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(12) United States Patent (10) Patent No.: US 9,616,074 B2 Podolski (45) Date of Patent: *Apr

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(12) United States Patent (10) Patent No.: US 9,616,074 B2 Podolski (45) Date of Patent: *Apr USOO961. 6074B2 (12) United States Patent (10) Patent No.: US 9,616,074 B2 Podolski (45) Date of Patent: *Apr. 11, 2017 (54) COMPOSITIONS AND METHODS FOR WO O1/04795 A1 4/2001 SUPPRESSING ENDOMETRIAL WO 01.74840 A2 10, 2001 PROLIFERATION WO 2006/01OO97 A2 1, 2006 (71) Applicant: REPROS THERAPEUTICS INC., OTHER PUBLICATIONS The Woodlands, TX (US) Gemzell-Danielsson et al. (Effect of low weekly doses of (72) Inventor: Joseph S. Podolski. The Woodlands, mifepristone on ovarian function and endometrial development. TX (US) Hum. Reprod. (1996) 11 (2): 256-264).* Attardi et al. (CDB-4124 and its putative monodemethylated (73) Assignee: REPROS THERAPEUTICS INC., metabolite, CDB-4453, are potent antiprogestins with reducedanti The Woodlands, TX (US) glucocorticoid activity: in vitro comparison to mifepristone and CDB-2914. Molecular and Cellular Endocrinology 188 (2002) (*) Notice: Subject to any disclaimer, the term of this 111-123).* patent is extended or adjusted under 35 Donnez, Jacques, M.D., et al., “Long-Term Medical Management of U.S.C. 154(b) by 10 days. Uterine Fibroids with Ulipristal Acetate.” Fetility and Sterility, vol. 105, No. 1, pp. 165-173.e4 (Jan. 2016). This patent is Subject to a terminal dis Donnez, Jacques, M.D., et al., “Efficacy and Safety of Repeated Use claimer. of Ulipristal Acetate in Uterine Fibroids.” Fertility and Sterility, vol. 103, No. 2, pp. 519-527.e3 (Feb. 2015). (21) Appl. No.: 14/251,192 Galliano, D., “Ulipristal Acetate in Uterine Fibroids.” Fertility & Sterility, vol. 13, No. 2, pp. 359-360 (Feb. 2015). (22) Filed: Apr. 11, 2014 ESMYA Summary of Product Characteristics issued by the Euro pean Medicines Agency, pp. 1-28 (Feb. 23, 2012). (65) Prior Publication Data Attardi, B., et al., “CDB-4124 and Its Putative Monodemethylated Metabolite, CDB-4453, are Potent Antiprogestins with Reduced US 2014/0235602 A1 Aug. 21, 2014 antiglucocorticoid Activity. In Vitro Comparison to Mifepristone and CDB-2914.” Molecular and Cellular Endocrinologoy, vol. 188, pp. 111-123 (Feb. 25, 2002). Related U.S. Application Data Blithe, Diana... et al., “Development of the Selective Progesterone (63) Continuation of application No. 12/446,567, filed as Receptor Modulator CDB-2914 for Clinicalindications.” Steroids, application No. PCT/US2007/082432 on Oct. 24, vol. 68, Issues 10-13, pp. 1013-1017 (Nov. 2003). 2007, now Pat. No. 9,283,234. Bulun, S., “Uterine Fibroids.” The New England Journal of Medi cine, vol. 369, pp. 1344-1355 (Oct. 3, 2013). Chabbert-Buffet, N., et al., “Effects of the Progesterone Receptor (60) Provisional application No. 60/862,632, filed on Oct. Modulator VA2914 in a Continuous Low Dose on the Hypotha 24, 2006, provisional application No. 60/885,348, lamic-Pituitary-Ovarian Axis and Endometrium in Normal Women: filed on Jan. 17, 2007. A Prospective, Randomized, Placebo-Controlled Trial.” Journal of Clinical Endocrin. & Metabol., vol. 92, No. 9, pp. 3582-3589 (Jun. (51) Int. Cl. 19, 2007). A6 IK3I/56 (2006.01) Chwalisz, K., et al., “Antiproliferative Effects of Progesterone A 6LX 3/573 (2006.01) Antagonists and Progesterone Receptor Modulators on the Endo (52) U.S. Cl. metrium.” Steroids, vol. 65, pp. 741-751 (Oct.-Nov. 2000). CPC ............ A61 K3I/573 (2013.01); A61 K3I/56 (Continued) (2013.01) (58) Field of Classification Search Primary Examiner — Layla Soroush USPC .......................................................... 514/179 (74) Attorney, Agent, or Firm — Morgan, Lewis & See application file for complete search history. Bockius LLP (56) References Cited (57) ABSTRACT The subject matter of the instant invention is pertinent to the U.S. PATENT DOCUMENTS field of hormone therapy. More specifically, the subject 4,038,389 A 7, 1977 Lamb matter of the instant invention concerns methods of treating 5,521,166 A 5, 1996 Grubb estrogen-dependent conditions such as endometrial hyper 5,681,817 A 10/1997 Hodgen et al. plasia and endometrial cancer in a female undergoing estro 5,780,050 A * 7/1998 Jain et al. ..................... 424/449 6,689,768 B2 2/2004 Oettel et al. gen and/or selective estrogen receptor modulator (SERM) 2002fOO58O35 A1 5, 2002 Garnicket al. therapy. The instant invention is also relevant to the Sup pression of endometrial proliferation. The instant invention FOREIGN PATENT DOCUMENTS is also relevant to the treatment of pain associated with endometriosis. The compositions for practicing the methods, JP 2000-509396 10, 2003 comprising progesterone antagonists are also disclosed. JP 2003-529604 10, 2003 Embodiments of the instant invention also disclose methods WO 94, 18983 9, 1994 WO 95/20972 8, 1995 for identifying new selective progesterone receptor modu WO 97,41145 11, 1997 lators for practicing disclosed methods of treatment. WO WO 9741145 A1 * 11, 1997 WO 99/45022 A1 9, 1999 10 Claims, 2 Drawing Sheets US 9,616,074 B2 Page 2 (56) References Cited Mutter, G. L., et al., “The Spectrum of Endometrial Pathology Induced by Progesterone Receptor Modulators.” Modern Pathology, pp. 1-8 (Feb. 1, 2008). OTHER PUBLICATIONS Nelson, A., “Extended-Cycle Oral Contraception: A New Option for Colca, J., “Discontinued drug in 2007: Renal, Endocrine and Metabolic drugs.” Expert Opinion on Investigational Drugs, vol. 17. Routine Use.” Treatments in Endocrinology, vol. 4, No. 3, pp. No. 11, pp. 1641-1650 (Nov. 2008). 139-145 (Jun. 2005). Cullen, A., “Schering, TAP Halt Trial of Drug for Uterine Growth Repros Therapeutics Inc. Announces That Proellex Administered to (Update5).” Bloomberg, 2 pages, (Oct. 12, 2005). Patients as Cyclic Therapy to Treat the Symptomsof Uterine Danielsson, K.G., et al., Human Reproduction, vol. 132, No. 1, pp. Fibroids for Up to 30 Months Shows No Adverse Effects on the 124-131 (Jan. 1997). Endometrium, Drug Information Online-Drugs.com, pp. 1-2 (Jul. Donnez, Jacques, M.D., et al., “Long-Term Treatment of Uterine 2008). Fibroids with Ulipristal Acetate.” Seminal Contributions, Fertility Spitz, Irving M.. “Clinical Utility of Progesterone Receptor Modu and Sterility, vol. 101, No. 6, pp. 1565-153 (Jun. 2014). lators and Their Effect on the Endometrium.” Current Opinion in Eisenberg, Ester, MD, “Endometriosis' The Merck Manuals Online Library, at http://www.merckmanuals.com/professional/gynecol Obstetrics & Gynecology, vol. 21, No. 4, pp. 318-324 (Aug. 2009). ogy-and-obstetrics/endometriosis/endometriosis (revised Feb. Steinauer, J., et al., “Systematic Review of Mifeptristone for the 2013). Treatment of Uterine Leiomyomata,” Obstet. Gynecol., vol. 103. Extended European Search Report, of EP 07871232.0 dated Aug. No. 6, pp. 1331-1336 (Jun. 2004) Abstract. 16, 2011. Wang. X., et al., "Clinical Study on the Treatment of Adenomyosis Gemzell-Danielsson, et al., Effect of low Weekly Doses of with Mifepristone.” Shanxi Clinical Medicine J., vol. 10, No. 9, pp. Mifepristone on Ovarian Function and endometrial Development, 660-661 (Sep. 2001) with English translation. Human Reproduction, vol. 11, No. 2, pp. 256-264 (Feb. 1996). Wiegratz, E., et al., “Long-Cycle Treatment with Oral Contracep Greb, R.R., et al., Human Reproduction, vol. 14, No. 1, pp. 198-206 tives.” Drugs, vol. 64, No. 21, pp. 2447-2462 (Nov. 2004). (Jan. 1999). U.S. Appl. No. 12/446,567—Restriction Requirement dated Dec. 1, International Preliminary Report on Patentability of PCT/US2007/ 2010. 082432 dated May 7, 2009. U.S. Appl. No. 12/446,567. Non-final office action dated Mar. 18, International Search Report of PCT/US2007/82432 dated Sep. 9, 2011. 2008. U.S. Appl. No. 12/446,567 Final office action dated Sep. 15, 2011. Kettel, L., et al., Preliminary Report on the Treatment of U.S. Appl. No. 12/446,567. Non-final office action dated May 23, Endometriosis with Low-Dose Mifepristone (RU 486), Am. J. 2014. Obstet. Gynecol., vol. 178, pp. 1151-1156 (Jun. 1998). U.S. Appl. No. 12/446,567. Non-final office action date Jul. 6, Murphy, A., et al., “Endometrial Effects of Long-Term Low-Dose 2015. Administration of RU486,” Fertil Steril., vol. 63, No. 4, pp. 761-766 (Apr. 1995) Abstract. * cited by examiner U.S. Patent Apr. 11, 2017 Sheet 1 of 2 US 9,616,074 B2 F N N s S U.S. Patent Apr. 11, 2017 Sheet 2 of 2 US 9,616,074 B2 F N S. S (f) O D CN | S D W 9CD CD S L CD s 4an ? CD O O z as a a 5 E: S CD O 2. D O 9 55 V Y) CN V o D US 9,616,074 B2 1. 2 COMPOSITIONS AND METHODS FOR termed selective estrogen receptor modulators (SERMs). SUPPRESSING ENDOMETRIAL SERMs exert their estrogenic or antiestrogenic effects in a PROLIFERATION tissue-specific manner. The mechanism underlying this tis Sue-specificity is not clear, but may involve, inter alia, the CROSS-REFERENCE TO RELATED recruitment of corepressor and coactivator proteins whose APPLICATIONS relative expression levels vary among tissue types and tissue-specific expression of estrogen receptor isoforms C. The application is a continuation of U.S. application Ser. and B. Estrogen receptor C. is an activator whereas estrogen No. 12/446,567, filed Apr. 27, 2010 which is the U.S. receptor B can inhibit estrogen receptor C. activity by form national stage of International Patent Application No. PCT/ 10 ing a heterodimer with it. US07/082,432 filed Oct. 24, 2007, and which claims the The dual activities of SERMs provide several potential benefit of U.S. Provisional Patent Application No. 60/862, advantages to women. The estrogenic properties of SERMs 632, filed Oct. 24, 2006, and U.S. Provisional Patent Appli may be used to treat or prevent diseases caused by estrogen cation No. 60/885,348, filed Jan. 17, 2007, the contents of deficiency Such as osteporosis, while minimizing some of each of which is incorporated herein by reference in its 15 the undesirable effects of estrogen.
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