US008822438B2
`
`(12) United States Patent
`Auerbach et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,822,438 B2
`Sep. 2, 2014
`
`(54)
`
`METHODS AND COMPOSITIONS FOR
`TREATING CANCER
`
`(75) Inventors: Alan H. Auerbach, Hermosa Beach, CA
`(US); Arie S. Belldegrum, Los Angeles,
`CA (US)
`
`(73) Assignee: J anssen Oncology, Inc., Los Angeles,
`CA (us)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`
`(22)
`
`(65)
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`App1.No.: 13/034,340
`
`Filed:
`
`Feb. 24, 2011
`
`Prior Publication Data
`
`US 2011/0144016A1
`
`Jun. 16,2011
`
`Related US. Application Data
`
`Continuation of application No. 11/ 844,440, ?led on
`Aug. 24, 2007, now abandoned.
`
`Provisional application No. 60/921,506, ?led on Aug.
`25, 2006.
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 31/56
`A61K 31/58
`US. Cl.
`CPC .................................... .. A61K31/58 (2013.01)
`USPC ......................................... .. 514/170; 514/180
`Field of Classi?cation Search
`USPC ................................................ .. 514/170, 182
`See application ?le for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2006/0030608 A1
`
`2/2006 Nelson et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`
`2478907
`2006027266
`
`7/2012
`3/2006
`
`OTHER PUBLICATIONS
`
`O’Donnell et al., British Journal of Cancer, 2004;90:2317-2325.*
`Tannock et al., J. Clin. Oncol., 1996;14:1 756-1764.*
`ASCO Cancer Foundation, Poster Session F: Hormone Refractory,
`ASCO, 2005.
`Bruno et al, Targeting cytochrome P450 enzymes: A new approach in
`anti-cancer drug development, Elsevier, 2007, pp. 5047-5060, vol.
`15.
`Cannell, 100th Annual Meeting of the American Association for
`Cancer Research, Los Angeles, CA, USA;, http://oncologythelancet.
`com, 2007, pp. 471, vol. 8.
`Collins, et al. “A Systematic Review of the effectiveness of Docetaxel
`and Mitoxantrone for the Treatement of Metastatic Hormone-Refrac
`tory Prostate Cancer”, British J. of Cancer, 95, pp. 457-462 (2006).
`Cougar Biotechnology, Cougar Biotechnology Announces Initiation
`of Phase I/ II Trial for CB7630 (Arbiraterone Acetate), Cougar
`Biotechnology, Dec. 14, 2004.
`
`Cougar Biotechnology, Cougar Biotechnology Announces Presenta
`tion of Positive CB7630 Clinical Data at AACR-NCI-EORTC Inter
`national Conference on Molecular Targets and Cancer Therapeutics,
`Cougar Biotechnology, Oct. 2007.
`Cougar Biotechnology, Cougar Biotechnology Announces Presenta
`tion of Positive CB7630 Clinical Data at ESMO Conference, Drugs.
`com, Jul. 2007.
`Cougar Biotechnology, Cougar Biotechnology announces presenta
`tion of positive phase I and phase II data at ASCO Prostate Cancer
`Symposium, Cougar Biotechnology, Feb. 23, 2007.
`Cougar Biotechnology, Cougar Biotechnology presents CB7630
`Phase I clinical data at the 2005 Prostate Cancer Symposium,
`AllBusiness, 2005.
`Cougar Biotechnology, Cougar Biotechnology presents positive
`CB7630 Clinical Data at AACR Annual Meeting Late-Breaking
`Clinical Trials Session, Cougar Biotechnology, Apr. 17, 2007.
`Cougar Biotechnology, Cougar Technology Announces Presentation
`of Positive CB7630 Clinical Data at ASCO Annual Meeting, The
`Free Library, Jun. 4, 2007.
`De Bono et al, Inhibition of CYP4500 17 by abiraterone administered
`once daily to castrate patients with prostate cancer resistant to LHRH
`analogues, anti-androgens and steriod therapy is well tolerated .
`.
`.
`,
`The institute of Cancer Research, 2007.
`De Coster, et al., Effects of High-Dose Ketoconazole and
`Dexamethason on ACTH-Stimulated Adrenal Steriodogenesis in
`Orchiectomized Prostatic Cancer Patients, ACTA Endocrinologica
`(Copenh), 1987, pp. 265-271, vol. 115.
`Due et al, In Vitro and in vivo models for the evaluation of potent
`inhibitors of male rat 17 -hydroxylase/C-lyase, Pergamon, 2003, pp.
`537-542, vol. 84.
`Endocrinology, Inhibition of Androgen Synthesis in Human
`Testicular and Prostatic Microsomes and in Male Rats by Novel
`Steroidal Compounds, Endocrinology, 1999, pp. 2891-2897, vol. 140
`No. 6.
`Fossa, et al., Weekly Docetaxel and Prednisone Versus Prednisolone
`Alone in Androgen-Independent Prostate Cancer: A Randomized
`Phase II Study, European Urology, 2007, pp. 1691-1699, vol. 52.
`Gerber, et al., Prostate Speci?c Antigen for Assessing Response to
`Ketoconazole and Prednisone in Patients with Hormone Refractory
`Metastatic Prostate Cancer, The Journal of Urology, 1990, pp. 1177
`1179, vol. 1444, No. 5.
`Hakki et al, CYP17- and CYPl lB-dependent steriod hydroxylases as
`drug development targets, Elsevier, 2006, pp. 27-52, vol. 11.
`Harris, et al., Low Dose Ketoconazole with Replacement Doses of
`Hydrocortisone in Patients with Progressive Androgen Independent
`Prostate Cancer, The Journal ofUrology, 2002, pp. 542-545, vol. 168.
`Moreira et al, Synthesis and evaluation of novel 17-indazole
`androstene derivatives designed as CYP17 inhibitors, Elsevier, 2007,
`pp. 939-948, vol. 72.
`Newell et al, The Cancer Research UK experience of pre-clinical
`toxicology studies to support early clinical trials with novel cancer
`therapies, Elsevier, 2004, pp. 899-906, vol. 40.
`(Continued)
`
`Primary Examiner * San-Ming Hui
`
`ABSTRACT
`(57)
`Methods and compositions for treating cancer are described
`herein. More particularly, the methods for treating cancer
`comprise administering a 170t-hydroxylase/Clmo-lyase
`inhibitor, such as abiraterone acetate (i.e., 3B-acetoxy-17-(3
`pyridyl)androsta-5,16-diene), in combination with at least
`one additional therapeutic agent such as an anti-cancer agent
`or a steroid. Furthermore, disclosed are compositions com
`prising a 170t-hydroxylase/Cl7,20-lyase inhibitor, and at least
`one additional therapeutic agent, such as an anti-cancer agent
`or a steroid.
`
`20 Claims, No Drawings
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 1
`
`

`
`US 8,822,438 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Petrylak, et al., Future Directions in the Treatment of Androgen
`Independent Prostate Cancer, Urology, 2005, pp. 8-13, vol. 65,
`Supplement 6A.
`ScholZ, et al., Long-Term Outcome for Men with Androgen Indepen
`dent Pro state Cancer Treated with Ketoconazole and Hydrocortisone,
`The Journal ofUrology, 2005, pp. 1947-1952, vol. 173.
`Small et al, The Case for Socondary Hormaonal Therapies in the
`Chemotherapy Age, The Journal of Urology, 2006, pp. S66-S71, vol.
`176.
`Wikipedia, Corticosteriod, undated, website, 2013.
`Third Party Observations dated Oct. 18, 2012 for EP Appln. No.
`078373263.
`Third Party Observations dated Mar. 28, 2013 for EP Appln. No.
`078373263.
`Third Party Observations dated Jul. 1, 2013 for EP Appln. No.
`078373263.
`Berry, W. et al. Phase III Study of Mitoxantrone Plus Low Dose
`Prednisone Versus Low Dose Prednisone Alone in Patients with
`Asymptomatic Hormone Refractory Prostate Cancer, The Journal of
`Urology, 2002, pp. 2439-2443, vol. 168.
`Chang, Ching-Yi, et al. Glucocorticoids Manifest Androgenic Activ
`ity in a Cell Derived from a Metastatic Prostate Cancer, Cancer
`Research, 2001, pp. 8712-8717, vol. 61.
`Dorff, TB, Crawford, ED. Management and challenges of
`corticosteroid therapy in men with metastatic castrate-resistant pros
`tate cancer, Annals of Oncology, 2013, pp. 31-38, vol. 24(1).
`Efstathiou, Eleni, et al. Effects of Abiraterone Acetate on Androgen
`Signaling in Castrate-Resistant Prostate Cancer in Bone, American
`Society of Clinical Oncology, Journal of Clinical Oncology, 2011,
`pp. 1-8.
`Huggins, Charles, et al. Studies on Prostatic Cancer.I. The Effect of
`Castration, of Estrogen and of Androgen Injection on Serum
`Phosphatases in Metastatic Carcinoma of the Prostate, Cancer
`Research, 1941, pp. 293-297, vol. 1.
`Mostaghel, EA. et al. Molecular Pathways: Targeting resistance in
`the androgen receptor for therapeutic bene?t, Clin Cancer Res, Dec.
`4, 2013.
`Nishimura, Kazuo, et al. Potential Mechanism for the Effects of
`Dexamethasone on Growth of Androgen-Independent Pro state Can
`cer, Journal of the National Cancer Institute, 2001, pp. 1739-1746,
`vol. 93.
`Oudar, Stephane, et al. Actualite dans le cancer de la prostate,
`Synthese, Bull Cancer 2005; 92 (10), pp. 865-873 (relevance in
`English abstract).
`Petrylak, et al. Docetaxel and Estramustine Compared with
`Mitoxantrone and Prednisone for Advanced Refractory Prostate Can
`cer, The New England Journal of Medicine, 2004, pp. 1513-1520,
`vol. 351.
`Ryan, et al., Aberaterone Acetate in Metastatic Prostate Cancer With
`out Previous Chemotherapy, The New England Journal of Medicine,
`2013, 368:138-148.
`Sartor, et al, Abiraterone Prolongs Survival in Metastatic Prostate
`Cancer, Nature Reviews Clinical Oncology, 2011, pp. 515-516, vol.
`8.
`Tannock, IF, et al. Docetaxel plus prednisone or mitoxantrone plus
`prednisone for advanced prostate cancer, The New England Journal
`ofMedicine, 2004, pp. 1502-1512, vol. 351(15).
`Assessment Report for Zytiga (abiraterone) published 2011 by the
`CHMP of the EMA.
`Aucth-3, R.J,, “The genetics, pathophysiology, and the manage
`ment of human de?ciencies of P450c17”, Endocrinol Metab Clin
`North Am (2001), 30, p. 101-119.
`Ayub, M., Inhibition of testicular 17a-hydroxylase and 17,20-Iyase
`but not 3B-hydroxysteroid dehydrogenase-isomerase or 17B
`hydroxysteroid oxidoreductase by ketoconazole and other imidazole
`drugs, Journal of Steroid Biochemistry (1987) 28(5), p. 521-531.
`Campbell-Walsh Urology, Ninth Edition, Saunders, vol. 3, Chapters
`104 and 105, 2007.
`
`http://clinicaltrials. gov/archive/NCT00485303/
`
`Cecil Textbook of Medicine, Wyngaarden & Smith 18th edition;
`Chapter on “Glucocorticosteroid Therapy”, Wyngaarden & Smith
`18th edition, (1988) p. 128-131.
`Coudar Biotechnology Inc. with the US. Securities and Exchange
`Commission, Form 10-QSB, 2013.
`Czock, et al., “Pharmacokinetics and Pharmacodynamics of Sys
`temically Administered Glucocorticoids”, Pharmacokinet (2005),
`44(1), p. 61-98.
`Ergun-Longmire, Berrin, et al., “Two Novel Mutations Found in a
`Patient with 17a-Hydroxylase Enzyme De?ciency”, The Journal of
`Clinical Endocrinology & Metabolism (2006), 91(10), p. 4179-4 182.
`Fakih, et al., Urology (2002) 60, p. 553-561.
`Friel, Patrick N., et al., “Suppression of adrenal function by low-dose
`prednisone: assessment with 24-hour urinary steroid hormone pro
`?lesiA review of ?ve cases”, Alternative Medicine Review (2006),
`1 1(1).
`article:
`Internet
`2007i06i1 1 .
`Information concerning Zytiga (abiraterone acetate) from http://
`www.kompendium.ch/prod/pnr/1 18323 8/de?Platform:Desktop as
`ofMar. 25, 2014.
`http ://clinicaltrials . gov/ct2/show/study/
`Internet
`article:
`NCT00485303?sec:X501, 2014.
`Mostaghel, E.A., “Abiraterone in the treatment of metastatic castra
`tion-resistant pro state cancer”, Cancer Management Res. (2014) 6, p.
`39-5 1 .
`Osaba, D., et al., “Health-Related Quality of Life in Men with Meta
`static Pro state Cancer Treated with Prednisone alone or
`Mitoxantrone and Prednisone”, J Clin. Oncol. (1999), 17(6), p. 165
`1663.
`Petrylak, D.P., “New Paradigms for Advanced Pro state Cancer”, Rev.
`Urol. (2007), 9, Suppl. 2, S3-S12.
`Prostate Cancer Principles and Practice, Taylor & Francis (2006)
`Chapter 93.
`Reid, A., et al., “Annals of Oncology”, Educational and Abstract
`Book of the ESMO Conference Lugano (ECLU), (2007), 18(Supple
`ment 9), iX173-iX174. Abstract 50PD.
`Remington, The Science and Practice of Pharmacy, 20th Edition
`(2000), p. 1363-1370.
`Runge, Marschall S., et al., Principles of Molecular Medicine; Sec
`ond edition; (2006) Humana Press Inc. ISBN: 1-58829-202-9. pp.
`365-376 and 482-484.
`Sills, Irene N., et al., “17a-hydroxylase de?ciency in a genetic male
`and female sibling pair”, Int. J. Gynaecol. Obstet., (1981), 19, p.
`473 -479.
`Summary of Product Characteristics for Zytiga 250mg tablets (Jan.
`16, 2014).
`Tannock., et al., “Docetaxel Plus Prednisone or Mitoxantrone Plus
`Prednisone for Advanced Prostate Cancer”, Journal of Urology
`(2005), 173(2), p. 456.
`The reply of applicant (i.e. the Proprietor of herein opposed patent)
`dated Jun. 4, 2013 in relation to the corresponding US2011/
`0144016A1 US proceedings.
`Wang, C., et al., “Hypertension due to 17a-Hydroxylase de?ciency”,
`Australian and New Zealand Journal of Medicine (1978), 8(3), p.
`295-299.
`Yano, A., et al., “Glucocorticoids Suppress Tumor Angiogensis and
`In vivo Growth ofProstate Cancer Cells”, Clin. Cancer Res., (2006)
`12, 3003-3009.
`Statement of Opposition, Actavis Group PTC ehf, 2014.
`Statement of Opposition, Alfred E. Tiefenbacher, 2014.
`Statement of Opposition, Alison Gallafent, 2014.
`Statement of Opposition, Arnold Siedsma, 2014.
`Statement of Opposition, Cabinet LavoiX, 2014.
`Statement of Opposition, Galenicum Health, S.L., 2014.
`Statement of Opposition, Generics Ltd., 2014.
`Statement of Opposition, Helm AG, 2014.
`Statement of Opposition, Hetero Drugs, 2014.
`Statement of Opposition, Isenbruck Bosl Horschler LLP, 2014.
`Statement of Opposition, Laboratorios Leon Farma, SA, 2014.
`Statement of Opposition, Maiwald Patentanwalts GmbH, 2014.
`Statement of Opposition, Stada Arzneimittel, 2014.
`Statement of Opposition, Synthon B.V., 2014.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 2
`
`

`
`US 8,822,438 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Statement of Opposition, Teva Pharmaceutical Industries, Ltd., 2014.
`Statement of Opposition, Zentiva k.s., 2014.
`Carducci, M.A,, “What is more exciting? The Activity of Docetaxel
`in Early Prostate Cancer or the Successful Collaboration between
`Urologists and Medical Oncologists to complete a study in early
`Prostate Cancer’?”, Journal ofClinical Oncology (2005), vol. 23, No.
`15, pp. 3304-3307.
`Sahu, B., et al,, “FoxAl Speci?es Unique Androgen and
`Glucocorticoid Receptor Binding Events in Prostate Cancer Cells”,
`Cancer Research (2013), vol. 73, pp. 1570-1580.
`Storlie, J .A., et al., “Prostate Speci?c Antigen Levels and Clinical
`Response to Low Dose Dexamethasone for Hormone-Refractory
`Metastatic Prostate Carcinoma”, Cancer (1995) vol. 76, No. 1, p.
`96-100.
`Tanagho, EA, et al., “The Leading Single-Volume Resource in
`Urology”, Smith’s General Urology, 16th Edition, (2004), Chapter
`19, pp. 321-323; Chapter 22, pp. 380-385.
`Tomic, R.,
`et
`al,, “Hormonal Effects of High Dose
`Medroxyprogesterone Acetate Treatment in Males With Renal or
`Prostatic Adenocarcinoma”, (1988), vol. 22 (1), Abstract.
`Venkitaraman, R., et al., “Ef?cacy of Low-Dose Dexarnethasone in
`Castration-Refractory Prostate Cancer”, BJU Int (2008), 101, pp.
`1756-1764.
`
`Vogelzang, N.J., Curriculum Vitae, 15 pages.
`Suppress Tumor
`Yana,
`A.,
`et
`al.,
`“Glucocorticoids
`Lymphandiogenesis of Prostate Cancer Cells”, Clin Cancer Res
`(2006), vol. 12, pp. 6012-6017.
`Declaration by Dr. Jacqueline Anne Warner in the matter of Opposi
`tion by Northern Rivers Pty Ltd., 25 pages, 2004.
`Declaration by Helen Grimes in the matter of Opposition by Northern
`Rivers Pty Ltd., 43 pages, 2004.
`Statement of Opposition, Actavis Group PTC ehf.
`Statement of Opposition, Alfred E. Tiefenbacher (translated in
`English).
`Statement of Opposition, Arnold Siedsma (Synthon B.V.).
`Statement of Opposition, Cabinet LavoiX.
`Statement of Opposition, Galenicum Health, S.L.
`Statement of Opposition, Generics Ltd.
`Statement of Opposition, Helm AG (translated in English).
`Statement of Opposition, Hetero Drugs.
`Statement of Opposition, Laboratorios Leon Farma, S.A.
`Statement of Opposition, Maiwald Patentanwalts GmbH.
`Statement of Opposition, Stada Arzneimittel AG (translated in
`English).
`Statement of Opposition, Teva Pharmaceutical Industries, Ltd.
`
`* cited by examiner
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 3
`
`

`
`US 8,822,438 B2
`
`1
`METHODS AND COMPOSITIONS FOR
`TREATING CANCER
`
`FIELD OF THE INVENTION
`
`Methods and compositions for treating cancer are
`described herein. More particularly, the methods for treating
`cancer comprise administering a 170t-hydroxylase/C 17,20
`lyase inhibitor, such as abiraterone acetate (i.e., 3[3-acetoxy
`17-(3-pyridyl) androsta-5,16-diene), in combination with at
`least one additional therapeutic agent, such as an anti-cancer
`agent or a steroid. Furthermore, disclosed are compositions
`comprising a 170t-hydroxylase/Cl7,20-lyase inhibitor, and at
`least one additional therapeutic agent such as an anti-cancer
`agent or a steroid, e.g., a corticosteroid or, more speci?cally,
`a glucocorticoid.
`
`BACKGROUND
`
`The number of people diagnosed with cancer has signi?
`cantly increased. Of special interest are individuals diagnosed
`with androgen-dependent disorders, such as prostate cancer,
`and estrogen-dependent disorders, such as breast cancer since
`such diagnoses are increasing in number at an alarming rate.
`Prostate cancer is currently the most common non-skin
`cancer and the second leading cause of cancer-related death in
`men after lung cancer. The primary course of treatment for
`patients diagnosed with organ-con?ned prostate cancer is
`usually prostatectomy or radiotherapy. Not only are these
`treatments highly invasive and have undesirable side effects,
`such localized treatments are not effective on prostate cancer
`after it has metastasized. Moreover, a large percent of indi
`viduals who receive localized treatments will suffer from
`recurring cancer.
`Additionally, breast cancer incidence in women has
`increased from one out of every 20 women in 1960 to one out
`of every eight women in 2005. Moreover, it is the most com
`mon cancer among white and African-American women.
`Similar to treating prostate cancer, most options for women
`diagnosed with breast cancer are highly invasive and have
`signi?cant side-effects. Such treatments include surgery,
`radiation and chemotherapy.
`Hormone therapy is another treatment option for individu
`als diagnosed with prostate or breast cancer. Hormone
`therapy is a form of systemic treatment for prostate or breast
`cancer wherein hormone ablation agents are used to suppress
`the production or block the effects of hormones, such as
`estrogen and progesterone in the body, which are believed to
`promote the growth of breast cancer, as well as testosterone
`and dihydrotestosterone, which are believed to promote the
`growth of pro state cancer. Moreover, hormone therapy is less
`invasive than surgery and does not have many of the side
`effects associated with chemotherapy or radiation. Hormone
`therapy can also be used by itself or in addition to localized
`therapy and has shown to be effective in individuals whose
`cancer has metastasized.
`Even though hormone therapy is less invasive and can be
`used on more advanced stages of cancer, some individuals
`administered current hormone therapy treatments may not
`show a signi?cant response or may not show any response at
`all to such treatments. Additionally, some patients treated
`with current hormone therapy treatments may also suffer
`from relapsing or recurring cancer. Currently, such refractory
`cancer patients are left with very few treatment options.
`Despite the progress made in the treatment of cancer, there
`remains a need for more effective ways to treat cancer such as,
`but not limited to, prostate cancer and breast cancer. Addi
`
`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`60
`
`65
`
`2
`tionally, there is a need for effective anti-cancer treatment
`options for patients who are not responding to current anti
`cancer treatments. Also, there is a need for effective anti
`cancer treatment options for patients whose cancer has
`recurred.
`
`SUMMARY OF THE INVENTION
`
`Described herein are methods for treating a cancer in
`which a therapeutically effective amount of a 170t-hydroxy
`lase/ClmO-lyase inhibitor, such as abiraterone acetate (i.e.
`3 [3-acetoxy-17-(3 -pyridyl)androsta-5,16-diene), is adminis
`tered to a patient, e. g., a patient in need thereof, in combina
`tion with a therapeutically effective amount of at least one
`additional therapeutic agent including, but not limited to, an
`anti-cancer agent or steroid. Such methods can also provide
`an effective treatment for individuals with a refractory cancer,
`including individuals who are currently undergoing a cancer
`treatment. Therefore, in certain embodiments, the method is
`directed to treating a refractory cancer in a patient, in which a
`therapeutically effective amount of 170t-hydroxylase/C 17,20
`lyase inhibitor is administered to a patient currently receiving
`an anti-cancer agent.
`For example, in certain embodiments, the method for the
`treatment of a cancer in a mammal comprises administering
`an amount of about 0.01 mg/kg/day to about 100 mg/kg/day
`of abiraterone acetate and an amount of about 0.1 mg/m2 to
`about 20 mg/m2 of mitoxantrone.
`In another embodiment, the method for the treatment of a
`cancer in a mammal comprises administering an amount of
`about 0.01 mg/kg/day to about 100 mg/kg/day of abiraterone
`acetate and an amount of about 1 mg/m2 to about 175 mg/m2
`of paclitaxel.
`In still other embodiments, the method for the treatment of
`a cancer in a mammal comprises administering an amount of
`about 0.01 mg/kg/day to about 100 mg/kg/day of abiraterone
`acetate and an amount of about 1 mg/m2 to about 100 mg/m2
`of docetaxel.
`Furthermore, described herein is a method for the treat
`ment of a cancer in a mammal comprising administering an
`amount of about 0.01 mg/kg/day to about 100 mg/kg/day of
`abiraterone acetate; and an amount of about 0.01 mg to about
`200 mg of leuprolide, wherein the leuprolide is administered
`over a period of about 3 days to about 12 months.
`In other embodiments, the method for the treatment of a
`cancer in a mammal comprises administering an amount of
`about 0.01 mg/kg/day to about 100 mg/kg/day of abiraterone
`acetate and an amount of about 0.01 mg to about 20 mg of
`goserelin, wherein the goserelin is administered over a period
`of about 28 days to about 3 months.
`Additionally, in another embodiment, the method for the
`treatment of a cancer in a mammal comprises administering
`an amount of about 0.01 mg/kg/day to about 100 mg/kg/day
`of abiraterone acetate and an amount of about 0.01 mg to
`about 20 mg of triptorelin, wherein the triptorelin is admin
`istered over a period of about 1 month.
`The method for the treatment of a cancer in a mammal can
`also comprise administering an amount of about 0.01 mg/kg/
`day to about 100 mg/kg/day of abiraterone acetate and an
`amount of about 0.1 ug/ day to about 500 ug/day of seocalci
`tol, such as about 100 ug/day of seocalcitol.
`Also, the method for the treatment of a cancer in a mammal
`can comprise administering an amount of about 0.01 mg/kg/
`day to about 100 mg/kg/day of abiraterone acetate and an
`amount of about 1 mg/day to about 300 mg/day of bicaluta
`mide.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 4
`
`

`
`US 8,822,438 B2
`
`3
`In yet another embodiment, the method for the treatment of
`a cancer in a mammal can comprise administering an amount
`of about 0.01 mg/kg/day to about 100 mg/kg/day of abirater
`one acetate and an amount of about 1 mg/day to about 2000
`mg/day of ?utamide.
`Moreover, the method for the treatment of a cancer in a
`mammal can comprise administering an amount of about 50
`mg/day to about 2000 mg/day of abiraterone acetate and an
`amount of about 0.01 mg/day to about 500 mg/day of a
`glucocorticoid including, but not limited to, hydrocortisone,
`prednisone or dexamethasone.
`Also described herein are compositions for the treatment of
`cancer that comprise a combination of a therapeutically effec
`tive amount of at least one l70t-hydroxylase/C 17,20-lyase
`inhibitor and a therapeutically effective amount of at least one
`additional anti-cancer agent, such as, but not limited to,
`mitoxantrone, paclitaxel, docetaxel, leuprolide, goserelin,
`triptorelin, seocalcitol, bicalutamide, ?utamide, or a steroid
`including, but not limited to, hydrocortisone, prednisone, or
`dexamethasone.
`Finally, single unit dosage forms comprising abiraterone
`acetate and a glucocorticoid, optionally with carriers, diluents
`or excipients, are contemplated. Also, kits comprising at least
`one 1 70t-hydroxylase/ C 17,20-lyase inhibitor and an additional
`anti cancer agent or steroid are contemplated. For example,
`the kit may include a vial containing abiraterone acetate and
`another vial containing a glucocorticoid.
`
`DEFINITIONS
`
`As used herein and unless otherwise de?ned the word
`“cancer,” refers to the growth, division or proliferation of
`abnormal cells in the body. Cancers that can be treated with
`the methods and the compositions described herein include,
`but are not limited to, prostate cancer, breast cancer, adrenal
`cancer, leukemia, lymphoma, myeloma, Waldenstrom’s mac
`roglobulinemia, monoclonal gammopathy, benign mono
`clonal gammopathy, heavy chain disease, bone and connec
`tive tissue sarcoma, brain tumors, thyroid cancer, pancreatic
`cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar
`cancer, cervical cancer, uterine cancer, ovarian cancer, esoph
`ageal cancer, stomach cancer, colon cancer, rectal cancer,
`liver cancer, gallbladder cancer, cholangiocarcinoma, lung
`cancer, testicular cancer, penal cancer, oral cancer, skin can
`cer, kidney cancers, Wilms’ tumor and bladder cancer.
`As used herein, and unless otherwise de?ned, the terms
`“treat,” “treating” and “treatment” include the eradication,
`removal, modi?cation, management or control of a tumor or
`primary, regional, or metastatic cancer cells or tissue and the
`minimization or delay of the spread of cancer.
`As used herein, and unless otherwise de?ned, the term
`“patient” means an animal, including but not limited to an
`animal such as a human, monkey, cow, horse, sheep, pig,
`chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea
`pig. In one embodiment, the patient is a mammal and in
`another embodiment the patient is a human. In certain
`embodiments, the patient can be an adult male or female. In
`some embodiments, the patient is a male of age about 30 years
`to about 85 years. In other embodiments, the patient is a
`female of age about 30 years to about 85 years. In a particular
`embodiment, the patient has or is susceptible to having (e. g.,
`through genetic or environmental factors) cancer. In a further
`embodiment, the patient has or is susceptible to having (e. g.,
`through genetic or environmental factors) a tumor. In other
`embodiments, the patient can be castrated or non-castrated.
`The term “l70t-hydroxylase/C17,2O-lyase inhibitor” as
`used herein refers to an inhibitor of l70t-hydroxylase/C 17,20
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`lyase, (which is an enzyme in testosterone synthesis), an
`analog thereof, derivative thereof, metabolite thereof or phar
`maceutically acceptable salt thereof. Also, unless otherwise
`noted, reference to a particular l70t-hydroxylase/C 17,2O-lyase
`inhibitor can include analogs, derivatives, metabolites or
`pharmaceutically acceptable salts of such particular I70.
`hydroxylase/C 17,20-lyase inhibitor.
`The term “anti-cancer agent” as used herein refers to any
`therapeutic agent that directly or indirectly kills cancer cells
`or directly or indirectly prohibits stops or reduces the prolif
`eration of cancer cells. It should be noted that even though
`throughout this speci?cation and in the claims the phrase
`“anti-cancer agent” is written as a singular noun, for example;
`“an anti-cancer agent” or “the anti-cancer agent,” the phrase
`“anti-cancer agent” should not be interpreted as being limited
`to the inclusion of a single anti-cancer agent.
`As used herein, and unless otherwise de?ned, the phrase
`“therapeutically effective amount” when used in connection
`with a l70t-hydroxylase/C17,20-lyase inhibitor or therapeutic
`agent means an amount of the l70t-hydroxylase/C 17,2O-lyase
`inhibitor or therapeutic agent effective for treating a disease
`or disorder disclosed herein, such as cancer.
`As used herein and unless otherwise de?ned the phrase
`“refractory cancer,” means cancer that is not responding to an
`anti-cancer treatment or cancer that is not responding suf?
`ciently to an anti-cancer treatment. Refractory cancer can also
`include recurring or relapsing cancer.
`As used herein and unless otherwise de?ned the phrase
`“refractory patient,” means a patient who has refractory can
`cer.
`As used herein and unless otherwise de?ned the phrase
`“relapse cancer,” means cancer that was at one time respon
`sive to an anti-cancer treatment but has become no longer
`responsive to such treatment or is no longer responding suf
`?ciently to such treatment.
`As used herein and unless otherwise de?ned the phrase
`“recurring cancer,” means cancer that has returned after a
`patient has been earlier diagnosed with cancer, under gone
`treatment or had been previously diagnosed as cancer-free.
`As used herein and unless otherwise de?ned the term
`“derivative” refers to a chemically modi?ed compound
`wherein the chemical modi?cation takes place at one or more
`functional groups of the compound. The derivative may retain
`or improve the pharmacological activity of the compound
`from which it is derived.
`As used herein and unless otherwise de?ned the term “ana
`log” refers to a chemical compound that is structurally similar
`to another but differs slightly in composition (as in the
`replacement of one atom by an atom of a different element or
`in the presence of a particular functional group).
`As used herein and unless otherwise de?ned the phrase
`“pharmaceutically acceptable salt” refers to any salt of a
`l70t-hydroxylase/C17,20-lyase inhibitor which retains the
`biological effectiveness of the l70t-hydroxylase/Cl7,20-lyase
`inhibitor. Examples of pharmaceutically acceptable salts
`include, but are not limited to, acetates, sulfates, pyro sulfates,
`bisulfates, sul?tes, bisul?tes, phosphates, monohydrogen
`phosphates, dihydrogenphosphates, metaphosphates, pyro
`phosphates, chlorides, bromides, iodides, acetates, propi
`onates,
`decanoates,
`caprylates,
`acrylates,
`formates,
`isobutyrates, caproates, heptanoates, propiolates, oxalates,
`malonates, succinates, suberates, sebacates, fumarates, male
`ates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates,
`chlorobenzoates,
`methylbenzoates,
`dinitrobenzoates,
`hydroxybenzoates, methoxybenzoates, phthalates, sul
`fonates, xylenesulfonates, phylacetates, phenylpropionates,
`phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 5
`
`

`
`US 8,822,438 B2
`
`5
`glycollates, tartarates, alkanesulfonates (e.g. methane-sul
`fonate or mesylate), propanesulfonates, naphthalene-l-sul
`fonates, naphthalene-2-sulfonates, and mandelates. Several
`of the of?cially approved salts are listed in Remington: The
`Science and Practice of Pharmacy, Mack Publ. Co., Easton.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The methods described herein for treating cancer comprise
`administering to a mammal, preferably a human, a l70t-hy
`droxylase/Cl7,2O-lyase inhibitor in addition to at least one
`therapeutic agent, such as an anti-cancer agent or steroid,
`particularly a glucocorticoid. The compositions described
`herein comprise a l70t-hydroxylase/ C Ugo-lyase inhibitor
`and at least one additional therapeutic agent, such as an anti
`cancer agent or steroid, particularly a corticosteroid or glu
`cocorticoid. Other anti-cancer treatments such as, adminis
`tration of yet another anti-cancer agent, radiotherapy,
`chemotherapy, photodynamic therapy, surgery or other
`immunotherapy, can be used with the methods and composi
`tions.
`l70t-Hydroxylase/C 17,20-Lyase Inhibitors
`l70t-hydroxylase/Cl7,2O-lyase inhibitors have been shown
`to be useful in the treatment of cancer, speci?cally hormone
`dependent disorders such as, androgen-dependent and estro
`gen-dependent disorders like prostate cancer and breast can
`cer respectively, as described in US. Pat. No. 5,604,213 to
`Barrie et al., which is herein incorporated by reference in its
`entirety.
`In certain embodiments, the l70t-hydroxylase/ C 1 7,20 -lyase
`inhibitor can be l7-(3-pyridyl)androsta-5,l6-dien-3Bol; l7
`(3-pyridyl)androsta-3,5,l6-triene; l7-(3-pyridyl)androsta-4,
`l6-dien-3-one; 17-(3 -pyridyl)estra- l ,3,5[10] , l 6-tetraen-3
`ol; l7-(3-pyr‘idyl)-50t-androst- l 6-en-30t-ol; l7-(3-pyridyl)
`50t-andro st-l 6-en-3 -one;
`17-(3 -pyridyl) -androsta-4, l 6
`diene-3, l l -dione; l7-(3-pyridyl)-androsta-3,5, l 6-trien-3-ol;
`60.- and 6B-?uoro-l7-(3-pyridyl)androsta-4,l6-dien-3-one;
`17-(3 -pyridyl)androsta-4, l 6-dien-3,6-dione; 30t-tri?uorom
`ethyl-l7-(3-pyridyl)androst-l6-en-3[3-ol or their acid addi
`tion salts and 3-esters as well as metabolites, analogs, deriva
`tives or a pharmaceutically acceptab