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`International application number: PCT/IB2010/054866
`
`International filing date:
`
`27 October 2010 (27.10.2010)
`
`Document type:
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`61/293,903
`Number:
`11 January 2010 (11.01.2010)
`Filing date:
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`HIPO
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`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
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`August 25, 2010
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`THE RECORDS OF THE UNITED STATES PATENT AND TRADEMARK
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`APPLICATION NUMBER: 61/293,903
`FILING DATE: January 11, 2010
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`PARIS
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`By Authority of the
`Under Secretary of Commerce for Intellectual Property
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`
`Title of Invention:
`
`NOVEL ANTITUMORAL USE OF CABAZITAXEL
`
`First Named Inventor/Applicant Name:
`
`Sunil GUPTA
`
`Customer Number:
`
`05487
`
`Filer:
`
`Kelly L Bender/Linda
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`Remer
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`sanofi-aventis Docket No. FR2009/121 US
`
`PSP1
`
`In re Application of:
`GUPTA
`
`Application No.:
`Not Yet Assigned
`
`Filed:
`Concurrently Herewith
`
`Examiner:
`Not Applicable
`
`Art Unit:
`Not Applicable
`
`Conf. No.:
`Not Yet Assigned
`
`Title
`NOVEL ANTITUMORAL USE OF CABAZITAXEL
`
`TRANSMISSION
`EPS-WEB
`CERTIFICATF. OF
`I hereby certify that the
`correspondence
`
`below is being transmitted via the
`USPTO's
`electronic filing system
`in
`
`accordance with 1.6(aX4),
`on
`
`11 January 2010
`Date of Deposit
`
`Signature
`
`/Linda J. Remer/
`
`TO: Commissioner for Patents
`P. O. Box 1450
`Alexandria, VA 22313-1450
`
`Attached are
`
`the following
`
`documents:
`
`Application Data Sheet
`
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`Number of Pages
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`12
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`and
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`Specification
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`sanofi-aventis U.S.
`
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`00006
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`

`
`FR2009/121 US PSP1
`
`NOVEL ANTITUMORAL USE
`
`
`
`OF CABAZITAXEL
`
`in the treatment of prostate
`
`novel antitumoral use of cabazitaxel
`
`invention relates to a
`The present
`cancer, which may be metastatic, especially for patients who are not catered for by a taxane-
`based treatment. In particular, the present invention relates to the use of cabazitaxel in the
`treatment of patients with castration resistant metastatic prostate cancer, who have been
`previously treated with a docetaxel based regimen, an unmet medical need.
`
`[Technical problem]
`Prostate cancer affects a large proportion of the male population worldwide: 680 000 cases
`worldwide in 2002; it is predicted that there will be 900 000 new cases per year up to 2010 (CA
`Cancer J. Clin., 2005, 55, 74-108). It is the most frequently occurring cancer in men after lung
`cancer.
`
`Prostate cancer is generally treated at the start by depriving the androgenic hormones, i.e. by
`
`Therapy for Prostate Cancer
`surgical excision of the testicles The Current State of Hormonal
`CA Cancer J. Clin.,
`May 2002; 52: 154-179, or by radiotherapy treatment External beam
`for prostate
`cancer
`
`CA Cancer J. Clin., Nov. 2000; 50: 349-375. Treatments
`radiation therapy
`with antiandrogens or hormone manipulations are associated with responses of short duration
`and without any
`
`
`in improvement the survival time.
`
`The use of cytotoxic chemotherapy is not a routine treatment, whereas
`its role in alleviating the
`symptoms and reducing the levels of PSA (prostate-specific antigen) is established. No
`monotherapy has obtained a
`degree
`
`
`of response greater than 30%; combinations with an effect of
`
`on PSA levels were tested. No effect on the survival time was seen and, what is more, the
`toxicity of these treatments, particularly on elderly patients, is problematic since, in addition to
`their tumour, they are generally
`
`
`from suffering related health problems and have a limited reserve
`of bone marrow.
`
`Until recently, the chemotherapies used were limited to cyclophosphamide, anthracyclines
`(doxorubicin or mitoxantrone) and estramustine, and the effects of these treatments
`are
`mediocre. Palliative effects were observed in patients following the administration of corticoids
`alone or of mitoxantrone with either prednisone or hydrocortisone. Following Phase II trials, the
`combination of mitoxantrone with corticoids was recognized as the reference treatment for
`hormone-resistant prostate cancer. More recently, treatments with docetaxel in combination with
`estramustine or prednisone have made it possible to treat cancers that are resistant to hormone
`deprivation Advances in Prostate Cancer Chemotherapy: A New Era Begins CA Cancer J.
`Clin., Sep. 2005;
`55:
`300-318,
`the
`
`survival by 2.4 months. was
`
`improved
`
`relatively
`
`5
`
`1 0
`
`15
`
`2 0
`
`25
`
`30
`
`35
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00007
`
`

`
`FR2009/121 US PSP1
`
`are difficult to evaluate
`
`in advanced prostate cancers
`It is generally accepted that the responses
`regarding
`the
`on account of the heterogeneity
`
`of the disease
`and
`
`the lack of consensus
`
`
`response criteria. Many patients metastatic prostate with
`
`cancer
`have no measurable
`disease,
`have symptoms
`dominated by bone metastases. Measurement of the PSA level has been found
`to be a means for evaluating
`novel
`
`candidates also the measurement and
`
`of the
`
`tumour when this
`is possible, the measurement of bone tumours, the quality of life and the measurement of the
`pain.
`
`treatment
`but
`
`Furthermore, cancer may become resistant to the agents used, in particular to taxanes, which
`limits the possible treatment options. Several taxane resistance mechanisms have been
`described (expression of P-glycoprotein P-gp, mdr-1 gene, modified metabolism of taxane,
`mutation of the tubulin gene, etc.): see Drug Resistance Updates 2001, 4(1), 3-8; J. Clin. One.
`1999, 17(3), 1061-1070.
`
`The technical problem that the invention intends to solve is that of providing a novel therapeutic
`option for treating prostate cancer, especially for patients who are not catered for by a taxane-
`
`who have
`based treatment, such as patients with castration resistant metastatic prostate cancer
`been previously treated with docetaxel (sold under the
`brand name Taxotere®) based
`regimen,
`unmet medical need.
`
`an
`
`Four clinical trials on cabazitaxel are known since April 2006. Three monotherapy tests have
`made it possible to determine
`the maximum tolerated dose and the toxicities at the limit doses:
`these
`tests were performed on breast, sarcoma and prostate tumours. Doses of 10-30 mg/m2
`every three
`
`used. hours were A phase II trial was performed on patients with a breast cancer, who
`
`
`had previously received taxanes and
`anthracyclines
`as
`adjuvant
`(i.e. a first-
`
`line treatment. The response
`
`levels were 14.6% as adjuvant and
`
`as 9.5% second-line
`treatment.
`
`
`
`[Brief description of the invention]
`The invention relates to a novel antitumoral pharmaceutical therapeutic use comprising
`cabazitaxel of formula
`
`5
`
`10
`
`1 5
`
`2 0
`
`2 5
`
`3 0
`
`Copy
`
`provided
`
`by
`
`Image
`
`
`
`USPTO Database
`
`on
`
`from
`
`08/24/2010
`
`00008
`
`

`
`FR2009/121 US PSP1
`
`?H3
`
`O
`
`H3C
`
`H3C
`
`H
`
`Q
`
`H3C
`
`HN
`
`Oi"1^
`
`o*
`HO
`
`H
`
`?H3
`I
`o
`
`/CH3
`o
`o
`CH3
`
`CH3
`
`CH./=
`
`HO
`o
`
`o
`
`H ^ o y
`
`.0
`
`CH3
`
`o
`
`The invention also relates to methods of treating patients with prostate cancer comprising
`administering
`the
`antitumoral
`agent
`cabazitaxel said patient.
`
`to
`
`intended
`base, hydrate or a solvate, a
`
`
`This antitumoral agent may be in the form of anhydrous
`treating prostate cancer, in particular for treating patients who are not catered for by a taxane-
`based treatment, such as patients who have been previously treated with a docetaxel-based
`regimen.
`This compound is preferably administered to a patient with advanced metastatic
`disease.
`In particular, the
`
`compound is administered to a patient with castration resistant prostate
`cancer. Cabazitaxel is preferably administered in combination with a corticoid chosen especially
`from prednisone and prednisolone. This corticoid is preferably administered at a daily dose
`10
`mg orally.
`
`of
`
`for
`
`Cabazitaxel may be administered at a dose (defined for each administration) of between 20 and
`25 mg/m2. Cabazitaxel may be in the form of an acetone solvate. More particularly, the acetone
`solvate of cabazitaxel contains between 5% and 8% and preferably between 5% and 7% by
`weight of acetone.
`
`Cabazitaxel may be administered by intravenous infusion at a dose
`and 25 mg/m2,
`of between 20
`an
`
`interval of 3 weeks between
`this administration cycle
`
`of the antitumour agent
`
`being repeated at
`each cabazitaxel administration, which interval may be prolonged by 1 to 2 weeks depending on
`the tolerance
`to
`the
`preceding
`
`cabazitaxel administration.
`
`5
`
`10
`
`15
`
`2 0
`
`25
`
`[Brief Description of the Drawings]
`Figure 1 displays
`the
`
`
`
`
`
`
`
`
`in curves Kaplan-Meier of the overall survival a cabazitaxel
`
`study.
`
`Figure 2 displays
`
`the
`
`Kaplan-Meier
`
`
`
`curves progression-free
`
`
`
`of survival
`
`
`
`in a cabazitaxel
`
`study.
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00009
`
`

`
`FR2009/121 US PSP1
`
`~ 4 ~
`
`invention]
`
`[Description of the
`Definitions
`• Effective amount, as used herein, means an amount of a pharmaceutical compound,
`cabazitaxel,
`that
`
`produces an effect on the
`cancer
`to
`be
`treated.
`
`5
`
`
`
`such as
`
`Cabazitaxel belongs
`
`to
`
`the
`
`
`
`taxoid has the formula: family
`
`
`
`and
`
`9H3
`I
`o
`
`CH3
`o
`/
`o
`CH3
`
`9H3
`
`o
`
`O
`
`HN
`
`H
`
`O
`
`H3C
`
`H3C
`
`H3C
`
`HO
`
`H
`
`CH3
`
`CH
`
`HO
`o
`
`o
`
`o
`
`CHg
`
`H ^ o y
`
`o
`
`1 0
`
`15
`
`2 0
`
`25
`
`The chemical name
`of cabazitaxel is 4a-acetoxy-2a-benzoyloxy-5(3,20-epoxy-1 p-hydroxy-7p,103-
`
`dimethoxy-9-oxo-11-taxen-13a-yl
`(2R,3S)-3-fe/t-butoxycarbonylamino-2-hydroxy-3-
`phenylpropionate. Cabazitaxel is synonymously known as (2a,5|3,7p,10p,13a)-4-acetoxy-13-
`({(2R,3S)-3-[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1 -hydroxy-7,10-
`dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl
`benzoate.
`
`in WO 96/30355, EP 0 817 779 B1
`a This compound and preparative method thereof is described
`
`
`and US 5 847 170. Cabazitaxel may be administered in base form (cf. above formula), or in the
`form of a hydrate. It may also be a solvate, i.e. a molecular complex characterized by the
`incorporation of the crystallization solvent into the crystal of the molecule of the active principle
`Sci. 1975, 64(8), 1269-1288). In particular, it may be
`(see in this respect page 1276 of J.
`Pharm.
`an acetone solvate, and, more particularly, may be the solvate described in WO 2005/02846. It
`may be an acetone solvate of cabazitaxel containing between 5% and 8% and preferably
`between 5% and 7% by weight of acetone (% means content of acetone/content of
`acetone+cabazitaxel
`*
`
`100). average value An
`
`of the
`acetone
`
`content approximately is
`
`represents the acetone stoichiometry, which is 6.5% for a solvate containing one molecule of
`acetone. The procedure described below allows the preparation of an acetone solvate of
`cabazitaxel:
`
`7%,
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00010
`
`

`
`FR2009/121 US PSP1
`
`to a solution of 207 g of 4a-
`940 ml of purified water are added at 20±5oC (room temperature)
`acetoxy-2a-benzoyloxy-5p,20-epoxy-1 p-hydroxy-7(3,10|3-dimethoxy-9-oxo-11-taxen-13a-yl
`(2R,3S)-3-fe/t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate at about 92% by weight in
`about 2 litres of acetone, followed by seeding with a suspension of 2 g of 4a-acetoxy-2a-
`(2R,3S)-3-ferf-
`benzoyloxy-53,20-epoxy-1 (B-hydroxy-7(3,103-d i methoxy-9-oxo-11 -taxen-13a-yl
`butoxycarbonylamino-2-hydroxy-3-phenylpropionate isolated from acetone/water in a mixture of
`20 ml of water and 20 ml of acetone. The
`resulting mixture is stirred
`for about 10
`to 22
`hours,
`1.5 litres of purified water are
`added
`
`4 over hours. This mixture
`
`
`
`to is stirred 5 for 60 to 90 minutes,
`
`and the suspension is then filtered under reduced pressure. The
`cake
`
`is washed on the filter with
`a solution prepared from 450 ml of acetone and 550 ml of purified water, and then oven-dried at
`550C under reduced pressure (0.7 kPa) for 4 hours. 197 g of 4a-acetoxy-2a-benzoyloxy-5p,20-
`epoxy-1 P-hydroxy-7p, 10P-dimethoxy-9-oxo-11 -taxen-13a-yl (2R,3S)-3-terf-butoxycarbonylamino-
`2-hydroxy-3-phenylpropionate acetone containing 0.1% water and 7.2% acetone (theoretical
`amount: 6.5% for a stoichiometric solvate) are obtained.
`
`and
`
`Cabazitaxel may be administered parenterally, such
`administration. galenical
`
`intravenous
`via
`as
`form of cabazitaxel suitable for administration by intravenous infusion is that in which the
`cabazitaxel is dissolved in water in the presence of excipients chosen from surfactants,
`cosolvents, glucose
`or
`
`chloride, sodium etc. For example, a
`
`
`galenical form of cabazitaxel may be
`prepared by diluting a premix solution of cabazitaxel contained in a sterile vial (80 mg of
`cabazitaxel + 2 ml of solvent + Polysorbate 80) with a sterile vial containing a solution of 6 ml of
`water and ethanol (13% by weight of 95% ethanol)
`in order
`to
`obtain
`8
`ml of ready to be
`
`rediluted in a perfusion bag. The concentration of cabazitaxel in this ready-to-redilute
`solution is
`about 10 mg/ml. The perfusion is then prepared by injecting the appropriate
`amount
`of this
`to-redilute solution into the perfusion bag containing water and glucose (about 5%) or sodium
`chloride (about 0.9%).
`
`a
`
`ready-
`
`5
`
`10
`
`15
`
`2 0
`
`25
`
`Cabazitaxel may be administered in combination with a corticoid, such as prednisone or
`prednisolone, as
`
`two distinct pharmaceutical preparations.
`
`30
`
`Accordingly, one aspect of the invention is a method of treating prostate cancer comprising
`administering
`to a patient in need thereof an effective amount
`
`of cabazitaxel
`in combination with a
`corticoid, such
`as
`prednisone
`or
`prednisolone.
`
`35
`
`The combination is administered repeatedly according
`the to
`
`on
`a to protocol that depends
`
`
`be treated (age, weight, treatment history, etc.), which can be determined by a skilled physician.
`is administered by perfusion to
`the patient according
`In one aspect of the invention, cabazitaxel
`
`to
`
`patient
`
`Copy provided by USPTO
`
`from the IFW
`
`Image Database
`08/24/2010
`on
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`FR2009/121 US PSP1
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`an intermittent program with an interval between each administration of 3 weeks, which may be
`prolonged by 1 to 2 weeks depending on the tolerance to the preceding administration. The
`prednisone or prednisolone may be administered daily, for example in the form of one dosage
`intake per day, throughout the duration of the treatment. Examples of doses for the two
`antitumoral agents are
`
`given in the "Example" section. The recommended dose is 25 mg/m2 of
`
`mg cabazitaxel and 10 per day of prednisone
`
`or
`prednisolone.
`
`that is resistant to
`In one aspect of the invention, the patient to be treated has prostate cancer
`hormone therapy and has previously been treated with docetaxel. In another aspect, the patient
`has prostate cancer that progressed during or after treatment with docetaxel. In another aspect,
`the patient was previously treated with at least 225 mg/m2cummulative dose of docetaxel. In a
`particular aspect, the patient showed progression of their disease in the six months following
`hormone therapy
`or
`during
`
`docetaxel treatment or after
`docetaxel
`
`treatment. In another particular
`aspect, the patient showed progression of their disease in the three months following hormone
`therapy or after docetaxel
`treatment.
`
`tumour and may
`In another aspect of the invention, the patient to be treated has a measurable
`show progression of the disease
`soft
`tissue
`
`via a metastatic
`lesion of the viscera or
`of a
`1 cm determined by MRI or by an axial
`tomographic
`scan
`(CT
`scan).
`
`of at
`
`tumour may
`
`patient the be treated has an unmeasurable to
`
`
`
`invention,
`of the
`In another aspect
`show an increase in the PSA level with three measurements at a 1-week interval or the
`appearance
`of new
`lesions.
`
`and
`
`In another aspect of the invention, the patient to be treated has undergone castration by
`orchidectomy or with LHRH agonists, elimination of the androgens or monotherapy with
`estramustine.
`
`In a preferred aspect,
`
`the
`
`life expectancy
`
`
`
`of the to be treated patient
`
`
`
`should be at
`
`least 2 months.
`
`In one aspect, the treatment does not include patients who have previously received
`mitoxantrone, or who have received less than 225 mg/m2 of docetaxel, or who have undergone a
`radiotherapy that has eliminated more than 40% of the marrow, who have received a treatment
`within the 4 weeks preceding the test, who have a neuropathy or
`a
`
`stomatitis, involving the brain
`or the meninges, who have shown severe
`
`hypersensitivity to polysorbate or
`
`to prednisone, whose
`blood analysis shows an appreciable decrease in neutrophils, haemoglobin or platelets, an
`increase in bilirubin and/or liver enzymes and creatinine, or who have heart problems or an
`infection requiring antibiotics.
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
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`3 0
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`35
`
`Cabazitaxel may be administered in combination with a medication to prevent or control nausea
`and vomiting or to prevent or control hypersensitivity to the cabazitaxel treatment. Preferably, a
`patient is pre-medicated with the medication, for example, at least 30 minutes prior to
`administering each
`
`of dose cabazitaxel.
`
`
`Examples of medications which may be used to prevent or control nausea and vomiting include
`histamine H2 antagonists and antiemetics, such as ondansetron, granisetron and dolesetron.
`Examples of medications which may be used to prevent hypersensitivity to the cabazitaxel
`treatment include antihistamines, such as dexchloropheniramine (preferably 5 mg), and
`diphenhydramine (preferably 25 mg) or equivalent antihistamines; and corticosteroids, such as
`dexamethasone
`(8 mg) or
`an
`equivalent
`steroid.
`
`A possible side
`with is neutropenia, which is characterized by a
`treatment cabazitaxel
`
`
`of the
`effect
`If neutropenia occurs, cabazitaxel treatment may be
`reduced number of neutrophils.
`discontinued, and restarted when neutrophil counts recover to a level of >1,500 /mm3. The
`present
`invention therefore also relates to a method of treating prostate cancer with cabazitaxel
`comprising administering cabazitaxel to the patient, monitoring blood counts in the patient,
`measuring neutrophil levels, discontinuing cabazitaxel treatment if neutropenia occurs, and
`optionally restarting cabazitaxel treatment when neutrophil counts recover to a level of >1,500
`/mm3
`
`One aspect of the invention is a method of reducing the risk of neutropenia comprising
`administering cabazitaxel in combination with an agent useful for treating neutropenia. Such a
`neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the
`as
`
`human a granulocyte colony stimulating
`
`factor,
`production and function of neutrophils such
`CSF).
`In a particular aspect of the invention, the neutropenia is complicated neutropenia.
`Complicated neutropenia includes febrile neutropenia, prolonged neutropenia, or neutropenic
`the
`neutropenia
`
`treatment agent is administered prior to the
`infection. In a preferred embodiment,
`administration of cabazitaxel.
`
`(G-
`
`[Example]
`A clinical study was performed wherein patients received either treatment with cabazitaxel or
`reference
`treatment based on mitoxantrone each
`combined with prednisone or prednisolone.
`
`the
`
`More specifically, patients with metastatic castration resistant metastatic prostate cancer, ECOG
`PS 0—2, and adequate organ function who had had prior hormone therapy, chemotherapy, and
`radiotherapy, but had progressive during or after docetaxel treatment (cumulative dose 2225
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
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`FR2009/121 US PSP1
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`mg/m2) were randomized to 10 mg/day of prednisone with either mitoxantrone 12 mg/m2
`
`cabazitaxel 25 mg/m2, administered 3-weekly. both
`
`
`or
`
`720 patients were planned to be included in the clinical study: 360 in each cabazitaxel +
`prednisone and mitoxantrone + prednisone group. Seven hundred and fifty-five patients (755)
`(median age 68; 84% white) were actually enrolled, 378
`in
`the cabazitaxel and
`prednisone/prednisolone
`group and 377 in the mitoxantrone and prednisone/prednisolone
`group.
`The median number of treatment cycles was 6 for cabazitaxel and 4 for mitoxantrone. The
`median prior dose of docetaxel treatment was 576 mg/m2 for the cabazitaxel group and 529
`mg/m2 for the mitoxantrone
`group. Median follow-up was
`12.8
`months.
`
`The measurements
`performed via the same
`of the results are
`
`computed tomographic
`(CT) scans
`are
`
`as
`tests
`preferably
`
`at and spiral
`
`used.
`
`inclusion.
`
`following criteria:
`the
`evaluated according to
`
`The results are
`
`the date of death
`overall survival (OS): the time from inclusion to the study
`to
`lesions
`complete response
`(CR): disappearance
`of the
`
`of 30% of the largest diameter reduction the lesion
`
`
`partial response
`(PR):
`at
`least
`
`progression (PD): at least 20% increase in the sum of the largest diameter of the lesion or
`of one
`or
`more
`new
`lesions
`appearance
`stable disease
`(SD):
`
`reduction of the tumour
`insufficient
`to be included in PR and increase of
`the tumour
`insufficient
`to
`be
`included in PD.
`
`
`5
`
`10
`
`15
`
`2 0
`
`The confirmations of the measurements
`has been established
`for
`the
`
`are made at least 4 weeks after the response
`first
`time.
`
`2 5
`
`criterion
`
`The progression-free survival (PFS) is the time from inclusion in the study and the date of
`progression or death when the progression is either an increase of the PSA, or of the tumour, or
`of the pain.
`
`It was found that the combination of cabazitaxel and prednisone is a well-tolerated combination
`with the safety profile of taxanes. At the dose
`
`investigated in this trial (LD2: 25 mg/m2 cabazitaxel
`+ 10 mg/m2/day prednisone), patients receiving cabazitaxel demonstrated statistically significant
`longer overall survival (OS) compared to mitoxantrone (p<0.0001).
`The hazard ratio was 0.70
`(95%CI. 0.59, 0.83)
`
`
`of in favor cabazitaxel corresponding
`to
`30% a reduction in risk of death. The
`
`
`median survival for patients in the cabazitaxel group was 15.1 months in comparison to 12.7
`months in the mitoxantrone group.
`
`30
`
`35
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
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`FR2009/121 US PSP1
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`— 9 —
`
`The data
`
`related to the treated patients
`
`
`
`given are Table 1:
`
`
`
`in
`
`Table 1: Efficacy analysis
`
`(intention-to-treat)
`
`PFS
`
`Overall survival Median (months)
`Hazard ratio (95% CI)
`p-value1
`Median (months)
`Hazard ratio (95% CI)
`p-value1
`Tumor response
`rate
`p-value2
`PSA Response
`p-value2
`PSA PFS
`
`rate
`
`Median (months)
`Hazard ratio (95% CI)
`p-value1
`rate
`
`Pain Response
`p-value2
`Pain PFS
`
`5
`
`1 Log-rank test,
`
`Median (months)
`Hazard ratio (95% CI)
`p-value1
`^Chi-square
`
`test
`
`CbzP
`MP
`N=377
`N=378
`Median
`Median
`(months)
`(months)
`12.7
`15.1
`0.70 (0.59; 0.83)
`0.0001
`
`0.86)
`
`1.4
`2.8
`0.74 (0.64 -
`0.0001
`
`14.4%
`
`39.2%
`
`4.4%
`0.0005
`17.8%
`0.0002
`
`3.1
`6.4
`0.75 (0.63 - 0.90)
`0.0010
`
`9.2%
`
`7.8%
`
`0.6526
`Not reached
`11.1
`0.91 (0.69-1.19)
`0.5192
`
`CbzP : cabazitaxel with prednisone
`MP: mitoxantrone with prednisone
`
`Progression free survival (PFS) defined as the earliest progression in tumor, PSA or pain was
`also statistically
`significantly longer
`in the cabazitaxel group
`
`compared the mitoxantrone group to
`
`(p<0.0001, hazard ratio = 0.74
`(95%CI, 0.64,
`
`and 0.86), the median progression-free
`
`survival was
`2.8 months versus 1.4 months. Response
`rates
`
`
`and PFS for PSA and tumor assessments
`were
`statistically significant
`in favor
`of cabazitaxel,
`while
`response
`rate not show a
`
`statistically significant difference.
`
`10
`
`15
`
`The most frequent Grade
`observed with a higher frequency in the
`toxicities 3/4 were neutropenia
`
`
`cabazitaxel group
`
`with 81.7% compared to the mitoxantrone group with 58.0%. Rates of febrile
`neutropenia were
`
`7.5% the cabazitaxel group in
`
`and
`1.3% the mitoxantrone group. in
`
`
`
`2 0
`
`Subgroup analyses by risk factors and a multivariate analysis showed that OS outcomes were
`consistent and
`
`robust in favor of cabazitaxel as shown in the herebelow
`table:
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
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`FR2009/121 US PSP1
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`- 1 0 -
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`Table 2
`
`CbzP
`Median OS
`(mos)
`15.1
`14.2
`
`N (%)
`378(100)
`113(30)
`
`10.3
`
`17.7
`
`158(42)
`
`103(27)
`
`13.9
`
`17.5
`
`MP
`Median OS
`(mos)
`12.7
`12.0
`
`N (%)
`ITT
`377 (100)
`PD while on D
`103 (27)
`PD after last D
`dose, S3 mos 180 (48)
`PD after last D
`91(24)
`dose, >3 mos
`
`CbzP vs MP
`
`HR (95%CI)
`0.70 (0.59-0.83)
`0.65 (0.47-0.90)
`
`0.70 (0.54-0.90)
`
`0.78(0.53-1.14)
`
`5
`
`mos = months
`D = Docetaxel
`
`The results of this study are further illustrated
`
`to
`
`Figures
`
`1
`
`and
`
`2.
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00016
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`

`
`FR2009/121 US PSP1
`
`- 1 1 -
`
`CLAIMS
`
`What is claimed is:
`1.
`Antitu moral pharmaceutical use comprising cabazitaxel of formula
`CH3
`I
`o
`
`?H3
`
`O
`
`H3C
`
`H3C
`
`HN
`
`H O
`
`H3C
`
`Oil!1
`
`o'
`HO
`
`H
`
`CH3
`
`CH.
`
`HO
`o
`
`o
`
`yCH3
`o
`o
`CH3
`
`.0
`
`|_| C
`
`O Y O
`
`CH3
`
`5
`
`which may be in base form or in the form of a hydrate or a solvate, intended for treating
`prostate cancer, especially for patients who are not catered for by a taxane-based
`treatment, in combination with prednisone or prednisolone.
`
`1 0
`
`2.
`
`Use according to Claim 1, comprising an
`
`effective amount of cabazitaxel.
`
`Use according to Claim 1 or 2, in which the cabazitaxel is in the form of an acetone
`solvate.
`
`15
`
`4.
`
`Use according to Claim 3, in which the acetone solvate of cabazitaxel contains between
`
`and 7% weight of acetone. by
`
`5% and 8% and preferably between 5%
`
`20
`
`5.
`
`6*
`
`Use according to Claims 1 to 4, in which the cabazitaxel is administered at a dose
`(defined for each administration) of between 15 and 25 mg/m2 and the prednisone or
`prednisolone is at a dose of 10 mg/day.
`
`Use according to Claims 1 to 4, wherein the patients have castration resistant metastatic
`prostate cancer who have been previously treated with docetaxel based regimen.
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`
`00017
`
`

`
`FR2009/121 US PSP1
`
`- 1 2 -
`
`Abstract
`
`The invention relates to an antitumoral pharmaceutical combination comprising cabazitaxel of
`formula:
`
`o TOI,
`
`?H»
`
`HjC
`
`H3C
`
`HN
`
`H
`
`O
`
`H3C
`
`On"
`
`o'
`HO
`
`H
`
`HO
`o
`
`CH3
`I
`o
`
`/CH3
`o
`o
`CH3
`
`CH3
`
`CH„/=
`H ^
`
`O
`
`O Y O
`
`CH3
`
`o
`
`5
`
`in the form of a
`form, or
`and prednisone or prednisolone, these two agents possibly being in base
`hydrate or a solvate, intended for treating metastatic prostate cancer, especially for patients who
`are not catered for by a
`taxane-based treatment.
`
`Copy provided by USPTO from the IFW Image Database on 08/24/2010
`