5-phosphate (PLP) plus ethylenediamine and trans-1,2-cyclohexyldiamine, and to calcium (and sodium-calcium) salt forms with defined molar ratios.
What does US 4,933,456 claim at the broad level?
Core claim construct (Claim 1)
Claim 1 is the broadest and sets four scoping levers:
-
Chelating compound identity by variable formula (formula shown as “formula I” in your excerpt)
- R is hydrogen or a substituted group (R is allowed to be non-hydrogen).
- R1 is hydrogen or a substituted group (R1 is allowed to be non-hydrogen).
- Proviso: at least one of R and R1 is other than hydrogen.
- R5 and R6 are independently from:
- hydroxy
- alkoxy C1-C18
- hydroxy-substituted alkoxy C1-C18
- amino
- alkylamido C1-C10
- R3 is:
- alkylene C1-C8, or
- 1,2-cycloalkylene C5-C8, or
- 1,2-arylene C6-C10
- R4 is:
- hydrogen
- hydroxymethyl
- alkyl C1-C6
- or a further substituted group (shown as “R4 is hydrogen ... or ##STR12##” in excerpt)
- R7 is independently:
- hydrogen
- hydroxy-substituted alkyl C1-C18
- aminoalkyl C1-C18
-
Chelated metal-ion identity
- The chelated metal is a paramagnetic ion of a metal having atomic number in:
- 21 to 29 inclusive (Sc-Zn range; covers Cr, Mn, Fe, Co, Ni, Cu)
- 42, 44 (Mo, Ru)
- or 58 to 70 inclusive (Ce-Lu range; covers Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er, etc.)
- Or “a physiologically biocompatible inorganic or organic salt of said metal ion chelate.”
-
Salts are explicitly within claim scope
- “or a salt of said metal ion chelate” appears repeatedly through dependent claims.
- Claim 14 adds specific calcium salt forms.
-
Paramagnetism is a claim requirement
- The metal must be paramagnetic, narrowing against diamagnetic ions even if they fall in an atomic number range.
Bottom line: Claim 1 is a broad genus claim spanning a substituted PLP-derived chelating scaffold (as defined by variables R/R1/R3/R4/R5/R6/R7) complexed with a paramagnetic metal in specified atomic-number sets (transition metals and select lanthanides), plus salts.
What narrower embodiments are carved out in dependent claims?
Claim 2: Non-hydrogen on both R and R1 (or salt)
- Requires R and R1 are each other than hydrogen, or a salt of the chelate.
Impact: tightens from “at least one” (Claim 1) to both substituents being non-hydrogen.
Claims 3 and 4: Control of R7 and of R5/R6 substitution set
- Claim 3: each R7 is hydrogen (or salt).
- Claim 4: R and R1 each other than hydrogen; and R5/R6 each independently from a smaller set:
- hydroxy
- alkoxy C1-C8
- hydroxyethyl
- dihydroxypropyl
- amino
- alkylamido C1-C8
Impact: Claim 4 is a mid-scope claim that limits R5/R6 to shorter-chain options (C1-C8 rather than C1-C18), and forces both R and R1 non-hydrogen.
Claims 5 and 7: Restrict R3 (the diamine backbone linker)
- Claim 5: R3 is alkylene C2-C6 (or salt).
- Claim 7: R3 is cyclohexyl (or salt).
Impact: these are structural limitations on the “R3” fragment representing alkylene/cycloalkylene/arylene connecting features in the chelating scaffold.
Which specific named chelates are expressly claimed?
Named embodiment group A: PLP + ethylenediamine + diacetic acid
- Claim 6:
N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid (or salt) with the metal ion as recited in Claim 1 (or salt).
Named embodiment group B: PLP + trans-1,2-cyclohexyldiamine + diacetic acid
- Claim 8:
N,N'-bis(pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid (or salt) with the metal ion as recited in Claim 1 (or salt).
Impact: These claims tie the variable-structure genus to at least two concrete, commercially relevant scaffold options often associated with MRI or bioinorganic chelation motifs: PLP bis-chelation on a diamine plus diacetic acid functionality.
What metal-specific and salt-specific claim layers exist?
Claim 9: Divalent or trivalent metals (within Claim 1)
- The metal is divalent or trivalent (or salt).
Impact: excludes monovalent metals even if they could be paramagnetic.
Claim 10: Enumerated metals within the atomic-number ranges
Claim 10 lists explicit metals:
- chromium (III)
- manganese (II)
- iron (III)
- iron (II)
- cobalt (II)
- nickel (II)
- copper (II)
- praseodymium (III)
- neodymium (III)
- samarium (III)
- ytterbium (III)
- gadolinium (III)
- terbium (III)
- dysprosium (III)
- holmium (III)
- erbium (III)
Impact: Claim 1’s atomic-number framework is converted into a closed set for Claim 10.
Claims 11-13: Focus on manganese(II)
- Claim 11: metal is manganese(II).
- Claim 12: Mn(II) chelate of:
- N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid (or salt).
- Claim 13: Mn(II) chelate of:
- N,N'-bis(pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid (or salt).
Impact: creates a manganese-specific sub-landscape within the broader paramagnetic-metal genus.
Claims 14-18: Calcium salt engineering and mixed sodium-calcium salt
- Claim 14:
“A metal ion chelate in the form of a calcium salt of an anionic chelate complex of a paramagnetic metal ion and a chelating compound of formula I” (or salt).
- Claim 15:
calcium-to-chelating compound molar ratio is 0.05 to 1.0.
- Claim 16:
calcium salt of the manganese(II) chelate of Claim 12 (or salt).
- Claim 17:
calcium-to-chelating compound molar ratio 0.05 to 1.0 for Claim 16.
- Claim 18:
sodium-calcium salt of a manganese(II) chelate of the Claim 12 scaffold (or salt).
Impact: these claims address formulation chemistry through:
- counterion selection (Ca2+; plus Na-Ca salt),
- and an explicit counterion stoichiometry window (0.05 to 1.0).
What is the claim coverage map in practice?
1) Structural coverage
The coverage is defined along three structural axes:
| Axis |
Claim 1 variable scope |
Tightened by dependent claims |
| PLP-based chelating scaffold substitution |
R, R1 non-hydrogen allowed; R5/R6 options; R3 link-type options; R4 and R7 substitution options |
Claim 2 (R & R1 both non-H), Claim 3 (R7 = H), Claim 4 (R5/R6 C1-C8 set), Claim 5 (R3 C2-C6), Claim 7 (R3 cyclohexyl) |
| Named chelates |
Ethylenediamine + bis(PLP) + diacetic acid (Claim 6) |
Claim 12 (Mn(II) variant), Claim 14-18 (Ca salts) |
| Named chelates |
trans-1,2-cyclohexyldiamine + bis(PLP) + diacetic acid (Claim 8) |
Claim 13 (Mn(II) variant) |
2) Metal coverage
| Metal basis |
Coverage expression |
| Generic metal set |
atomic number 21-29, 42, 44, 58-70; must be paramagnetic (Claim 1) |
| Enumerated list |
17 explicitly named metals (Claim 10) |
| Charge constraints |
divalent or trivalent (Claim 9) |
| Focus |
manganese(II) claims ladder (Claims 11-13) |
3) Salt/formulation coverage
| Counterion/formulation |
Claims |
| Calcium salt of anionic chelate complex |
Claim 14 |
| Stoichiometry window |
Claim 15 (0.05 to 1.0 Ca per chelator) |
| Calcium salt of Mn(II) chelates |
Claims 16-17 |
| Sodium-calcium salt of Mn(II) chelate |
Claim 18 |
What does this imply about infringement risk for alternative designs?
Likely “design-around” pressure points
-
Move outside the metal list
- Avoid metals that are paramagnetic and within atomic number sets (or not in Claim 10 list depending on targeted dependence).
- If targeting the manganese-specific embodiments, avoiding Mn(II) is the simplest route (Claims 11-13, 16-18).
-
Alter the chelating scaffold substitution pattern
- Claim 1 is genus-like but still variable-structure constrained; changes to R/R1/R5/R6/R3/R4/R7 outside recited sets can reduce risk.
-
Avoid the specific named chelators
- Claims 6 and 8 lock in two named scaffolds. Designing a structurally adjacent scaffold not captured by these exact named formulas reduces direct hit to those claims, but Claim 1 may still be relevant if the variable-structure bounds remain satisfied.
-
Avoid calcium/mixed sodium-calcium salt forms
- Calcium stoichiometry is constrained only in dependent claims (Claims 15 and 17), but the Ca-salt formulation class is explicit in Claims 14/16.
- If a product is an anionic chelate, selecting different counterion schemes not mapped to Ca salts can reduce exposure to those dependent claims.
Patent landscape: where does US 4,933,456 sit relative to typical competitive space?
Landscape axis A: Metal chelate platform patents
US 4,933,456 is a platform-type chelate patent with:
- a defined PLP-derived chelating scaffold,
- coverage across multiple paramagnetic metals,
- and salt-formulation variants.
In competitive filings, this type of patent often competes with:
- platform patents that define other chelators for MRI or diagnostic imaging,
- metal-chelate compositions that target Gd(III) specifically,
- counterion/stoichiometry formulation patents.
Landscape axis B: Manganese(II) imaging and formulation
Because Claims 11-13 and 16-18 are explicitly manganese-focused, the competitive overlap is most acute for:
- Mn(II) chelate compositions using PLP-derived chelators,
- calcium salts or sodium-calcium salts used to control stability, osmolality, or formulation tolerability.
Landscape axis C: MRI chelator counterions and stoichiometry
Claims 14-18 create a measurable constraint via:
- calcium salt selection,
- and a Ca:chelator ratio range (0.05-1.0).
This is the kind of formulation detail that can be used in claim charting and in settlement negotiations, because it turns “salt form” into a directly testable parameter.
Key “scope” summary for business diligence
What the patent protects (by claim layer):
- Composition-of-matter: metal-ion chelates with defined variable scaffold (Claim 1).
- Composition-of-matter (strong anchor): two exact named chelators (Claims 6 and 8).
- Metal-specific: manganese(II) (Claims 11-13).
- Formulation: calcium salts (Claims 14-17) and sodium-calcium salts (Claim 18).
- Stoichiometric constraint: Ca:chelator molar ratio of 0.05 to 1.0 (Claims 15 and 17).
Where it is tightest (strongest hooks):
- The manganese ladder and the named Mn(II) chelates.
- Calcium salt and mixed sodium-calcium salt forms with defined stoichiometry.
Where it is broadest (highest coverage risk):
- Claim 1’s variable-structure genus with paramagnetic metals in specified atomic ranges.
Key Takeaways
- US 4,933,456 Claim 1 is a genus composition claim for substituted PLP-based chelating compounds complexed to paramagnetic metals in defined atomic-number sets (and salts).
- The patent has explicit, commercially meaningful anchors: two named chelating scaffolds (ethylenediamine and trans-1,2-cyclohexyldiamine variants).
- Manganese(II) is the main dependent-claim focus (Claims 11-13), with additional calcium and sodium-calcium salt coverage (Claims 14-18).
- The calcium stoichiometry limitation (Ca:chelator 0.05 to 1.0) turns formulation into a directly testable compliance point in product characterization.
FAQs
1) Does US 4,933,456 cover gadolinium?
Yes, gadolinium(III) appears explicitly in Claim 10 within the enumerated metal set.
2) Is manganese(II) explicitly claimed?
Yes. Claims 11-13 and manganese-based calcium and sodium-calcium salt forms are explicitly covered.
3) Are calcium salts within scope even if the metal is not manganese?
Yes. Claims 14 and 15 cover calcium salts of an anionic chelate complex for a paramagnetic metal ion, with the Ca:chelator molar ratio window.
4) What is the Ca:chelator ratio constraint?
Claims 15 and 17 state the molar ratio of calcium to chelating compound is 0.05 to 1.0.
5) What are the two named chelating compounds?
- N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid (Claim 6)
- N,N'-bis(pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid (Claim 8)
References
[1] US Patent 4,933,456 (claims excerpt provided in user prompt).
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