Granted Patent
B2
US 12,329,739 · App. 18/363,328 · Granted Jun 17, 2025
Isoflavonoid compounds and methods for the treatment of cancer
Inventors:
George Jeoffreys (Baulkham Hills, AU); Alison Johnson (Drummoyne, AU); Andrew Heaton (Alexandria, AU); Ofir Moreno (Poway, CA)
Assignee:
Aardvark Therapeutic, Inc.
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Abstract
Provided herein is a pharmaceutical composition comprising at least one isoflavonoid. Also provided herein are methods of treating cancer, sensitizing cancer cells, and inducing apoptosis in cancer cells by administering such compositions.
Claims (18)
1. A pharmaceutical composition comprising d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol in at least 95% enantiomeric excess, and one or more pharmaceutically acceptable carriers, excipients, auxiliaries, binders and/or diluents.
2. The pharmaceutical composition of claim 1 , wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is provided in at least 99% enantiomeric excess.
3. The pharmaceutical composition of claim 1 , wherein the d-cis-3-(4-hydroxypheny 1)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is provided in 95% to 99.9% enantiomeric excess.
4. The pharmaceutical composition of claim 1 , comprising d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol in at least 95% enantiomeric excess, and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable carrier is an aqueous vehicle.
6. The pharmaceutical composition of claim 5 , wherein the aqueous vehicle comprises water, Ringer's solution, phosphate buffered saline solution, isotonic sodium chloride solution, ethanol, or 1,3-butanediol.
7. The pharmaceutical composition of claim 5 , wherein the aqueous vehicle is sterile water.
8. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier comprising an aqueous vehicle and an auxiliary comprising a solubility enhancing agent.
9. A method of treating cancer in an individual in need of cancer therapy, the method comprising administering to the individual a composition comprising d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol provided in at least 95% enantiomeric excess.
10. The method of claim 9 , wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is provided in at least 99% enantiomeric excess.
11. The method of claim 9 , wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is provided in 95% to 99.9% enantiomeric excess.
12. The method of claim 9 , wherein the cancer has lost sensitivity to a chemotherapeutic agent, anti-cancer agent, or radiation therapy.
13. The method of claim 9 , wherein the cancer is bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, leukemia, lung cancer, melanoma, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or brain cancer.
14. The method of claim 9 , wherein the cancer is breast cancer, colon cancer, rectal cancer, or lung cancer.
15. The method of claim 9 , wherein the cancer is metastatic colorectal cancer or metastatic HER2-negative breast cancer.
16. A kit comprising a composition comprising d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxypheny 1)-8-methy Ichroman-7-ol provided in at least 95% enantiomeric excess; and a sealable, plastic infusion bag.
17. The kit of claim 16 , wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is provided in at least 99% enantiomeric excess.
18. The kit of claim 16 , wherein the d-cis-3-(4-hydroxyphenyl)-4-(4-hydroxyphenyl)-8-methylchroman-7-ol is provided in 95% to 99.9% enantiomeric excess.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 27, 2024
From: MEI PHARMA, INC
To: AARDVARK THERAPEUTICS, INC.
Reel/Frame 069422/0065 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 15, 2023
From: JEOFFREYS, GEORGE; JOHNSON, ALISON; HEATON, ANDREW; MORENO, OFIR
To: MARSHALL EDWARDS, INC.
Reel/Frame 064594/0555 →
MERGER AND CHANGE OF NAME
Recorded Aug 15, 2023
From: MARSHALL EDWARDS, INC.; MEI PHARMA, INC.
To: MEI PHARMA, INC.
Reel/Frame 064701/0110 →
Continuity (7)
References Cited (327)
US 3340276A
· Carney et al.
· 1967
[cited by applicant]
US 3471520A
· Klaus et al.
· 1969
[cited by applicant]
US 3535344A
· Klaus et al.
· 1970
[cited by applicant]
US 4157984A
· Zilliken
· 1979
[cited by applicant]
US 4218489A
· Zilliken
· 1980
[cited by applicant]
US 4232122A
· Zilliken
· 1980
[cited by applicant]
US 4234577A
· Zilliken
· 1980
[cited by applicant]
US 4366082A
· Zilliken
· 1982
[cited by applicant]
US 4366248A
· Zilliken
· 1982
[cited by applicant]
US 4368264A
· Zilliken
· 1983
[cited by applicant]
US 4390559A
· Zilliken
· 1983
[cited by applicant]
US 4447622A
· Salman et al.
· 1984
[cited by applicant]
US 4644012A
· Tsuda et al.
· 1987
[cited by applicant]
US 4814346A
· Albert et al.
· 1989
[cited by applicant]
US 5024998A
· Bodor
· 1991
[cited by applicant]
US 5059609A
· Eggler et al.
· 1991
[cited by applicant]
US 5134127A
· Stella et al.
· 1992
[cited by applicant]
US 5280040A
· Labroo et al.
· 1994
[cited by applicant]
US 5376645A
· Stella et al.
· 1994
[cited by applicant]
US 5389646A
· Labroo
· 1995
[cited by applicant]
US 5464862A
· Labroo et al.
· 1995
[cited by applicant]
US 5696149A
· Korsgaard et al.
· 1997
[cited by applicant]
US 5726202A
· Shalmi et al.
· 1998
[cited by applicant]
US 5756539A
· Skrumsager et al.
· 1998
[cited by applicant]
US 5780503A
· Biftu et al.
· 1998
[cited by applicant]
US 5849461A
· Hatakeyama et al.
· 1998
[cited by applicant]
US 5874418A
· Stella et al.
· 1999
[cited by applicant]
US 5883118A
· Shalmi et al.
· 1999
[cited by applicant]
US 5919817A
· Jacobsen et al.
· 1999
[cited by applicant]
US 5958967A
· Jacobsen et al.
· 1999
[cited by applicant]
US 5985306A
· Jacobsen et al.
· 1999
[cited by applicant]
US 5994390A
· Jacobsen et al.
· 1999
[cited by applicant]
US 5998451A
· Eggler et al.
· 1999
[cited by applicant]
US 6005003A
· Nique
· 1999
[cited by applicant]
US 6043269A
· Jacobsen et al.
· 2000
[cited by applicant]
US 6316494B1
· Jacobsen et al.
· 2001
[cited by applicant]
US 6479467B1
· Buchanan et al.
· 2002
[cited by applicant]
US 6509323B1
· Davis
· 2003
[cited by applicant]
US 6610671B2
· Buchanan et al.
· 2003
[cited by applicant]
US 6610733B2
· Park et al.
· 2003
[cited by applicant]
US 6645951B1
· Jo et al.
· 2003
[cited by applicant]
US 6649648B1
· Kelly et al.
· 2003
[cited by applicant]
US 6660804B1
· Weltrowski et al.
· 2003
[cited by applicant]
US 7056952B1
· Joannou
· 2006
[cited by applicant]
US 7202273B2
· Kelly et al.
· 2007
[cited by applicant]
US 7601855B2
· Heaton et al.
· 2009
[cited by applicant]
US 7906554B2
· Kelly et al.
· 2011
[cited by applicant]
US 8080675B2
· Heaton
· 2011
[cited by examiner]
US 8084628B2
· Heaton
· 2011
[cited by examiner]
US 8163795B2
· Heaton
· 2012
[cited by examiner]
US 8461361B2
· Heaton
· 2013
[cited by examiner]
US 8697891B2
· Heaton et al.
· 2014
[cited by applicant]
US 8957109B2
· Heaton
· 2015
[cited by examiner]
US 9138478B2
· Heaton et al.
· 2015
[cited by applicant]
US 9198895B2
· Heaton
· 2015
[cited by examiner]
US 9381186B2
· Heaton et al.
· 2016
[cited by applicant]
US 9663484B2
· Jeoffreys
· 2017
[cited by examiner]
US 9708283B2
· Moreno
· 2017
[cited by examiner]
US 9981936B2
· Moreno
· 2018
[cited by examiner]
US 20020128468A1
· Buchanan et al.
· 2002
[cited by applicant]
US 20040063663A1
· Buchanan et al.
· 2004
[cited by applicant]
US 20040209825A1
· Lahey et al.
· 2004
[cited by applicant]
US 20060167037A1
· Kelly et al.
· 2006
[cited by applicant]
US 20060167083A1
· Kelly
· 2006
[cited by applicant]
US 20080014249A1
· Heaton et al.
· 2008
[cited by applicant]
US 20080069900A1
· Kelly et al.
· 2008
[cited by applicant]
US 20100130598A1
· Brown et al.
· 2010
[cited by applicant]
US 20100152284A1
· Brown et al.
· 2010
[cited by applicant]
US 20100173983A1
· Brown et al.
· 2010
[cited by applicant]
US 20120039917A1
· Husband et al.
· 2012
[cited by applicant]
US 20120251630A1
· Alvero et al.
· 2012
[cited by applicant]
US 20160136129A1
· Heaton et al.
· 2016
[cited by applicant]
US 20160287555A1
· Heaton et al.
· 2016
[cited by applicant]
US 20190142790A1
· Jeoffreys et al.
· 2019
[cited by applicant]
CA 2581316A1
· 2006
[cited by applicant]
EP 0267155A2
· 1988
[cited by applicant]
EP 0313295A2
· 1989
[cited by applicant]
EP 0470310A1
· 1992
[cited by applicant]
EP 0955286A1
· 1999
[cited by applicant]
GB 1433013
· 1976
[cited by applicant]
GB 1433013A
· 1976
[cited by applicant]
JP 2000502507A
· 2000
[cited by applicant]
JP 2001502706A
· 2001
[cited by applicant]
JP 2001502711A
· 2001
[cited by applicant]
JP 2002529372A
· 2002
[cited by applicant]
JP 2006096734A
· 2006
[cited by applicant]
JP 2008513376A
· 2008
[cited by applicant]
JP 2012144537A
· 2012
[cited by applicant]
JP 2014237638A
· 2014
[cited by applicant]
WO WO8002098A1
· 1980
[cited by applicant]
WO WO9408986A1
· 1994
[cited by applicant]
WO WO9420099A1
· 1994
[cited by applicant]
WO WO9621442A1
· 1996
[cited by applicant]
WO WO9621443A1
· 1996
[cited by applicant]
WO WO9621444A1
· 1996
[cited by applicant]
WO WO9622091A1
· 1996
[cited by applicant]
WO WO9622092A1
· 1996
[cited by applicant]
WO WO9622093A1
· 1996
[cited by applicant]
WO WO9725035A1
· 1997
[cited by applicant]
WO WO9725036A1
· 1997
[cited by applicant]
WO WO9725037A1
· 1997
[cited by applicant]
WO WO9725038A1
· 1997
[cited by applicant]
WO WO9802154A1
· 1998
[cited by applicant]
WO WO9802156A1
· 1998
[cited by applicant]
WO WO9808503A1
· 1998
[cited by applicant]
WO WO9817662A1
· 1998
[cited by applicant]
WO WO9818770A1
· 1998
[cited by applicant]
WO WO9818771A1
· 1998
[cited by applicant]
WO WO9818772A1
· 1998
[cited by applicant]
WO WO9818773A1
· 1998
[cited by applicant]
WO WO9818774A1
· 1998
[cited by applicant]
WO WO9818775A1
· 1998
[cited by applicant]
WO WO9818776A1
· 1998
[cited by applicant]
WO WO9818778A1
· 1998
[cited by applicant]
WO WO9818779A1
· 1998
[cited by applicant]
WO WO9825916A1
· 1998
[cited by applicant]
WO WO9832437A1
· 1998
[cited by applicant]
WO WO9833499A1
· 1998
[cited by applicant]
WO WO9833500A1
· 1998
[cited by applicant]
WO WO9949862A1
· 1999
[cited by applicant]
WO WO9955898A1
· 1999
[cited by applicant]
WO WO9963974A2
· 1999
[cited by applicant]
WO WO9965893A1
· 1999
[cited by applicant]
WO WO0049009A1
· 2000
[cited by applicant]
WO WO0066576A1
· 2000
[cited by applicant]
WO WO0117986A1
· 2001
[cited by applicant]
WO WO0126651A2
· 2001
[cited by applicant]
WO WO0154699A1
· 2001
[cited by applicant]
WO WO0202548A1
· 2002
[cited by applicant]
WO WO02059113A1
· 2002
[cited by applicant]
WO WO03016270A2
· 2003
[cited by applicant]
WO WO03035635A1
· 2003
[cited by applicant]
WO WO03063859A1
· 2003
[cited by applicant]
WO WO03086386A1
· 2003
[cited by applicant]
WO WO2004030662A1
· 2004
[cited by applicant]
WO WO2005049008A1
· 2005
[cited by applicant]
WO WO2006032085A1
· 2006
[cited by applicant]
WO WO2006032086A1
· 2006
[cited by applicant]
WO WO2008052256A1
· 2008
[cited by applicant]
WO WO2008113100A1
· 2008
[cited by applicant]
WO WO2010022467A1
· 2010
[cited by applicant]
WO WO2010045674A1
· 2010
[cited by applicant]
WO WO2012061409A1
· 2012
[cited by applicant]
WO WO2012061413A2
· 2012
[cited by applicant]
Co-pending U.S. Appl. No. 18/340,308, filed Jun. 23, 2023.
[cited by examiner]
Abegaz, et al., Isoflavonoids from the roots of Salsola somalensis. Phytochemistry. 30(4): 1281-4, 1991 (Abstract Only in English).
[cited by applicant]
Agarwal, et al., Isoflavones of two Iris species. Phytochemistry (Elsevier) 23(11):2703-4, 1984. (Abstract Only in English).
[cited by applicant]
Agarwal, et al., Phenolic constituents of Iris Milesii rhizomes, Phytochemistry (Elsevier) 23(6):1342-3, 1984. (Abstract Only in English).
[cited by applicant]
Aggarwal, et al., From chemoprevention to chemotherapy: common targets and common goals. Expert Opin. Investig. Drugs. 2004;13(10):1327-38.
[cited by applicant]
Akimoto, et al., Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro: possible involvement of inhibition of survival signal transduction pathways. Int. J. Rad…
[cited by applicant]
Aldrich Handbook of Fine Chemicals and Laboratory Equipment © 2002, Sigma-Aldrich Pty Limited, Australia: Note: Sigma-Aldrich is a US Company, catalogue/handbook from which the pages derive from is the AU publication.
[cited by applicant]
Antus, et al., Synthesis of some pterocarpenes obtained from Brya ebenus, J. Chem. Soc., Perkin Trans. 6:1389-94, 1982 (Abstract Only in English).
[cited by applicant]
Arnone, et al., Isoflavonoid constituents of the West African red wood,
[cited by applicant]
Bartelink et al. The combined use of radiotherapy and chemotherapy in the treatment of solid tumours. Eur J Cancer 38(2):216-222 (2002).
[cited by applicant]
Bellisarii, et al., Tumor necrosis factor-α and cardiovascular diseases. Ital Heart J. 2001;2(6):408-17.
[cited by applicant]
Berge et al. Pharmaceutical Salts. Journal of Pharmaceutical Sciences 66(1):1-19 (Jan. 1977).
[cited by applicant]
Berridge MV, Tan AS. (1998) Trans-plasma membrane electron transport a cellular assay for NADH- and NADPH-oxidase based on extracellular, superoxide-mediated reduction of the sulfonated tetrazolium salt WST-1. Protoplas…
[cited by applicant]
Bezuidenhoudt et al., Synthesis of Isoflavanoid Oligomers Using a Pterocarpan as Inceptive Electrophile. J Chem Soc Parkin Trans. 1984; 1:2767-78.
[cited by applicant]
Bradbury, Some oestrogenic 4-phenyl-substituted isoflav-3-ENS, Aust J Chem. 1953;6:447-49.
[cited by applicant]
Briviba, et al., Isoflavonoids as inhibitors of lipid peroxidation and quenchers of singlet oxygen. Antioxidants in Health and Disease, 7(Flavonoids in Health and Disease). 295-302, 1988 (Abstract Only in English).
[cited by applicant]
Bury, et al., Synthesis and pharmacological evaluation of novel cis-3,4-diaryl-hydroxychromanes as high affinity partial agonists for the estrogen receptor. Bioorg Med Chem. 2002;10:125-145.
[cited by applicant]
Caltagirone, et al., Flavanoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer Suppl. 87(4):595-600, 2002. (Abstract Only in English).
[cited by applicant]
PCT/AU2004/001619 International Search Report dated Feb. 2, 2005.
[cited by applicant]
Caltagirone, et al., Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer, American Journal of Respiratory Cell and Molecular Biol…
[cited by applicant]
Challa, et al. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech. Oct. 14, 2005;6(2):E329-357. doi: 10.1208/pt060243.
[cited by applicant]
Constantinou, et al. Phenoxodiol (2H-1-Benzopyran-7-0, 1, 3-(4-hydroxyphenyl), a Novel Isoflavone Derivative, Inhibits DNA Topoisomerase II by Stabilizing the Cleavable Complex. Anticancer Research. 2002;22:2581-86.
[cited by applicant]
Constantinou, et al., Phenoxodiol, a novel isofavone derivative, inhibits dimethylbenz[a]anthracene(DMBA)-induced mammary carcinogenesis in female Sprague—Dawley rats. Eur J Cancer. 2003; 39:1012-18.
[cited by applicant]
De Vincenzo, et al.,Flavanoids and negative control of cell proliferation in ovarian tumors. Acta Medica Romana. 30(1-2):126-32, 1992. (Abstract Only in English).
[cited by applicant]
Dorai, et al , Role of chemopreventive agents in cancer therapy. Cancer Lett. 215:129-40, 2004.
[cited by applicant]
Fukui, et al., The synthesis of irisolone, Bull. Chem. Soc. Japan. 38(6):887-93, 1965 (Abstract Only in English).
[cited by applicant]
Gamble, et al., Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int. J. Cancer. 118:2412-20, 2006.
[cited by applicant]
Giacomelli et al., Silybin and its bioavailable, phospholipid complex(IdB 1016) potentiate in vitro and in vivo the activity of cisplatin. Life Sciences. Feb. 8, 2002; 70(12):1447-59 (Abstract Only in English).
[cited by applicant]
Gupta et al., The use of Friedel-Crafts reactions for the synthesis of deoxybenzoins. Indian J Chem. 1968; 6(9):481-4 (Abstract Only in English).
[cited by applicant]
Hem Chandra Jha, et al., Carbon-13—chemical shift assignments of chromones and isoflavones. Can J Chem. 58:1211-19, 1980.
[cited by applicant]
Hersey, et al., How melanoma cells evade trail-induced apoptosis. Nat Rev Cancer. Nov. 2001; 1(2)142-50.
[cited by applicant]
Horie, et al.,Studies of the selective O-alkylation and dealkylation of flavonoids. XX. A convenient method for synthesizing 5,6,7-trihydroxyisoflavones and 5,6-dihydroxy-7-methoxyisoflavones. Pharm Bull. 44(3):486-91, …
[cited by applicant]
Hu et al., Identification of CYP1A2 as the main isoform for the Phase 1 hydroxylated metabolism of genistein and a prodrug converting exzyme of methylated isoflavones. Drug Metabolism and Dispostion, 31(7):924-931, 2003.
[cited by applicant]
Ito, et al., Isoflavonoids from Belamcanda chinensis. Pharm Bull. 49(9):1229-31, 2001 (Abstract Only in English).
[cited by applicant]
Kakeji, et al., Preclinical studies of the combination of angiogenic inhibitors with cytotoxic agents. Invest New Drugs. 15:39-48, 1997.
[cited by applicant]
Kamsteeg, et al., Phenoxodiol—an isoflavone analog—induces apoptosis in chemoresistant ovarian cancer cells. Oncogene. 22:2611-20, 2003.
[cited by applicant]
Kang, et al., “Scientific Analysis of Formulation Theory of Chungpesagan-tang; In vitro Cytotoxicity of Cisplatin Combined with Chungpesagan-tang”, Natural Product Sciences, vol. 6(4), pp. 165-169, 2000.
[cited by applicant]
Kanzawa, et al., Evaluation of synergism by a novel three-dimensional model for the combined action of cisplatin and etoposide on the growth of a human small-cell lung-cancer cell line, SBC-3. Int. J. Cancer 71, 311-319…
[cited by applicant]
Khoshyomn, et al., Synergistic Action of Genistein and Ciplatin on Growth Inhibition and Cytotoxicity of Human Medulloblastoma Cells. Pediatr Neurosurg. 33:123-31, 2000.
[cited by applicant]
Kinjo, et al., Novel santalin analogs from
[cited by applicant]
Klus, et al., Formation of polyhydroxylated isoflavones from the soybean seed isoflavones daidzein and glycitein by bacteria isolated from tempe. Arch Microbiol. 164(6):428-34, 1995 (Abstract Only in English).
[cited by applicant]
Kothari, et al. Inhibition of cholesterol ester transfer protein by CGS 25159 and changes in lipoproteins in hamsters: Atherosclerosis. (Shannon, Ireland) 128(1):59-66, 1997.
[cited by applicant]
Kulling, et al., Oxidative metabolism of the soy isoflavones daidzein and genistein in humans in vitro and in vivo. J Agric Food Chem. 2001; 49(6):3024-33 (Abstract Only in English).
[cited by applicant]
Lawson, Estrogenic activity of some derivatives of isoflaven and isoflavanol. J Chem Soc. 4448-50, 1954 (Abstract Only in English).
[cited by applicant]
Lei, et al., Enhancement of Chemosensitivity and Programmed Cell death by Tyrosine Kinase Inhibitors Correlates with EGFR Expression in Non-Small Cell Lung Cancer Cells. Anticancer Res. 19:221-28, 1989.
[cited by applicant]
Li, et al., Apoptosis-Inducing Effect of Chemotherapeutic Agents Is Potentiated by Soy Isoflavone Genistein, a Natural Inhibitor of NF-KB in BxPC-3 Pancreatic Cancer Cell Line. Pancreas. (28)4:e90-5, 2004.
[cited by applicant]
Mani, et al., Isoflavones. I. Bromination of isoflavones. J Inst Chem. 1974; 46(Pt.3):61-5 (Abstract Only in English).
[cited by applicant]
Mani, et al, Isoflavones. III. Nitration of 7,8- and 6,7-dihydroxyisoflavones and their methyl ether. J Inst Chem. 1971; 43(6):234-40 (Abstract Only in English).
[cited by applicant]
Mansour, et al., Enhancement of Chemotherapeutic Efficacy by Combining Agents that Block IL-10 in CLL Cell Lines. New Jersey Medical School, UMDNJ, Newark, NJ, USA Blood. Nov. 16, 2002; 100(11) Abstract No. 4997. Print …
[cited by applicant]
McDonnell, et al., Improvement in Efficacy of Chemoradiotherapy by Addition of and Antiangiogenic Agent in a Murine Tumor Model. J Surg Res. 2004; 116:19-23.
[cited by applicant]
Micheli, et al., “Coumestro, Plant Phenolics, and Synthetic Estrogens: a Correlation of Structure and Activity”, Journal of Medicinal and Pharmaceutical Chemistry, vol. 5, 1962, pp. 321-335.
[cited by applicant]
Montandon, et al., In-vitro versus in-vivo activities of new 5-lipoxygenase inhibitors with anti-inflammatory activity, Int J Tissue React. 1989; 11(3); 107-12 (Abstract Only in English).
[cited by applicant]
Nakata et al., C225 Antiepidermal Growth Factor Receptor Antibody Enhances the Efficacy of Docetaxel Chemoradiotherapy. Int J Radiation Oncology Biol Phys. 2004; 59(4): 1163-73.
[cited by applicant]
Neelam, et al., Combination of flavone acetic acid (FAA) with adriamycin, cis-platinum and diflouoromethylornithine (DFMO) in vitro against human colon cancer cells. Invest New Drugs. Aug. 1990; 8(3):263-8 (Abstract Onl…
[cited by applicant]
O'Dwyer, et al., Antitumor Activity and Biochemical Effects of Aphidicolin Glycinate(NSC 303812) Alone and in Combination with Cisplatin in Vivo. Cancer Res. Feb. 1, 1994; 54:724-29.
[cited by applicant]
O'Neill, et al., Inducible Isoflavonoids from the Lima Bean, Phaseolus Lunatus. Phytochemistry. 1986; 25(6): 1315-22.
[cited by applicant]
PCT/AU2005/001435 International Search Report dated Dec. 21, 2005.
[cited by applicant]
PCT/AU2005/001436 International Search Report dated Dec. 21, 2005.
[cited by applicant]
PCT/US2011/058815 International Preliminary Report on Patentability dated May 7, 2013.
[cited by applicant]
PCT/US2011/058815 International Search Report and Written Opinion dated Mar. 12, 2012.
[cited by applicant]
PCT/US2011/058820 International Preliminary Report on Patentability dated May 8, 2013.
[cited by applicant]
PCT/US2011/058820 Search Report and Written Opinion dated Jun. 21, 2012.
[cited by applicant]
Rafi, et al., Modulation of bcl-2 and Cytotoxicity by Licochalcone-A, a Novel Estrogenic Flavonoid. Anticancer Res. 20:2653-58, 2000.
[cited by applicant]
Ravindranath, et al., Anticancer Therapeutic Potential of Soy Isoflavone, Genistein. Complementary and Alternative Approaches to Biomedicine, edited by Edwin L. Cooper and Nobuo Yamaguchi. Kluwer Academic/Plenum Publish…
[cited by applicant]
Registration No. 1157-39-7, 4H-1-Benzopyran-4-one, 7-methoxy-3-(4-methoxyphenyl)-methyl- (9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 116703-40-3, 4H-1-Benzopyran-4-one, 2,3-dihydro-7,8-dimethoxy-3-(4-methoxyphenyl)-(9CI), Oct. 2, 1988.
[cited by applicant]
Registration No. 116703-49-2, 4H-1-Benzopyran-4-one, 2,3-dihydro-7,8-dihydroxy-3-(4-methoxyphenyl)-(9CI), Oct. 2, 1988.
[cited by applicant]
Registration No. 116718-51-5, 4H-1-Benzopyran-4-one, 7-hydroxy-3-(4-methoxyphenyl)-8-methyl-methyl-(9CI), Oct. 2, 1988.
[cited by applicant]
Registration No. 124093-18-1, 4H-1-Benzopyran-4-one, 2,3-dihydro-7-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-(9CI), Dec. 1, 1989.
[cited by applicant]
Registration No. 129159-04-2, 4H-1-Benzopyran-4-one, 2,3-dihydro-3-(4-hydroxyphenyl)-(9CI), Aug. 31, 1990.
[cited by applicant]
Registration No. 129159-05-3, 4H-1-Benzopyran-4-one, 3-(3,4-dihydroxyphenyl)-2,3-dihydro-(9CI), Aug. 31, 1990.
[cited by applicant]
Registration No. 13139-86-1, Magnesium, bromo(4-methoxyphenyl)-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 142050-44-0, 4H-1-Benzopyran-4-one, 7-hydroxy-3-[4-methoxy-3-(methoxy-t3)phenyl]-(9CI), Jun. 26, 1992.
[cited by applicant]
Registration No. 143358-24-1, 4H-1-Benzopyran-4-one, 2,3-dihydro-7-methoxy-3-(4-methoxyphenyl)-(+)-(9CI), Sep. 9, 1992.
[cited by applicant]
Registration No. 143358-39-8, 4H-1-Benzopyran-4-one, 2,3-dihydro-7-methoxy-3-(4-methoxyphenyl)-(-) (9CI), Sep. 9, 1992.
[cited by applicant]
Registration No. 15236-11-0, 4H-1-Benzopyran-4-one, 2,3-dihydro-7-methoxy-3-(4-methoxyphenyl)-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 16750-63-3, Magnesium, bromo(2-methoxyphenyl)-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 201678-33-3, 4H-1-Benzopyran-4-one, 3-(3,4-dimethoxyphenyl) -2,3-dihydro-7,8-dimethoxy-(9CI), Feb. 22, 1998.
[cited by applicant]
Registration No. 206257-38-7, 4H-1-Benzopyran-4-one, 2, 3-dihydro-3-(4-hydroxyphenyl)-7-methoxy-(9CI), Jun. 3, 1998.
[cited by applicant]
Registration No. 24160-14-3 , 4H-1-Benzopyran-4-one, 3-(3,4-dimethoxyphenyl)-7-hydroxy-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 288267-24-3, 4H-1-Benzopyran-4-one, 7-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-8-methyl-(9CI), Sep. 6, 2000.
[cited by applicant]
Registration No. 304892-19-1, 4H-1-Benzopyran-4-one, 3-(3,4-dihydroxyphenyl)-2,3-dihydro-7-hydroxy-(9CI), Nov. 29, 2000.
[cited by applicant]
Registration No. 36282-40-3, Magnesium, bromo(3-methoxyphenyl)-, Nov. 16, 1984.
[cited by applicant]
Registration No. 39604-72-3, 4H-1-Benzopyran-4-one, 2,3-dihydro-7methoxy-3-(4-methoxyphenyl)-8-methyl-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 4626-22-6, 4H-1-Benzopyran-4-one, 2,3-dihydro-7-hydroxy-3-(4- methoxyphenyl)-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 67492-31-3, 4H-1-Benzopyran-4-one, 2,3-dihydro-7-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 680195-83-9, 4H-1-Benzopyran-4-one, 2,3-dihydro-7,8-dihydroxy-3-(4-hydroxyphenyl)-(9CI), May 6, 2004.
[cited by applicant]
Registration No. 83206-83-1, 4H-1-Benzopyran-4-one, 3-(3,4-dimethoxyphenyl)-2,3-dihydro-7-hydroxy-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 85915-64-6, 2H-1-Benzopyran-7-ol, 4-[5-(3,4-dihydro-7-hydroxy-2-H-1-benzopyran-3-yl)-4-hydroxy-2-methoxypheny1]-3,4-dihydro-3-(2-hydroxy-4-methoxypheny1)-,[3S-[3 -4β(R*)]]-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 85915-66-8, 2H-1-Benzopyran, 4-[5-(3,4-dihydro-7-methoxy-2H-1-benzopyran-3-y1)-2,4-dimethoxypheny1]-3-(2,4-dimethoxypheny1)-3,4-dihydro-7-methoxy-, [3S-[3α4β(R*)]]-(9CI), Nov. 16, 1984.
[cited by applicant]
Registration No. 95307-73-6, 4H1-Benzopyran-4-one-2-d, 2,3-dihydro-2-d-7-hydroxy-3-(4-methoxyphenyl)-(9CI), Mar. 16, 1985.
[cited by applicant]
Registration No. 95457-39-9, 4H-1-Benzopyran-4-one-4-14C, 3-(3,4-dimethoxyphenyl)-7-hydroxy-(9CI), Mar. 23, 1985.
[cited by applicant]
Registration No. 95541-42-7, 1,3-Benzenediol, 4-[3,4-dihydro-3-(2-hydroxy-4-methoxypheny1)-7-methoxy-2H-1-benzopyran-4-yl]-,(3R-trans)-(9CI), Mar. 30, 1985.
[cited by applicant]
Registration No. 95541-43-8, 2H-Benzopyran, 3,4-bis(2,4-dimethoxyphenyl)-3,4-dihydro-7-methoxy-,(3R-trans)-(9CI), Mar. 30, 1985.
[cited by applicant]
Registration No. 95541-44-9, 1,3,5-Benzenetrio1,2-[3,4-dihydro-3-(2-hydroxy-4-methoxypheny1)-7-methoxy-2H-1-benzopyran-4-yl)-, (3R-trans)-(9CI) (1984).
[cited by applicant]
Registration No. 95541-45-0, 1,3,5-Benzenetrio1,2,4-bis[3,4-dihydro-3-(2-hydroxy-4-methoxypheny1)-7-methoxy-2H-1-benzopyran-4-yl]-,[3R-[3α,4α(3R*,4S″])-(9CI) (1984).
[cited by applicant]
Registration No. 95541-46-1, 2H-1-Benzopyran,3-(2,4-dimethoxyphyeny1)-3,4-dihydro-7-methoxy-4(2,4,6-trimethoxyphenyl)-, (3R-trans)-(9CI) (1984).
[cited by applicant]
Registration No. 95541-51-8, 2H-1-Benzopyran-7-ol, 3-[3,4-dihydro-3-(2-hydroxy-4-methoxypheny1)-7-methoxy-2H-1-benzopyran-4-y1]-2-hydroxy-4-methoxypheny1]-3,4-dihydro-,[3R-3α,4β(S*)]]-(9CI) (1984).
[cited by applicant]
Registration No. 95541-53-0, 2H-1-Benzopyran, 4-[5(3,4-dihyrdro-7-methoxy-2H-1-benzopyran-3-y1)-2,4-dimethoxypheny1]-3-(2,4-dimethoxypheny1)-3,4-dihydro-7-methoxy-,[3R-[3α,4β(S*)]]-(9CI) (1984).
[cited by applicant]
Registration No. 95541-54-1, 2H-1-Benzopyran-7-ol, 3-[-[4-dihydro-4-[4-hydroxy-5-(7-hydroxy-2H-1-benzopyran-3-y1)-2-methoxypheny1]-3-(2-hydroxy-4-methon/pheny1)-(3S-trans)-(9CI) (1984).
[cited by applicant]
Registration No. 95541-57-4, 2H-1-Benzopyran,4-[2,4-dimethoxy-5-(7-methoxy-2H-1-benzopyran-3-yl)pheny1]-3-(2,4-dimethoxyphenyl)-3,4-dihydro-7-methoxy-,(3S-trans)-(9CI) (1984).
[cited by applicant]
Registration No. 95541-66-5, 2H-1-Benzopyran, 4-(2,4-dimethoxypheny1)-3,4-dihydro-7-methoxy-3-[4-methoxy-2-(methoxymethoxy)phenyl]-,(3R-trans)-(9CI) (1984).
[cited by applicant]
Registration No. 95762-78-0, 2H-1-Benzopyran,4,4′-(2,4,6-trimethoxy-1,3-phenylene)bix[3-(2,4-dimethoxypheny1)-3,4-dihydro-7-methoxy-,[3R[3α,4β(3′R*,4′S*)]-(9CI) (1984).
[cited by applicant]
Scambia, et al., Antiproliferative effect of silybin on gynaecological malignancies;synergism with cisplatin and doxorubicin. Eur J Cancer. May 1996; 32A(5):877-82 (Abstract Only in English).
[cited by applicant]
Scambia, G. Synergistic antiproliferative activity of quercetin and cisplatin on ovarian cancer cell growth. Anti-Cancer Drugs Oct. 1990; 1(1):45-8 (Abstract Only in English).
[cited by applicant]
Sepulveda-Boza, et al., The preparation of new isoflavones, Synthetic Communications. 2001; 3(12):1933-40.
[cited by applicant]
Szlosarek, et al., Tumour necrosis factor a: a potential target for the therapy of solid tumours. The Lancet Oncology. Sep. 2003; 4:565-73.
[cited by applicant]
Tamura, et al., Genistein Enhances the Cisplatin-Induced Inhibition of Cell Growth and Apoptosis in Human Malignant Melanoma Cells. Pigment Cell Res. 2003; 16:470-76 (Abstract Only in English).
[cited by applicant]
Teo, et al., Synthesis of 3-(p-fluorophenyl)-4-arylchrom-3-enes as selective ligands for antiestrogen-binding sites. J Chem Res. Synopses. 1990; 1:4-5 (Abstract Only in English).
[cited by applicant]
Teo, et al., Synthesis of arylchromenes and arylchromans. Bulletin of the Singapore National Institute of Chemistry. 1994; 22:69-74 (Abstract Only in English).
[cited by applicant]
Therasse et al., New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institut…
[cited by applicant]
Todorov, et al., Role of a proteolysis-inducing factor(PIF) in a cachexia induced by a human melanoma(G361). Br J Cancer. 1999; 80(11):1734-37.
[cited by applicant]
Tubiana. The combination of radiotherapy and chemotherapy: a review. Int J Radiat Biol 55(4):497-511 (1989).
[cited by applicant]
U.S. Appl. No. 11/230,726 Office Action dated Jan. 22, 2007.
[cited by applicant]
U.S. Appl. No. 11/230,726 Office Action dated Mar. 4, 2008.
[cited by applicant]
U.S. Appl. No. 11/230,726 Office Action dated Oct. 28, 2008.
[cited by applicant]
U.S. Appl. No. 13/891,975 Office Action dated Apr. 23, 2014.
[cited by applicant]
U.S. Appl. No. 11/230,505 Office Action dated Dec. 17, 2009.
[cited by applicant]
U.S. Appl. No. 11/230,505 Office Action dated Jun. 9, 2008.
[cited by applicant]
U.S. Appl. No. 11/230,505 Office Action dated Mar. 12, 2009.
[cited by applicant]
U.S. Appl. No. 11/230,505 Office Action dated Sep. 4, 2007.
[cited by applicant]
U.S. Appl. No. 11/230,726 Office Action dated Aug. 10, 2007.
[cited by applicant]
U.S. Appl. No. 12/551,277 Office Action dated Jan. 6, 2011.
[cited by applicant]
U.S. Appl. No. 12/551,277 Office Action dated May 28, 2010.
[cited by applicant]
U.S. Appl. No. 13/293,947 Office Action dated Jul. 20, 2012.
[cited by applicant]
U.S. Appl. No. 13/293,947 Office Action dated May 24, 2013.
[cited by applicant]
U.S. Appl. No. 13/293,947 Office Action dated Nov. 8, 2012.
[cited by applicant]
U.S. Appl. No. 13/415,697 Office Action dated Jul. 6, 2012.
[cited by applicant]
U.S. Appl. No. 13/881,609 Office Action dated Apr. 10, 2015.
[cited by applicant]
U.S. Appl. No. 13/881,609 Office Action dated Aug. 7, 2015.
[cited by applicant]
U.S. Appl. No. 13/881,609 Office Action dated May 16, 2016.
[cited by applicant]
U.S. Appl. No. 14/186,940 Office Action dated Aug. 6, 2014.
[cited by applicant]
U.S. Appl. No. 14/186,940 Office Action dated Nov. 21, 2014.
[cited by applicant]
U.S. Appl. No. 14/922,472 Office Action dated Sep. 26, 2016.
[cited by applicant]
U.S. Appl. No. 15/175,386 Office Action dated Oct. 6, 2017.
[cited by applicant]
U.S. Appl. No. 15/456,182 Office Action dated Nov. 20, 2017.
[cited by applicant]
U.S. Appl. No. 15/622,569 Office Action dated Sep. 7, 2017.
[cited by applicant]
U.S. Appl. No. 15/961,259 Office Action dated Sep. 5, 2018.
[cited by applicant]
U.S. Appl. No. 16/129,589 Final Office Action dated Nov. 7, 2019.
[cited by applicant]
U.S. Appl. No. 16/129,589 Office Action dated Apr. 18, 2019.
[cited by applicant]
U.S. Appl. No. 16/129,589 Office Action dated Mar. 19, 2020.
[cited by applicant]
U.S. Appl. No. 16/444,981 Final Office Action dated Aug. 20, 2020.
[cited by applicant]
U.S. Appl. No. 16/444,981 Office Action dated Mar. 3, 2020.
[cited by applicant]
U.S. Appl. No. 17/193,335 Office Action dated Sep. 15, 2022.
[cited by applicant]
Varady, J. The flavonoids of Podocarpus spicatus. I. Structure of podospicatin. Synthesis of podospicatin mono-,di-, and trimethyl ethers. Periodica Polytech. 1963; 7(4):241-58 (Abstract Only in English).
[cited by applicant]
Verma et al., Smooth Conversion of 3,4-Diarylcoumarins and 3,4,5-Triaryl-2(5H)-furanones to 2H-Chromene and 2,5-Dihydrofuran Derivatives with Dimethyl Sulfide-Borane Complex. Synthesis. 1988; 1:68-70.
[cited by applicant]
Voss, C. et al., New isoflavonoids as inhibitors of porcine 5-lipoxygenase. Biochem Pharmacol. 1992; 44(1):157-62 (Abstract Only in English).
[cited by applicant]
Waud, et al., Antitumor drug cross-resistance in vivo in a cisplatin-resistant murine P388 leukemia, Cancer Chemotherapy and Pharmacology. 1991; 27 (6):456-63 (Abstract Only in English).
[cited by applicant]
Weidenborner, et al., Control of storage fungi of the genus
[cited by applicant]
Wolfbeis, et al., The Absorption and Fluorescence of Isoflavones and the Effect of Shift Reagents. Z Naturforsch. 39b:238-43, 1984.
[cited by applicant]
Zyner, et al., Platinum(II) and palladium(II) N,0-Chelates with substituted flavanone containing ligangs. Acta Pol Pharm. 1999; 56(2): 159-67.
[cited by applicant]
Zyner, et al., Pt(II) and Pt(II) complexes of 3-aminoflavone: In vitro and in vivo evaluation. Pharmazie. 1999; 54(12):945-46.
[cited by applicant]
U.S. Appl. No. 13/881,599 Office Action dated Apr. 9, 2015.
[cited by applicant]
U.S. Appl. No. 13/881,599 Office Action dated Aug. 18, 2016.
[cited by applicant]
U.S. Appl. No. 15/175,386 Office Action dated May 10, 2018.
[cited by applicant]
Co-pending U.S. Appl. No. 17/193,335, filed Mar. 5, 2021.
[cited by applicant]
European Patent Application No. 05779877.9 European Search Report dated Apr. 28, 2009.
[cited by applicant]
European Patent Application No. 05787045.3 European Search Report dated Oct. 20, 2008.
[cited by applicant]
European Patent Application No. 11180383.9 European Search Report dated Jul. 13, 2012.
[cited by applicant]
European Patent Application No. 11175917.1 European Search Report dated Dec. 16, 2011.
[cited by applicant]
Japanese Patent Application No. 2013-536929 First Office Action dated Aug. 25, 2015 (with English language translation).
[cited by applicant]