United States Patent 6,043,279: Scope, Claims, and Retinoid X Receptor Patent Landscape

United States Patent 6,043,279 is a broad retinoid chemistry and use patent built around a highly parameterized compound formula with downstream claims covering (i) compounds, (ii) selective RXR activation versus retinoic acid receptor (RAR) isoforms, (iii) pharmaceutical compositions, and (iv) multiple process and treatment methods mediated by one or more RXRs, including a specific cardiometabolic/HDL effect.

The claim set is dominated by a Markush-style generic formula that includes variable ring heteroatom patterns (Z, Z’, Z”, Z”’, Z””), multiple substitutable groups at defined positions (R1, R2, R6, R10, R11, R12, R13, R7, R8, R9, R17, R18), and a terminal ring-origin substituent X that can be acidic, sulfonic, phosphonic, aldehydic, hydroxymethyl, carboxamide, thioacid/ester, or salt forms. The independent “core” claim is Claim 1, while Claims 2, 10, 12, 13 tighten the biological selectivity and indication scope.

What Is the Core Claim Scope Under Claim 1?

Claim 1 defines a class of “A compound” by a generic structure:

A. The structural blueprint

Claim 1 requires a compound that has:

A defined scaffold (given as ##STR14## in the claim text) with variable substituents.
Variable ring substituent logic through:
- R1 and R2: each independently = hydrogen or lower alkyl or acyl (1 to 4 carbons).
- R’ and R”: each independently = hydrogen, lower alkyl or acyl (1 to 4), hydroxyl, alkoxy (1 to 4), thiol or thioether, amino; or R’ and R” taken together form specified functional groups:
  - oxo (keto), methano (bridged carbonyl motif), thioketo
  - HO–N═, NC–N═
  - (R7 R8)N–N═
  - R17 O–N═, R17 N═
  - epoxy
  - cyclopropyl or cycloalkyl (with further substitution allowances)
Conditional existence constraints for substituents:
- R6, R10, R11, R12, R13 each = hydrogen, lower alkyl (1 to 4), halogen, nitro, OR7, SR7, NR7R8, or (CF)nCF3
- Each of R6, R10, R11, R12, R13 “exist only if” the origin substituent position Z pattern is C (i.e., they are permitted only when the underlying ring atom is carbon).
- “and where one of R6, R10, R11, R12 or R13 is X”.
X (the ring-origin acidic/functional handle) can be:
- COOH
- tetrazole
- PO3H
- SO3H
- CHO
- CH2OH
- CONH2
- COSH
- COOR9
- COSR9
- CONHR9
- COOW where W is a pharmaceutically acceptable salt
- with the additional logic: “where X can originate from any C or N on the ring.”

B. Substituent ranges that expand breadth

R7 and R8: hydrogen or lower alkyl (R7: 1 to 6; R8: 1 to 6).
R9: lower alkyl (1 to 4), phenyl, aromatic alkyl, or q-hydroxyphenyl / q-bromo- / q-chloro- / q-fluoro- / q-iodophenyl with q = 2 to 4.
R17: hydrogen, lower alkyl (1 to 8), alkenyl (including halogen, acyl, OR7 and SR7 substituted alkenes), R9, alkyl carboxylic acids (with halogen/acyl/OR7/SR7 substitution), corresponding alkenyl carboxylic acids, alkyl amines (with halogen/acyl/OR7/SR7 substitution), and alkenyl amines (with halogen, aryl, OR7/SR7 substituted alkenes).
R18: hydrogen, lower alkyl (1 to 4), halogen, nitro, OR7, SR7, NR7R8, or (CF)nCF3.
n = 0 to 3 for the (CF)nCF3 group.
Z, Z’, Z”, Z”’, Z”” (ring atom variables): each independently = C, S, O, N, or a pharmaceutically acceptable salt, with restrictions:
- not O or S if attached by double bond to another Z/S/O
- not N if attached by a single bond to another N
- allows ring heteroatom permutations while maintaining valence constraints.

Net effect: Claim 1 is not a single molecule family; it is a large structural lattice with multiple degrees of freedom and explicit permission for multiple functional groups that map onto typical drug-like “acid head” and “linker” variations used for nuclear receptor ligands.

Which Dependent Claims Define the Biological Scope?

Claim 2: RXR-selective activation

“selectively activates Retinoid X Receptors in preference to Retinoic Acid Receptors.”

This claim turns the chemical class into a functional receptor selectivity category. It is biologically meaningful because it distinguishes compounds that activate RXR over those that activate RAR.

Claim 12: RXR selectivity vs all RAR isoforms

“selectively mediated by one or more Retinoid X Receptors”
RXR activation in preference to “all of Retinoic Acid Receptor isoforms α, β, and γ.”

This narrows selectivity from “RAR” broadly (Claim 2) to all canonical RAR isoforms.

Claim 13: Treatment indication for RXR therapy

“treating a mammalian subject requiring Retinoid X Receptor therapy”
requires “administering … compounds which selectively activate a Retinoid X Receptor in preference to all of Retinoic Acid Receptor isoforms α, β, and γ.”

This is a clinical-use style claim with receptor selectivity embedded.

Which Claims Expand to Methods, Composition, and Specific Indications?

Claim 4: Pharmaceutical composition

A composition claim that includes:

“one or more compound having the formula” of Claim 1
in “a pharmaceutically acceptable vehicle suitable for enteral, parenteral, or topical administration.”

This does not add mechanistic changes; it creates formulation coverage for the same chemical class.

Claims 5, 6, 7, 9, 10: Process and treatment methods

The patent uses multiple method claim “vectors”:

Claim 5: Modulating RXR-mediated processes

“modulating a process mediated by one or more Retinoid X Receptors”
by conducting the process in the presence of at least one formula compound.

Claim 6: Specific in vivo process domains

“in vivo modulation of lipid metabolism”
“in vivo modulation of skin-related processes”
“in vivo modulation of malignant cell development”
“in vivo modulation of premalignant lesions”
“in vivo modulation of programmed cell death”

This is a high-level therapeutic area map that covers metabolic, dermatologic, oncology, precancer, and apoptosis.

Claim 7: Growth/differentiation and morphogenesis

“in vivo or in vitro cellular growth and differentiation”
“in vivo limb morphogenesis”

This broadens beyond disease labels into developmental and cell biology.

Claim 8: Combination synergy (two-compound use)

Presence of:
- a first compound that selectively activates RXR over RAR receptors
- plus a second compound that activates “one or more intracellular receptors other than RXR”
and requires a greater-than-additive physiological effect:
- “greater than the additive effect achieved by utilizing each compound alone at that concentration.”

This claim is a formulation-like method claim for combination regimens emphasizing synergistic outcomes.

Claim 9: Treating mammalian subject requiring RXR therapy

A treatment method that mirrors Claim 13 but appears earlier in the numbering; the text includes RXR therapy language.

Claim 10: Increasing plasma HDL

“increasing plasma concentrations of high density lipoprotein”
by administering formula compounds.

This is an explicit cardiovascular/metabolic functional endpoint and can anchor prosecution and later licensing based on measurable pharmacodynamic outcomes.

Which Claims Name Specific Compounds?

Claim 3: Four specific examples

The claim recites specific members of the generic family:

4-[1-(2-methyl-4-t-butylphenyl)ethenyl]benzoic acid
4-[1-(2-methyl-4-t-butylphenyl)cyclopropyl]benzoic acid
4-[(2-methyl-4-t-butylphenyl)carbonyl]benzoic acid oxime
4-[1-(2-methyl-4-t-butylphenyl)carbonyl]benzoic acid methyloxime

These examples narrow the chemical space to at least one “aryl-alkenyl/cyclopropyl/oxime” motif anchored by a benzoic acid (and oxime derivatives). They also demonstrate that X includes COOH and oxime-functionalized analogs under the structural definition.

How Should a Freedom-to-Operate View the Scope? (Practical Reading of Claim Boundaries)

1) The claim is formula-based but function-locking occurs in dependent claims

Claim 1 is broad on structure.
Claims 2, 12, 13 add “selective activation” constraints.
For enforcement, the strongest hooks are likely Claims 2/12/13 because they translate to receptor selectivity tests.

2) “Exist only if origin is C” is an internal gating mechanism

The structure contains conditional allowances for substituents R6/R10/R11/R12/R13:

these substituents are permitted only when the corresponding Z-origin atom is C.
that gating reduces overbreadth and can be used to argue non-infringement if a competitor’s heteroatom pattern places the origin atom as S/O/N in the relevant positions.

3) X is the main functional head

Because Claim 1 requires one of R6/R10/R11/R12/R13 to equal X, and X is permitted to be multiple acidic/ionic and polar groups, the patent likely covers:

classic carboxylic acids and salts (COOH, COOW)
tetrazoles
sulfonic and phosphonic acids
aldehydes and hydroxymethyl
carboxamides and thioacids/esters

This makes it harder for competitors to evade by swapping acid heads alone, unless they also redesign the Z pattern so the “X placement” logic no longer maps to the claim.

4) The patent includes “epi/cyclopropyl/cycloalkyl substituted” language

Claim 1 explicitly allows:

epoxy, cyclopropyl, cycloalkyl groups that can be substituted with lower alkyl or halogen. This suggests the family includes constrained ring motifs common in RXR/RAR ligands.

Claim-by-Claim Landscape Summary (What Each Claim Covers)

Claim	Coverage type	Key limitations driving scope
1	Compound class	Complex Markush formula; X functional head; Z heteroatom logic; multiple substituent degrees of freedom
2	Compound use (functional)	RXR activation preferred to RAR (broad)
3	Specific compounds	Enumerated 4 benzoic acid / oxime derivatives with 2-methyl-4-t-butylphenyl motif
4	Composition	Same compounds in pharmaceutically acceptable vehicle; enteral/parenteral/topical
5	Method of modulation	Process mediated by one or more RXRs, presence of at least one formula compound
6	In vivo method sub-scope	Lipid metabolism, skin processes, malignant development, premalignant lesions, apoptosis
7	In vivo/in vitro + development	Cellular growth/differentiation; limb morphogenesis
8	Combination synergy method	RXR-selective first compound + second intracellular receptor agonist/activator; greater-than-additive effect
9	Treatment method	RXR therapy treatment language with the same formula compounds
10	Method with endpoint	Increase plasma HDL
11	Combination synergy (broader phrasing)	RXR-selective first compound + second compound for other intracellular receptor(s); greater-than-additive physiology
12	RXR-selective all-RAR-isoforms	RXR selectively vs RAR isoforms α, β, γ
13	Treatment with all-RAR-isoforms constraint	RXR-selective preference over all RAR isoforms; mammalian treatment

Patent Landscape: What This Family Likely Interacts With in US Practice

Given the claim content, the landscape risks typically come from three categories of later patents and marketed molecules:

RXR selective agonists with structural similarity in the “acid head” region (carboxylates, tetrazoles, sulfonic acids) and a substituted aryl region.
RAR vs RXR selectivity patents that emphasize preferential RXR activation over RAR α/β/γ.
Combination therapy patents that pair RXR agonists with other nuclear receptor modulators and claim synergy or enhanced efficacy.

This patent’s unique leverage is:

its breadth of chemical headgroup X plus heteroatom substitution logic, and
its explicit selectivity to RXR over RAR isoforms α/β/γ in Claims 12/13, and
its explicit HDL endpoint in Claim 10, which is an unusually concrete functional hook for licensing and claim construction.

Enforcement pattern expectation: A core infringer analysis would start with Claim 1 mapping to chemical structure (Markush match), then validate functional selectivity (Claim 2/12) and indication endpoints (Claim 10 and treatment claims). For combination products, Claims 8 and 11 add a “greater-than-additive” requirement that generally increases evidentiary burdens in litigation.

Key Takeaways

Claim 1 defines a large, parameterized chemical genus with a conditional heteroatom-substitution gating (“exist only if origin is C”) and a required “X” functional head selected from acids/salts and multiple polar groups.
Selectivity claims (Claims 2 and 12/13) lock the biological story to RXR preference over RAR, with Claims 12/13 requiring preference over RAR α, β, and γ.
Business-relevant downstream claims include pharmaceutical compositions (Claim 4) and specific functional endpoints such as HDL elevation (Claim 10), plus broad in vivo targets across lipids, skin, oncology, premalignancy, apoptosis, and developmental morphogenesis.
Combination regimen coverage (Claims 8 and 11) hinges on a second intracellular receptor activator plus greater-than-additive physiological effect at a given concentration.

FAQs

Is the patent limited to one molecule?
No. Claim 1 is a broad Markush-style genus; Claim 3 lists four exemplary specific compounds within that genus.
What distinguishes Claim 12 from Claim 2?
Claim 12 requires RXR activation preference over all RAR isoforms α, β, γ, while Claim 2 states preference over RAR without enumerating isoforms.
Does Claim 10 cover any general lipid effect or a specific measurement?
Claim 10 requires the method to increase plasma concentrations of HDL.
How do Z/Z’/Z’’/Z’’’/Z’’’’ variables affect infringement risk?
They define permissible ring heteroatom patterns and interact with conditional substituent allowance language (“exist only if origin is C”), creating structure-dependent boundaries.
Do the combination claims require synergy beyond additive effects?
Yes. Claims 8 and 11 explicitly require a physiological effect greater than the additive effect from each compound alone.

References

[1] United States Patent and Trademark Office. US 6,043,279 (claims text as provided).

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0637297	⤷ Start Trial	01C0027	France	⤷ Start Trial
European Patent Office	0637297	⤷ Start Trial	SPC013/2001	Ireland	⤷ Start Trial
European Patent Office	0637297	⤷ Start Trial	CA 2001 00032	Denmark	⤷ Start Trial
European Patent Office	0637297	⤷ Start Trial	C300054	Netherlands	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,043,279

Summary for Patent: 6,043,279