US 8,822,438 B2
`
`1
`METHODS AND COMPOSITIONS FOR
`TREATING CANCER
`
`FIELD OF THE INVENTION
`
`2
`tionally, there is a need for effective anti-cancer treatment
`options for patients who are not responding to current anti(cid:173)
`cancer treatments. Also, there is a need for effective anti(cid:173)
`cancer treatment options for patients whose cancer has
`recurred.
`
`SUMMAR Y OF THE INVENTION
`
`Methods and compositions for treating cancer are
`described herein. More particularly, the methods for treating
`cancer comprise administering a l 7a-hydroxylase/C17,20-
`lyase inhibitor, such as abiraterone acetate (i.e., 3~-acetoxy-
`17-(3-pyridyl) androsta-5,16-diene), in combination with at 10
`least one additional therapeutic agent, such as an anti-cancer
`agent or a steroid. Furthermore, disclosed are compositions
`comprising a l 7a-hydroxylase/C1 7,20-lyase inhibitor, and al
`least one additional therapeutic agent such as an anti-cancer
`agent or a steroid, e.g., a corticosteroid or, more specifically, 15
`a glucocorticoid.
`
`BACKGROUND
`
`The number of people diagnosed with cancer has signifi(cid:173)
`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 25
`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-confined prostate cancer is
`usually prostatectomy or radiotherapy. Not only are these
`treatments highly invasive and have undesirable side effects, 30
`such localized treatments are not effective on prostate cancer
`after it has metastasized. Moreover, a large percent of indi(cid:173)
`viduals who receive localized treatments will suffer from
`recurring cancer.
`Additionally, breast cancer incidence in women has 35
`increased from one out of every 20 women in l 960 to one out
`of every eight women in 2005. Moreover, it is the most com(cid:173)
`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 40
`significant 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 45
`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 lo
`promote the growth of breast cancer, as well as testosterone
`and dihydrotestosterone, which are believed to promote the 50
`growth of prostate 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 lo localized
`therapy and has shown to be effective in individuals whose 55
`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 significant response or may not show any response at 60
`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 65
`remains a need for more effective ways 10 treat cancer such as,
`but not limited to, prostate cancer and breast cancer. Addi-
`
`Described herein are methods for treating a cancer in
`which a therapeutically effective amount of a 17a-hydroxy(cid:173)
`lase/C, 7,20-lyase inhibitor, such as abiraterone acetate (i.e.
`3~-acetoxy-17-(3-pyridyl)androsla-5,16-diene), is adminis(cid:173)
`tered lo a patient, e.g., a patient in need thereof, in combina(cid:173)
`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
`20 treatment. Therefore, in certain embodiments, the method is
`directed to treating a refractory cancer in a patient, in which a
`therapeutically effective amount of l 7a-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 JOO mg/kg/day
`of abiraterone acetate and an amount of about 0.1 mg/m2 to
`about 20 mg/m2 ofmitoxantrone.
`In another embodiment, the method for the treatment of a
`cancer in a mammal comprises administering an amount of
`about 0.0 l 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 I 00 mg/kg/day of abiraterone
`acetate and an amount of about l mg/nr' to about 100mg/m2
`of docetaxel.
`Furthermore, described herein is a method for the treat(cid:173)
`ment of a cancer in a mammal comprising administering an
`amount of about 0.01 mg/kg/day to about JOO mg/kg/day of
`abiraterone acetate; and an amount of about 0.0 l 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 l 00 mg/kg/day of abiraterone
`acetate and an amount of about 0.0 l 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 l 00 mg/kg/day of abiraterone acetate and an
`amount of about 0.1 µg/day to about 500 ug/day ofseocalci-
`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 0.0 l mg/kg/
`day to about 100 mg/kg/day of abiraterone acetate and an
`amount of about 1 mg/day lo about 300 mg/day ofbicaluta-
`mide.
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 4
`
`JANSSEN EXHIBIT 2011
`Mylan v. Janssen IPR2016-01332
`
`

`

`US 8,822,438 B2
`
`3
`In yet another embodiment, the method for the treatment of
`a cancer in a mammal can comprise admiui stering an amount
`of about 0.01 mg/kg/day to about 100 mg/kg/day ofabirater(cid:173)
`one acetate and an amount of about I mg/day to about 2000
`mg/day of flutamide.
`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(cid:173)
`tive amount of at least one 17a-hydroxylase/C17,20-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, flutamide, 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
`orexcipients, are contemplated. Also, kits comprising at least
`one 17a-hydroxylase/C17 20-lyase inb.ibitorand 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
`
`4
`lyase, (which is an enzyme in testosterone synthesis), an
`analog thereof, derivative thereof, metabolite thereof or phar(cid:173)
`maceutically acceptable salt thereof. Also, unless otherwise
`noted, reference to a particular 17a-hydroxylase/C1 7,20-lyase
`inhibitor can include analogs, derivatives, metabolites or
`pharmaceutically acceptable salts of such particular I 7a(cid:173)
`hydroxylase/C, , ,0-lyase inhibitor.
`The term "anti~cancer agent" as used herein refers to any
`therapeutic agent that directly or indirectly kills cancer cells
`10 or directly or indirectly prohibits stops or reduces the prolif(cid:173)
`eration of cancer cells. It should be noted that even though
`throughout th.is specification 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
`15 "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 defined, the phrase
`"therapeutically effective amount" when used in connection
`with a 17a-hydrox-ylase/C17,20-lyase inhibitor or therapeutic
`20 agent means an amount of the 17a-hydroxylase/C17,20-lyase
`inhibitor or therapeutic agent effective for treating a disease
`or disorder disclosed herein, such as cancer.
`As used herein and unless otherwise defined the phrase
`"refractory cancer," means cancer that is not responding to an
`25 anti-cancer treatment or cancer that is not responding suffi(cid:173)
`ciently to an anti-cancer treatment. Refractory cancer can also
`include recurring or relapsing cancer.
`As used herein and unless otherwise defined the phrase
`"refractory patient," means a patient who has refractory can(cid:173)
`JO cer.
`As used herein and unless otherwise defined the phrase
`"relapse cancer," means cancer that was at one time respon(cid:173)
`sive to an anti-cancer treatment but has become no longer
`responsive to such treatment or is no longer responding suf-
`35 ficiently to such treatment.
`As used herein and unless otherwise defined 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 defined the term
`"derivative" refers to a chemically modified compound
`wherein the chemical modification takes place at one or more
`functional groups of the compound. The derivative may retain
`or improve the pharmacological activity of the compound
`45 from which it is derived.
`As used herein and unless otherwise defined the term "ana(cid:173)
`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
`;o in the presence of a particular functional group).
`As used herein and unless otherwise defined the phrase
`"pharmaceutically acceptable salt" refers to any salt of a
`17a-hydroxylase/C17,20-lyase inhibitor which retains the
`biological effectiveness of the 17a-hydroxylase/C17,20-lyase
`inhibitor. Examples of pharmaceutically acceptable salts
`include, but are not limited to, acetates, sulfates, pyrosulfates,
`bisulfates, sulfites, bisulfites, phosphates, monohydrogen(cid:173)
`phosphates, dihydrogeuphosphates, metaphosphates, pyro(cid:173)
`phosphates, chlorides, bromides, iodides, acetates, propi(cid:173)
`ouates, decanoates,
`caprylates,
`acrylaies,
`formates,
`isobutyrates, caproates, heptanoates, propiolates, oxalates,
`malonates, succinates, suberates, sebacates, fumarares, male(cid:173)
`ates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,
`chlorobenzoates,
`methylbenzoates,
`dinitrobenzoates,
`65 hydroxybenzoares, methoxybeuzoates, phthalates, sul(cid:173)
`fonates, xylenesulfonates, phylacetates, phenylpropionates,
`phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,
`
`As used herein and unless otherwise defined 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(cid:173)
`roglobulinernia, monoclonal ganuuopathy, benign mono(cid:173)
`clonal garnmopathy, heavy chain disease, bone and connec(cid:173)
`tive tissue sarcoma, brain rumors, thyroid cancer, pancreatic
`cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar 40
`cancer, cervical cancer, uterine cancer, ovarian cancer, esoph(cid:173)
`ageal cancer, stomach cancer, colon cancer, rectal cancer,
`liver cancer, gallbladder cancer, cholangiocarcinoma, lung
`cancer, testicular cancer, penal cancer, oral cancer, skin can(cid:173)
`cer, kidney cancers, Wilms' tumor and bladder cancer.
`As used herein, and unless otherwise defined, the terms
`"treat," "treating" and "treatment" include the eradication,
`removal, modification, 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 defined, 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 55
`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 60
`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.
`TI1e term "l 7a-hydroxylase/C17,20-lyase inhibitor" as
`used herein refers to an inhibitor of 17a-hydroxylase/C17,20-
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 5
`
`

`

`US 8,822,438 B2
`
`5
`glycollates, tartarates, alkanesulfonates ( e.g. methane-sul(cid:173)
`fonare or mesylare), propanesulfonates, naphthalene-1-sul(cid:173)
`fonates naphthalene-2-sulfonates, and mandelates. Several
`of the officially approved salts are listed in Remington: The
`Science and Practice of Pharmacy, Mack Puhl. Co., Easton.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`6
`3-desoxy derivatives; to have one or more hydroxy, halo,
`C,_4-aU...-yl, trifluoro-methyl, c,_..-alkoxy, C1_4-alkanoyloxy,
`benzoyloxy, oxo, methylene or alkenyl substituents in the A.
`B, or C-ring; or to be 19-nor;
`R represents a hydrogen atom or an alkyl group of 1-4
`carbon atoms;
`R 14 represents a hydrogen atom, a halogen atom or an alkyl
`group of I to 4 carbon atoms;
`each of the R 15 substiruents independently represents a
`hydrogen atom or an alkyl or alkoxy group of 1-4 carbon
`atoms, a hydroxy group or an alkylcarbonyloxy group of
`2 to 5 carbon atoms or together represent an oxo or
`methylene group or R14 and one of the R15 Jlroups
`together represent a double bond and the other R 1 group
`represents a hydrogen atom or an alkyl group of I to 4
`carbon atoms· and
`R 16 represents a hydrogen atom, halogen atom, or an alkyl
`group of I to 4 carbon atoms, in the form of the free bases
`or pharmaceutically acceptable acid addition salts, but
`excluding 3~-acetoxy-17-(3-pyridyl)androsta-5,14,16-
`triene. 3~, I Sa- and 3~, J 5~-diacetoxy-17-(3-pyridyl)
`androsta-5,16-diene and 3~-methoxy-17-(3-pyridyl(cid:173)
`Sa-androst-l 6-ene.
`Suitable inhibitors also include metabolites, derivatives,
`analogs, or pharmaceutically acceptable salts of'formula (]).
`In another embodiment, the l 7a-hydroxylase/C17,20-lyase
`inhibitor can have the structure of formula (]):
`
`(I)
`
`The methods described herein for treating cancer comprise
`administering to a mammal, preferably a human, a l 7a-hy- 10
`droxylase/C, , ,0-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 I 7a-hydroxylase/C17,20-lyase inhibitor
`and at least one additional therapeutic agent, such as an anti- 15
`cancer agent or steroid, particularly a corticosteroid or glu(cid:173)
`cocorticoid. Other anti-cancer treatments such as, adminis(cid:173)
`tration of yet another anti-cancer agent, radiotherapy,
`chemotherapy, photodynamic therapy, surgery or other
`immunotherapy, can be used with the methods and composi- 20
`tions.
`l 7a-Hydroxylase/C17,20-Lyase Inhibitors
`17a-hydroxylase/C17,20-lyase inhibitors have been shown
`to be useful in the treatment of cancer, specifically hormone(cid:173)
`dependent disorders such as, androgen-dependent and estro- 25
`gen-dependent disorders like prostate cancer and breast can(cid:173)
`cer respectively, as described in U.S. Pat. No. 5,604,213 to
`Barrie et al., which is herein incorporated by reference in its
`entirety.
`In certain embodiments, the l 7a-hydroxylase/C17 20-lyase
`inhibitor can be 17-(3-pyridyl)androsta-5, l 6-dien-3°~01; 17- 30
`(3-pyridyl)androsta-3,5,16-triene; 17-(3-pyridyl)androsta-4,
`16-dien-3-one;
`17-(3-pyridyl)estra-l ,3,5( I 0),16-tetraen-3-
`ol; J 7-(3-pyridyl)-5a-androst-16-en-3a-ol; 17-(3-pyridyl)(cid:173)
`Sa-androst-l 6-en-3-one;
`17-(3-pyridyl)-androsta-4,l 6-
`diene-3, l I-dione; 17-(3-pyridyl)-androsta-3,5, 16-trien-3-ol; 35
`6a- and 6~-fluoro-17-(3-pyridyl)androsta-4,16-dien-3-one;
`17-(3-pyridyl)androsta-4, I 6-dien-3,6-dione; 3a-trifluorom(cid:173)
`ethyl-I 7-(3-pyridyl)androst-l 6-en-3~-oI or their acid addi(cid:173)
`tion salts and 3-esters as well as metabolites, analogs, deriva(cid:173)
`tives or a pharmaceutically acceptable salt thereof.
`In certain embodiments, the l 7a-hydroxylase/C17 20-lyase
`inhibitor can have the structure of formula (]):
`'
`
`40
`
`(I)
`
`45
`
`wherein R represents hydrogen or a lower acyl group having
`I to 4 carbons. Suitable inhibitors also include derivatives,
`analogs, or pharmaceutically acceptable salts of formula (]).
`In still another embodiment, the 17a-hydroxylase/C17_20-
`lyase inhibitor can be a 3~-alkanoyloxy-17-(3-pyridyl)
`androsta-5,16-diene in which the alkanoyloxy group has
`from 2 to 4 carbon atoms.
`In a preferred embodiment, the 17a-hydroxylase/C17 ,0-
`lyase inhibitor comprises abiraterone acetate or 3~-acetoxy-
`50 17-(3-pyridyl)androsta-5,16-diene which has the following
`structural formula:
`
`wherein X represents the residue of the A, B and C rings of a 55
`steroid which can be, with.out limitation. androstan-3a- or
`3~-ol; androsr-S-en-Sp- or 3~-ol; androst-4-en-3-one;
`androst-2-ene; androst-4-ene; androst-5-ene; androsta-5,7-
`dien-3a or 3~-ol; androsta-1,4-dien-3-one; androsta-3,5-di(cid:173)
`eue; androsta-3,5-diene-3-ol; estra-1,3,5[ I 0)-triene; estra-1,
`3,5[1 O)-trien-3-ol; Sa-androstan-3-one; androst-4-ene-3,11- 60
`dione: 6-fluoroandrost-4-ene-3-one; or androstan-4-ene-3,6-
`dione; each of which, where structurally permissible, can be
`further derivatized in one or more of the following ways,
`including, but not limited to, to form 3-esters; to have oue or
`more carbon or carbon ring double bonds in any oftb.e 5,6-, 65
`6,7-, 7,8-, 9,1 I- and 11,12-positions; as 3-oximes; as 3-me-
`thylenes; as 3-carboxylates; as 3-nitriles; as 3-nitros; as
`
`and pharmaceutically acceptable salts thereof.
`
`(II)
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 6
`
`

`

`US 8,822,438 B2
`
`(Ill)
`
`15
`
`o,,._ / e
`--::s::::::::.o
`I HO
`
`~o
`
`7
`Preferred salts of abiraterone acetate and methods of mak(cid:173)
`ing such salts are also disclosed in U.S. Provisional Applica(cid:173)
`tion No. 60/603,559 to Hunt, which is incorporated by refer(cid:173)
`ence in its entirety. Preferred salts include, but are not limited
`to, acetates, citrates, lactates, alkanesulfonates ( e.g. methane(cid:173)
`sulfonate or mesylate) and tartarates. Of special interest is the
`abiraterone acetate mesylate salt (i.e. 3P-acetoxy-l 7-(3-py(cid:173)
`ridyl)androsta-5,16-diene mesylate salt) which has the fol(cid:173)
`lowing structural formula:
`
`8
`singular noun, for example; "a hormonal ablation agent" or
`"the hormonal ablation agent," the phrase "hormonal ablation
`agent" should not be interpreted as being limited to the inclu(cid:173)
`sion of a single hormonal ablation agent. The amount of the
`hormonal ablation agent administered to a mammal having
`cancer is an amount that is sufficient to treat the cancer
`whether administered alone or in combination with a l 7a(cid:173)
`hydroxylase/C17,20-lyase inhibitor.
`Suitable anti-androgen agents include but are not limited to
`10 bicalutarnide, flutamide and nilutamide. The amount of the
`anti-androgen agent administered to a mammal having cancer
`is an amount that is sufficient to treat the cancer whether
`administered alone or in combination with a I 7a-hydroxy(cid:173)
`lase/C17,20-lyase inhibitor.
`In another embodiment, the J 7a-hydroxylase/C1 7,20-lyase
`inhibitor may be administered with a differentiating agent.
`Suitable differentiating agents include, but are not limited to,
`polyamine inhibitors; vitamin D and its analogs, such as,
`calcitriol, doxercalciferol and seocalcitol; metabolites of
`20 vitamin A, such as, ATRA, retinoic acid, retinoids; short(cid:173)
`chain fatty acids; phenylburyrare; and nonsteroidal anti-in(cid:173)
`flammatory agents. The amount of the differentiating agent
`administered to a mammal having cancer is an amount that is
`sufficient to treat the cancer whether administered alone or in
`25 combination with a I 7a-hydroxylase/C17,20-lyase inhibitor,
`In another preferred embodiment, the J 7a-hydroxylase/
`TI1e l 7a-hydroxylase/C17,20-lyase inhibitors can be made
`C17,20-lyase inhibitor may be administered with an anti-neo(cid:173)
`according to any method known to one skilled in the art. For
`plastic agent, including, but not limited to, rubulin interacting
`example, such inhibitors can be synthesized according to the
`agents, topoisomerase inhibitors and agents, acitretin, alsto-
`method disclosed in U.S. Pat. Nos. 5,604,213 and 5,618,807
`30 nine, amonafide, amphethinile, amsacrine, ankinomycin,
`to Barrie et al., herein incorporated by reference. Another
`anti-neoplaston, aphidicolin glycinate, asparaginase, baccha(cid:173)
`method of making 17a-hydroxlase/C17,20-lyase inhibitors is
`rin, batracylin, benfluron, benzotript, bromofosfamide, cara(cid:173)
`disclosed in U.S. provisional application 60/603,558 to Bury,
`cemide, carmethizole hydrochloride, chlorsulfaquinoxalone,
`herein incorporated by reference.
`clanfenur, claviridenone, crisnatol, curaderm, cytarabine,
`The amount of I 7a-hydroxylase/C17,20-lyase inhibitor
`35 cytocytin, dacarbazine, datelliptinium, dihaematoporphyrin
`administered to a mammal having cancer is an amount that is
`ether, dihydrolenperone, dinaline, distamycin, docetaxel,
`sufficient to treat the cancer, whether the 17a-hydroxylase/
`elliprabin, elliptinium acetate, epotbilones, ergotamine, eto(cid:173)
`C, 7,20-lyase inhibitor is administered alone or in combination
`poside, errerinate, fenretinide, gallium nitrate, gen.kwadaph(cid:173)
`with an additional anti-cancer treatment, such as an additional
`nin, hexadecylphosphocholine, homoharringronine, hydrox-
`anti-cancer agent.
`40 yurea, ilmofosine, isoglutamine, isotretinoin, leukoregulin,
`Additional Therapeutic Agents
`lonidamine, merbarone, merocyanlne derivatives, methyls(cid:173)
`Suitable compounds that can be used in addition to 17o.(cid:173)
`nilinoacridine, minactivin, mitonafide, mitoquidone, rnitox(cid:173)
`hydroxylase/C, , ,0-lyase inhibitors as an anti-cancer agent
`antrone, mopidamol, motretinide, N-(retinoyl)amino acids,
`include, but are ~ot limited to, hormone ablation agents, anti(cid:173)
`N-acylated-dehydroalanines,
`nafazatrom,
`nocodazole
`androgen agents, differentiating agents, anti-neoplastic
`45 derivative, ocreotide, oquizanocinc, paclitaxel, pancratista(cid:173)
`agents, kinase inhibitors, anti-metabolite agents, alkylating
`tin, pazelliptine, piroxantrone, polyhaematoporphyrin,
`agents, antibiotic agents, immunological agents, interferon(cid:173)
`polypreic acid, probimane, procarbazine, proglumide, razox(cid:173)
`type agents, intercalating agents, growth factor inhibitors,
`ane, retelliptine, spatol, spirocyclopropane derivatives,
`cell cycle inhibitors, enzymes, topoisomerase inhibitors, bio(cid:173)
`spirogennanium, strypoldinone, superoxide dismutase, teni-
`logical response modifiers, mitotic inhibitors, matrix rnetal(cid:173)
`50 poside, thaliblasti.ne, tocotrienol, topotecan, ukrain, vi.nblas(cid:173)
`loprotease inhibitors, genetic therapeutics, and anti-andro(cid:173)
`ti.ne sulfate, vincristi.ne, vi.ndesine, vinestramide, vinorelbi.ne,
`gens. The amount of the additional anti-cancer agent
`vintriptol, vinzolidi.ne, and withanolides. The amount of the
`administered to a mammal having cancer is an amount that is
`anti-neoplastic agent administered to a mammal having can(cid:173)
`sufficient to treat the cancer whether administered alone or in
`cer is an amount that is sufficient to treat the cancer whether
`combination with a I 7a-hydroxylase/C17,20-lyase inhibitor.
`55 administered alone or in combination with a 17a-hydroxy(cid:173)
`Below are lists of examples of some of the above classes of
`lase/C, , ,0-lyase inhibitor.
`anti-cancer agents. The examples are not all inclusive and are
`The 17a-hydroxylase/C17,20-lyase inhibitors may also be
`for purposes of illustration and not for purposes oflimitation.
`used with a kinase inhibitor including p38 inhibitors and
`Many of the examples below could be listed in multiple
`CDK inhibitors, TNF inhibitors, metallomatrix proteases
`classes of anti-cancer agents and are not restricted in any way
`60 inhibitors (MMP), COX-2 inhibitors including celecoxib,
`to the class in which they are listed in.
`rofecoxib, parecoxib, valdecoxib, and etoricoxib, SOD mim(cid:173)
`Suitable hormonal ablation agents include, but are not lim(cid:173)
`ics or a.,p3 inhibitors. The amount of the kinase inhibitor
`ited to, androgen ablation agents and estrogen ablation
`administered to a mammal having cancer is an amount that is
`agents. In preferred embodiments, the J 7a-hydroxylase/
`sufficient to treat the cancer whether administered alone or in
`C1 7,20-lyase inhibitor is administered with a hormonal abla(cid:173)
`65 combination with a l 7a-hydroxylase/C17,20-lyase inhibitor.
`tion agent, such as deslorelin, leuprolide, goserelin or trip(cid:173)
`In another embodiment, the l 7a-hydroxylase/C17 ,0-lyase
`torelin. Even though throughout this specification and in the
`inhibitor may be administered with an anti-metabolite agent.
`claims the phrase "hormonal ablation agent" is written as a
`
`MYLAN PHARMS. INC. EXHIBIT 1001 PAGE 7
`
`

`

`US 8,822,438 B2
`
`9
`Suitable anti-metabolite agents may be selected from, but not
`limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadia(cid:173)
`zole. brequinar sodium, carmofur, cyclopentyl cytosine, cyt(cid:173)
`arabine phosphate stearate. cytarabine conjugates, dezagua(cid:173)
`nine,
`dideoxycytidine,
`dideoxyguanosine,
`didox,
`doxifluridine, fazarabine, floxuridine, fludarabine phosphate,
`5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, isopropyl
`pyrrolizine, methobenzaprim, methotrexate, norspermidine,
`pentostatin, piritrexim, plicamycin, thioguanine, tiazofurin,
`trimetrexate, tyrosine kinase inhibitors, and uricytin. The 1 o
`amount of the anti-metabolite agent administered to a mam(cid:173)
`mal having cancer is an amount that is sufficient to treat the
`cancer whether administered alone or in combination with a
`l 7a-hydroxylase/C17 ,0-lyase inhibitor.
`In another embodiment, the l 7a-hydroxylase/C17 ,0-lyase 15
`inhibitor may be administered with an alkylaring agent. Suit(cid:173)
`able alkylating agents may be selected from, but not limited
`to, aldo-phosphamide analogues, altretamine, anaxirone,
`bestrabucil, budotitane, carboplatin, carmustine, chloram(cid:173)
`bucil, cisplatin, cyclophosphamide, cyplatate, diphenylspiro- 20
`mustine, di platinum cytostatic, elmustine, estramustine phos(cid:173)
`phate sodium,
`fotemustine, hepsul-fam,
`ifosfamide,
`iproplatin, lomustine, mafosfamide, mitolacrol, oxaliplatin,
`prednimusrine, ranimustine, semustine, spiromustine, tauro(cid:173)
`mustine, temozolomide, teroxirone, tetraplatin and tri- 25
`melamol. The amount of the alkylating agent administered to
`a mammal having cancer is an amount that is sufficient to treat
`the cancer whether administered alone or in combination with
`al 7a-hydroxylase/C17,20-lyase inhibitor.
`In another preferred embodiment, the l 7a-hydroxylase/ 30
`C, 7,20-lyase inhibitor may be administered with an antibiotic
`agent. Suitable antibiotic agents may be selected from, but not
`limited to. aclarubiciu, actinomycin D, actinoplanone, adria(cid:173)
`mycin, aeroplysinin derivative, amrubicin, anthracycline,
`azino-mycin-A, bisucaberin, bleomycin sulfate, bryostatin-l , 35
`calichemyciu, chromoximycin, dactinomycin, daunorubicin,
`ditrisarubicin B, dexamethasone, doxorubicin, doxorubicin(cid:173)
`fibrinogen, elsarnicin-A, epirubicin, erbstatin, esorubicin,
`esperamicin-Al , esperamicin-Al b, fostriecin, glidobactin,
`gregarin-A, grincamycin, herbimycin, corticosteroids such as 40
`hydrocorrisone, idarubicin, illudins, kazusamycin, kesarirho(cid:173)
`dins, menogaril, rnitomycin, neoenactin, oxalysine, oxauno(cid:173)
`mycin, peplomycin, pilatin, pirarnbicin, porothramycin,
`prednisone, prednisolone, pyrindanycin A, rapamycin,
`rhizoxin, rodornbicin, sibanomicin, siwenmycin, sorangicin- 45
`A, sparsomycin, talisomycin, terpentecin, thrazine, tric(cid:173)
`rozarin A, and zornbicin. The amount of the antibiotic agent
`administered to a mammal having cancer is an amount that is
`sufficient to treat the cancer whether administered alone or in
`combination withal 7a-hydroxylase/C17,20-lyase inhibitor. 50
`Alternatively, the l 7a-hydroxylase/C17,20-lyase inhibitors
`may also be used with other anti-cancer agents, including but
`not limited to, acemannan, aclarnbicin, aldesleukin, alemru(cid:173)
`zumab, alitretinoin, altretamine, amifostine, amsacrine,
`anagrelide, anastrozole, ancestim, bexarotene, broxuridiue, 55
`capecitabine, celmoleukin, cetrorelix, cladribine, clotrima(cid:173)
`zole, daclizumab, dexrazoxane, dilazep, docosanol, doxiflu(cid:173)
`ridine, bromocriptine, carmustine, cytarabine, diclofenac,
`edelfosine, edrecolomab, eflornithine, emitefur, exemestane,
`exisulind, fadrozole, filgrastim, finasteride, fludarabine phos- 60
`phate, fonnestane, fotemustine, gallium nitrate, gemcitabine,
`glycopine, heptaplatin, ibandronic acid, irniquimod, ioben(cid:173)
`guane.
`irinotecan, irsogladine, lanreotide, Jeflunomide.
`Jenograstim, Jentinan sulfate, letrozole, liarozole, Jobaplatin,
`lonidamine, masoprocol, melarsoprol, metoclopramide, 65
`mifepristone, miltefosine, mirimostim, mitoguazone, mito(cid:173)
`lactol, molgramostim, nafarelin, nartograstim, nedaplatin,
`
`10
`nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin,
`parnidrouic acid, pegaspargase, pentosan polysulfate sodium,
`pentostatin, picibanil, pirarubicin, porfimer sodium, ralox(cid:173)
`ifene, raltitrexed, rasburicase, rituximab, romurtide, sargra(cid:173)
`mostim, sizofiran, sobuzoxane. sonennin, suramin, tasoner(cid:173)
`min, tazarotene, tegafur,
`temoporfin, temozolomide,
`teniposide, tetracWorodecaoxide, thalidomide, thymalfasin,
`thyrotropin alfa, topotecan, toremifene. trastuzumab, treosul(cid:173)
`fan, tretinoin, trilostane, trimetrexa