IP Library › Granted Patent US 12,403,139
Granted Patent B2
US 12,403,139 · App. 18/243,572 · Granted Sep 2, 2025

Methods and compositions for prevention and treatment of cardiac hypertrophy

Inventor: Alexander Stokes (Honolulu, HI)
Assignee: University of Hawaii
A61K31/496A61K31/00A61K31/497A61P9/04
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Quick Facts
Patent No.
US 12,403,139
App. No.
18/243,572
Granted
Sep 2, 2025
Kind
B2
Abstract

Methods are provided of treating cardiac hypertrophy in a mammalian subject comprising administering to the subject an anti-hypertrophic effective amount of an ion channel TR-PV1 inhibitor. The methods include treatment of a symptom of cardiac hypertrophy in the subject comprises cardiac remodeling, cardiac fibrosis, apoptosis, hypertension, or heart failure.

Claims (187)

1. A method of reducing the plasma concentration of a marker of cardiac hypertrophy in a mammalian subject with cardiac hypertrophy comprising administering to the subject an anti-hypertrophic effective amount of an ion channel TRPV1 inhibitor.

2. The method according to claim 1 wherein the marker of cardiac hypertrophy is atrial natriuretic peptide (ANP), TGFβ, MMP2, CMA1, or a combination thereof.

3. The method according to claim 2 wherein the marker of cardiac hypertrophy is atrial natriuretic peptide (ANP).

4. The method according to claim 2 wherein the marker of cardiac hypertrophy is TGFβ.

5. The method according to claim 2 wherein the marker of cardiac hypertrophy is MMP2.

6. The method according to claim 2 wherein the marker of cardiac hypertrophy is CMA1.

7. The method according to claim 1 wherein the ion channel TRPV1 inhibitor is selected from the group consisting of:

N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide;

N-(3-Methoxyphenyl)-4-chlorocinnamide;

1-lsoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea;

(2E)-N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1,1-dimethylethyl) phenyl]-2-propenamide;

2-Acetylamino-4-[6′-(4-trifluoromethylphenyl)-pyrimidin-4′-yl-oxy]-benzothiazole;

N-(2-bromophenyl-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl) pyrrolidin-3-yl)]urea;

N-(2-bromophenyl)-N′-{2-[ethyl (3-methylphenyl)amino]ethyl}urea;

(R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea;

N-(Isoquinolin-5-yl)-N′-[spiro-(cyclobutane-1,2′-(3′,4′-dihydro-benzopyran-4′-yl))]urea;

(2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl) phenyl]-1-piperazinecarboxamide;

4-(4′-Trifluoromethyl-anilino)-7-(3′-trifluoromethyl-pyridin-2-yl)-quinazoline;

N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide;

(5R*,8R*,6E,9E)-5,8-Dimethyl-4-methylenetetradeca-6,9-dienoic acid;

1-(3-Fluorobenzyl)-2-(N-(1,2-dimethyl-1,3-isoindazol-5-yl)-acetamido)-{pyridine-[3,4-b]-pyrrole};

N-(4-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(4-tert-butylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(3-fluoro-4-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea;

N-(4-fluoro-3-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea;

N-(3,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(2,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(4-ethylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(2-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(4-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(2-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-[1-(bromophenyl)ethyl-N′-(1-methyl-1H-Indazol-4-yl)urea;

N-(1-methyl-1H-indazol-4-yl)-N′-{4-[(trifluoromethyl)thio]benzyl}urea;

1-(2,3-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-[2-(N-ethyl-3-methylanilino)ethyl]-3-naphthalen-1-ylurea;

1-(4-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-(3-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-(chlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-[2-(N-ethyl-3-methylanilino)ethyl]-3-(2-fluorophenyl)urea;

1-[2-{N-ethyl-3-methylanilino)ethyl]-3-(2-methylphenyl)urea;

1-[2-(N-ethyl-3-methylanilino)ethyl]-3-phenylurea;

2-[(2-bromophenyl)carbamoylamino]ethyl-ethylmethyl-(3-methylphenyl) azanium iodide;

1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoro-4-methylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-3,4-difluoroanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoroanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-4-methylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-2-methylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethylanilino)ethyl]urea;

N-[2-[(2-bromophenyl)carbamoylamino]ethyl]-N-(3-methylphenyl)acetamide;

1-[2-{N-benzyl-3-methylanilino)ethyl]-3-(2-bromophenyl)urea;

1-(2-bromophenyl)-3-[2-(2,3-dimethylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(3-methylanilino)ethyl]urea;

1-(2,5-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4 (pyridin-2-yl)N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4 (pyridine-2-yl)N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide;

2-{4-fluoro-1-[4-trifluoromethylbenzoyl]piperidin-4-yl}pyridine;

2-(4-fluoro-1-{[4-trifluoromethylphenyl]acetyl}piperidin-4-yl) pyridine;

2-(4-fluoro-1-{3-[4-trifluoromethylphenyl]propanoyl}piperidin-4-yl) pyridine;

4-fluoro-4-(1-methyl-1H-imidazol-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide;

4-fluoro-N-(4-isopropylphenyl)-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-{4-[1,2,2,2-tetrafluoro-1-trifluoromethylethyl]phenyl}piperidine-1-carboxamide;

N-(4-Tert-butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(pentafluoro-lambda (sup 6)-sulfanyl) phenyl]piperidine-1-carboxamide;

N-(4-Butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-(4-Benzylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-biphenyl-4-yl-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[5-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide;

4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-methoxypyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carbothioamide;

N′-cyano-4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N′-(1-phenylpiperidin-4-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide;

4-fluoro-4-phenyl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

(+/−)-(syn)-4-fluoro-2-methyl-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl] piperidine-1-carboxamide;

4-(fluoromethyl)-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

syn- and anti-3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2.1]octane-8-carboxamide;

3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2.1]octane-8-carboxamide;

4-fluoro-4-pyrimidin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-phenylpropyl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

2-[4-fluoro-4-(3-methylpyridin-2-yl) piperidin-1-yl]-6-trifluoromethyl-1H-benzimidazole;

2-(4-fluoro-4-pyridin-2-ylpiperidin-1-yl)-6-(trifluoromethyl)-1H-benzimidazole;

4-fluoro-N-[4-trifluoromethylphenyl]-4-[3-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide;

4-fluoro-N-(4-methylphenyl)-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-(4-ethylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-(4-chlorophenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethoxyphenyl]piperidine-1-carboxamide;

N-(4-cyanophenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-[4-dimethylaminophenyl]-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

1-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazo-1-4-yl)urea;

N-acetyl-1-phenylalanyl-l-leucinamide;

and pharmaceutically acceptable salts thereof.

8. The method according to claim 1 wherein the inhibitor comprises N-(4-t-butyl-phenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide or a pharmaceutically acceptable salt thereof.

9. A method of reducing the plasma concentration of atrial natriuretic peptide (ANP) in a mammalian subject with cardiac hypertrophy comprising administering to the subject an anti-hypertrophic effective amount of an ion channel TRPV1 inhibitor.

10. The method according to claim 9 wherein the ion channel TRPV1 inhibitor is selected from the group consisting of:

N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide;

N-(3-Methoxyphenyl)-4-chlorocinnamide;

1-lsoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea;

(2E)-N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1,1-dimethylethyl) phenyl]-2-propenamide;

2-Acetylamino-4-[6′-(4-trifluoromethylphenyl)-pyrimidin-4′-yl-oxy]-benzothiazole;

N-(2-bromophenyl-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl) pyrrolidin-3-yl)]urea;

N-(2-bromophenyl)-N′-{2-[ethyl (3-methylphenyl)amino]ethyl}urea;

(R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea;

N-(Isoquinolin-5-yl)-N′-[spiro-(cyclobutane-1,2′-(3′,4′-dihydro-benzopyran-4′-yl))]urea;

(2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl) phenyl]-1-piperazinecarboxamide;

4-(4′-Trifluoromethyl-anilino)-7-(3′-trifluoromethyl-pyridin-2-yl)-quinazoline;

N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide;

(5R*,8R*,6E,9E)-5,8-Dimethyl-4-methylenetetradeca-6,9-dienoic acid;

1-(3-Fluorobenzyl)-2-(N-(1,2-dimethyl-1,3-isoindazol-5-yl)-acetamido)-{pyridine-[3,4-b]-pyrrole};

N-(4-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(4-tert-butylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(3-fluoro-4-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea;

N-(4-fluoro-3-(trifluoromethyl)benzyl)-N′-(1-methyl-1H-indazol-4-yl)-urea;

N-(3,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(2,4-dichlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(4-ethylbenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(2-chlorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(4-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-(2-fluorobenzyl)-N′-(1-methyl-1H-indazol-4-yl)urea;

N-[1-(bromophenyl)ethyl-N′-(1-methyl-1H-Indazol-4-yl)urea;

N-(1-methyl-1H-indazol-4-yl)-N′-{4-[(trifluoromethyl)thio]benzyl}urea;

1-(2,3-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-[2-(N-ethyl-3-methylanilino)ethyl]-3-naphthalen-1-ylurea;

1-(4-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-(3-bromophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-(chlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

1-[2-(N-ethyl-3-methylanilino)ethyl]-3-(2-fluorophenyl)urea;

1-[2-{N-ethyl-3-methylanilino)ethyl]-3-(2-methylphenyl)urea;

1-[2-(N-ethyl-3-methylanilino)ethyl]-3-phenylurea;

2-[(2-bromophenyl)carbamoylamino]ethyl-ethylmethyl-(3-methylphenyl) azanium iodide;

1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoro-4-methylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-3,4-difluoroanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-3-fluoroanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-4-methylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethyl-2-methylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(N-ethylanilino)ethyl]urea;

N-[2-[(2-bromophenyl)carbamoylamino]ethyl]-N-(3-methylphenyl)acetamide;

1-[2-{N-benzyl-3-methylanilino)ethyl]-3-(2-bromophenyl)urea;

1-(2-bromophenyl)-3-[2-(2,3-dimethylanilino)ethyl]urea;

1-(2-bromophenyl)-3-[2-(3-methylanilino)ethyl]urea;

1-(2,5-dichlorophenyl)-3-[2-(N-ethyl-3-methylanilino)ethyl]urea;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4 (pyridin-2-yl)N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4 (pyridine-2-yl)N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide;

2-{4-fluoro-1-[4-trifluoromethylbenzoyl]piperidin-4-yl}pyridine;

2-(4-fluoro-1-{[4-trifluoromethylphenyl]acetyl}piperidin-4-yl) pyridine;

2-(4-fluoro-1-{3-[4-trifluoromethylphenyl]propanoyl}piperidin-4-yl) pyridine;

4-fluoro-4-(1-methyl-1H-imidazol-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-methoxy-4-pyridin-2-yl-N-[4-trifluoromethylbenzyl]piperidine-1-carboxamide;

4-fluoro-N-(4-isopropylphenyl)-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-{4-[1,2,2,2-tetrafluoro-1-trifluoromethylethyl]phenyl}piperidine-1-carboxamide;

N-(4-Tert-butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(pentafluoro-lambda (sup 6)-sulfanyl) phenyl]piperidine-1-carboxamide;

N-(4-Butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-(4-Benzylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-biphenyl-4-yl-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[5-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide;

4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-methoxypyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carbothioamide;

N′-cyano-4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N′-(1-phenylpiperidin-4-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboximidamide;

4-fluoro-4-phenyl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

(+/−)-(syn)-4-fluoro-2-methyl-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-(fluoromethyl)-4-pyridin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

syn- and anti-3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2.1]octane-8-carboxamide;

3-fluoro-3-pyridin-2-yl-N-[4-trifluoromethylphenyl]-8-azabicyclo[3.2.1]octane-8-carboxamide;

4-fluoro-4-pyrimidin-2-yl-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

4-fluoro-4-(3-phenylpropyl)-N-[4-trifluoromethylphenyl]piperidine-1-carboxamide;

2-[4-fluoro-4-(3-methylpyridin-2-yl) piperidin-1-yl]-6-trifluoromethyl-1H-benzimidazole;

2-(4-fluoro-4-pyridin-2-ylpiperidin-1-yl)-6-(trifluoromethyl)-1H-benzimidazole;

4-fluoro-N-[4-trifluoromethylphenyl]-4-[3-trifluoromethylpyridin-2-yl]piperidine-1-carboxamide;

4-fluoro-N-(4-methylphenyl)-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-(4-ethylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-(4-chlorophenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-trifluoromethoxyphenyl]piperidine-1-carboxamide;

N-(4-cyanophenyl)-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

N-[4-dimethylaminophenyl]-4-fluoro-4-(3-methylpyridin-2-yl) piperidine-1-carboxamide;

1-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazo-1-4-yl)urea;

N-acetyl-1-phenylalanyl-l-leucinamide;

and pharmaceutically acceptable salts thereof.

11. The method according to claim 9 wherein the ion channel TRPV1 inhibitor comprises N-(4-t-butyl-phenyl)-4-(3-chloropyridin-2-yl)-tetrahydropyrazine-1(2H)-carboxamide or a pharmaceutically acceptable salt thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 31, 2025
From: STOKES, ALEXANDER
To: UNIVERSITY OF HAWAII
Reel/Frame 071898/0800 →
Continuity (7)
Continuation 16928967 · Jul 14, 2020
Continuation 16181204 · Nov 5, 2018
Continuation 15583867 · May 1, 2017
Continuation 14745060 · Jun 19, 2015
Division 13824912
Provisional Application 61409781 · Nov 3, 2010
Related Publication 20240189303A1 · Jun 13, 2024
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