Sanofi Ref. FR2009/121 US CNT
`
`US Application No. 13/456,720
`
`39.
`
`BMS's recombinant, human monoclonal
`
`antibody Yervoy® (ipilimumab)
`
`is approved for tlie treatment of unresectable
`
`
`
`or metastatic myeloma. December 2013 Yervoy
`
`Labeling. A phase I/II study evaluating ipilimumab
`
`
`
`alone or in combination with radiotherapy in
`
`patients with mCRPC "suggested clinical
`
`antitumor
`
`
`
`activity with disease control and manageable
`
`AEs [adverse events]." Slovin et aL, Ipilimumab Alone or in Combination with Radiotherapy in
`
`Metastatic Castration-Resistant Prostate Cancer: Results from an Open-Label, Multicenter
`
`Phase I/II Study, 24 Annals of Oncol. 1813-21, 1813
`
`
`
`(2013). Eight patients receiving
`
`ipilimumab and radiotherapy had PSA declines greater
`
`than
`
`
`
`to equal or 50%. and one had a
`
`
`
`
`
`complete response with a duration of
`
`Id. Another phase 11 study comparing
`over 11.3 months.
`
`
`
`
`
`
`
`to ipilimumab as a single agent combination therapy with docetaxel in CRPC patients reported
`
`of more than 50%. Small et al. Randomized
`three patients in each arm with a PSA decrease
`
`
`
`Phase II Study Comparing 4 Monthly Doses of
`
`Ipilimumab (MDX-010) as a Single Agent or in
`
`Combination with a Single Dose of Docetaxel in Patients with Hormone-Refractory Prostate
`
`Cancer, 24(18S) J. Clin. Oncol
`
`(Meeting Abstracts)
`
`S4609
`
`
`
`
`
`2006). (June The authors concluded
`
`Id. In September 2013 BMS reported that
`that further studies in prostate cancer were warranted.
`
`a phase 111, double-blind study comparing
`
`ipilimumab
`
`to
`
`placebo
`
`following
`
`radiation
`
`in
`
`patients
`
`with advanced mCRPC who had previously
`
`received
`
`
`
`treatment with docetaxel no
`
`showed
`
`statistically significant improvement in
`
`overall survival,
`
`the
`
`Bristol-Myers
`endpoint.
`primary
`
`Squibb Reports Results for Phase 3 Trial of Yervoy® (Ipilimumab) in Previously-Treated
`
`Castration Resistant Prostate Cancer, Business Wire NewsHQ Press Release (September
`
`12,
`
`2013), httT)://news.bms.cotn/'press-release/fd-»esvs/'bristol-royers-SGuibb-reports-res'ults-Dha$c-3-
`
`The phase II data did not translate
`
`
`
`into phase III success.
`
`14
`
`00177
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`
`

`
`Sanofi Ref. FR2009/121 US CNT
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`US Application No. 13/456,720
`
`40. to
`
`April 2014 OrscoGetiex announced that custirsen plus docetaxel and
`
`prednisone in first line therapy did not provide a statistically significant
`
`improvement
`
`in
`
`overall
`
`survival in men with mCRPC compared to docetaxel plus prednisone alone. OncoGenex
`
`Announces Top-Line Survival Results of Phase 3 SYNERGY Trial Evaluating Custirsen for
`
`Metastatic Castrate-Resistant Prostate Cancer, Acquire Media Press Release
`
`(April 28,
`
`2014),
`
`lntp;/V'ir.o?icoa&riex,com/re!eas&detail,cfin?R&ieaseID:::842949. A phase 11 trial evaluaiing
`
`custirsen plus docetaxel and prednisone compared
`
`to
`
`docetaxel
`
`plus
`
`prednisone
`
`in
`
`chemotherapy-naive mCRPC had indicated an increase in overall survival with
`
`custirsen,
`
`and
`
`19% of patients had a
`
`partial
`
`Zielinski & Chi, Custirsen (OGX-Q11): A Second-
`response.
`
`Generation Antisense Inhibitor of Clusterin in Development for the Treatment of Prostate
`
`Cancer, 8(1) Future Oncol. 1239-51, 1245-46 (2012). A phase II trial evaluating custirsen plus
`
`docetaxel in mCRPC patients
`
`
`
`previously treated with docetaxel
`
`also
`
`reported 15%
`
`of
`
`patients
`
`having a partial
`
`response
`
`of patients as having a
`40%
`and
`
`PSA
`
`Id. at 1246.
`response.
`
`41.
`
`In June 2014 Takeda. announced that
`
`it was terminating development of
`
`orteronel, an inhibitor of 17,20 -lyase, after
`
`two
`
`disappointing
`
`phase
`
`III
`
`trials
`
`in
`
`mCRPC.
`
`Takeda Announces Termination of Orteronel (TAK-700) Development for Prostate Cancer in
`
`Japan, U.S.A. and Europe, Takeda Latest News Release
`
`(June
`
`19,
`
`2014),
`
`
`
`lritp;//ww-.takeda.coin/new;s/2014/20140619 6615.html. The first reported phase III trial was
`
`in men with mCRPC that had progressed during
`
`or
`
`following
`
`Id. An interim
`chemotherapy.
`
`analysis indicated that orteronel plus prednisone would not
`
`likely
`
`meet
`
`the
`
`primary
`
`endpoint
`
`overall survival. Id. The second phase III failure was in men with mCRPC who had not
`
`previously received
`
`chemotherapy. Id. There was no
`
`significant improvement in
`statistically
`
`overall survival, one
`
`of
`
`the
`
`Id. These failures came
`primary endpoints.
`
`
`
`after at least six phase 1
`
`15
`
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`
`

`
`Sanofi Ref. FR2009/121 US CNT
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`US Application No. 13/456,720
`
`and II studies in patients with CRPC. Van Hook et a!., Orteronel for the Treatment of Prostate
`
`Cancer, 10(5) Future Oncol. 803-11, 807 (2014). A phase II study of orteronel plus docetaxei
`
`and prednisone in mCRPC
`
`
`
`patients reported an overall objective response rate of 56%, with 72%
`
`of men experiencing a PSA. decline of more
`
`equal to 50%. Id. at 805-06. A phase 1/11
`than or
`
`study of orteronel in chemotherapy naive mCRPC
`
`patients
`
`
`
`with prednisone reported or without
`
`
`
`an objective response rate of 19% with 41-63%
`
`of patients
`
`experiencing
`
`a PSA
`
`decline
`
`of more
`
`than or equal to 50% depending on dose and
`
`the
`
`addition
`
`Id. at 807.
`of prednisone.
`
`42.
`
`
`
`Anionarakis and Eisenberger report on the failure of eight phase III
`
`clinical trials in patients with mCRPC. These trials were of eight different combination therapies
`
`with docetaxei: bevacizumab, aflibercept, atrasentan, zibotentan, dasatinib, GVAX,
`
`lenalidomide, and calcitriol. Anionarakis & Eisenberger at 1709-10. The authors suggest thai
`
`these late stage failures could be
`
`reduced
`
`
`
`if more stringent standards were required
`
`in
`
`
`
`phase 11
`
`before proceeding to phase III. Id. at 1711 ("[Pjhase III trials should not be pursued without
`
`the
`
`prior conduct of at least one phase
`
`II study
`
`that has met
`
`a prespecified
`
`rationally
`
`selected
`
`end point and its predefined metric
`
`for success
`
`. . .
`
`43.
`
`A person of ordinary skill would have understood, as can be seen
`
`from
`
`the
`
`above mentioned studies, that
`
`it would have been
`
`extremely difficult
`
`to predict
`
`whether
`
`a
`
`compound would provide a clinically meaningful
`
`benefit
`
`such
`
`
`
`as prolongation of survival in
`
`mCRPC patients while providing a reasonable
`
`side
`
`effect
`
`profile,
`
`even
`
`after
`
`positive
`
`phase
`
`results in the same indication. This understanding was true
`
`in
`
`2009
`
`and remains
`
`true
`
`today.
`
`16
`
`00179
`
`

`
`Sanofi Ref. FR2009/121 US CNT
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`US Application No. 13/456,720
`
`II,
`
`Disclosure of Cited Art
`
`A.
`
`Beardslev
`
`44.
`
`Beardsiey is a review article describing research developments on
`
`a wide
`
`variety of different approaches
`
`to
`
`
`
`treating mCRPC. Of the eleven compounds discussed, only
`
`one is a taxane: cabazitaxel.
`
`45.
`
`
`
`Beardsiey states that XRP6258 (cabazitaxel) "is semi-synthetic a
`
`
`
`taxoid
`
`compound with low affinity for the P-glycoprotein ("P-gp")
`
`drug
`
`efflux
`
`transporter
`
`and
`
`cytotoxic
`
`in cell lines with acquired resistance to paclitaxel or docetaxel." Beardsiey at 163. The P-gp
`
`See, e.g.
`drag efflux transporter is a protein that removes toxins, such as drugs, from cells.
`
`Cabral, Factors Delermining Cellular Mechanisms of Resistance to Antimitotic Drugs, 4 Drug
`
`Resistance Updates 3-8, 3 (2001) ("Cabral").
`It was hypothesized
`
`that one cause of
`
`taxane
`
`
`
`
`
`in resistance was a proliferation of P-gp resistant cells, which pumped the drug out of
`
`the
`
`cell
`
`before it could have an effect. See id.
`
`46.
`
`Beardsiey discloses that a phase II
`
`cabazitaxel was conducted
`of
`study
`
`in
`
`patients with docetaxel-refractory metastatic
`
`breast
`
`cancer,
`
`with an
`
`objective
`
`response
`
`rate
`
`14%. Beardsiey at 163. Two patients reportedly achieved a compieie
`
`
`
`response with a median
`
`response duration of 7.6 months. Id.
`
`47.
`
`Beardsiey notes that "given
`
`
`
`
`
`in its activity the docetaxel refractory setting"
`
`
`
`in a of the phase 11 study in breast cancer, cabazitaxel was being investigated phase III trial
`
`
`
`
`
`"comparing 3-weekly XRP6258 with prednisone
`
`to
`
`with prednisone in patients
`mitoxantrone
`
`with castrate resistant metastatic prostate cancer previously
`
`treated with
`
`docetaxel-containing
`
`treatment." Id. The doses of cabazitaxel and prednisone are not disclosed.
`
`17
`
`00180
`
`

`
`Sanofi Ref. FR2009/121 US CNT
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`US Application No. 13/456,720
`
`48.
`
`Beardsley does not report any results
`
`
`
`from a phase study
`
`
`
`111 on cabazitaxei
`
`or any clinical data from administration of cabazitaxei
`
`to
`
`
`
`patients prostate cancer. In fact, with
`
`
`
`this article simply catalogues
`
`the various approaches
`
`being
`
`used
`
`
`
`or studied that time.
`
`at
`
`B. Mita
`
`49.
`
`Mita describes the results of a phase I and pharmacokinetic
`
`study
`
`of
`
`cabazitaxei administered as a 1-hour
`
`infusion
`
`tumors. The objectives of the study were
`
`to
`
`
`
`
`
`three every weeks in patients with advanced solid
`
`
`
`
`
`the characterize toxicities of cabazitaxei without
`
`premedication, determine the maximum
`
`tolerated dose
`
`and
`
`recommended
`
`dose
`
`for
`
`phase
`
`studies, characterize the pharmacokinetic profile
`
`of
`
`and cabazitaxei, document preliminary to
`
`
`
`
`
`
`
`evidence of antitumor activity. Mita at 724. Phase I studies are not designed for, and
`
`therefore
`
`cannot provide a person of ordinary skill with a reasonable expectation
`
`population.
`
`
`
`of, efficacy a treatment in
`
`
`
`50. Mita discloses that cabazitaxei was more potent
`
`than
`
`docetaxel
`
`in
`
`a broad
`
`array of cancer ceil lines with acquired resistance
`
`to
`
`Id. at 723-24. Although a
`docetaxel.
`
`
`
`substrate for the ATP-dependent drug efflux pump P-gp, cabazitaxei is described as a weaker
`
`substrate than docetaxel. Id. at 723.
`
`51. Mita states that cabazitaxei has "shown
`
`a broad
`
`spectrum
`
`of
`
`antitumor
`
`activity in mice." Id. at 724. However, cabazitaxei did not retain activity
`
`against Calcl8/TXT
`
`and P388/VCR tumors, which Mita describes as expressing higher levels of ABCBI mRNA, the
`
`mRNA coding for P-gp. Id. This finding casts doubt on the
`
`role of P-gp in
`
`cabazitaxel's
`
`ability
`
`to overcome resistance to docetaxel.
`
`52.
`
`Twenty-five patients received cabazitaxei
`
`in
`
`four dose
`
`levels:
`
`10 mg/mJ\
`
`15 mg/mz, 20 mg/m2, and 25 mg/m2. Id. at 726. The patients had a variety of documented
`
`18
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`Sanofi Ref. FR2009/121 US CNT
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`
`advanced solid malignancies "refractory
`
`to conventional
`
`treatment," Id. at 724. Twenty-two
`
`patients (88%) had previously received chemotherapy with
`
`eight
`
`patients
`
`having
`
`received
`
`prior
`
`taxane-based therapy. Id. at 726. Prior anticancer therapy had to be completed at least 28 days
`
`before study enrollment, 42 days for nitrosureas
`
`C. Id. at 72.4. Eight of the
`and mitomycin
`
`iwenty-fTve patients had prostate cancer. Id. at 725.
`
`53. Mita reports that neutropenia was the principal
`
`toxicity
`
`of
`
`Id.
`cabazitaxel.
`
`at 726. Severe neutropenia was reported at
`
`
`
`
`
`25 the mg-'m"' level, with grade 4 events occurring in
`
`8 of the 19 (42%) evaluable courses. Id. Diarrhea was reported in 52% of patients, nausea
`in
`
`40%, and vomiting in 16%). Id. Mita suggests that the gastric toxicities may be caused
`
`by
`
`accumulation of cabazitaxel
`
`in
`
`that constitutively express P-gp
`enterocytes
`
`because cabazitaxel
`
`is
`
`a poorer substrate for the transporter pump than docetaxel. Id. at 728.
`
`54.
`
`Evidence of anti-cancer activity due
`
`to
`
`
`
`cabazitaxel was noted in two
`
`responses. Id. at 727. The first patient was an 80
`prostate cancer patients with confirmed partial
`
`
`
`
`
`to year old male with prostate cancer metastatic the liver and bones whose disease had
`
`
`
`progressed through castration, bicalutamide, diethyl stilbestrol, and mitoxantrone and
`
`
`
`prednisone. Id. He declined further treatment after his sixth course. Id. I note that he had never
`
`
`
`
`
`first received docetaxel, thus cabazitaxel was his taxane.
`
`55.
`
`The second patient was a 50 year old male with hormone and docetaxel-
`
`refractory prostate cancer metastatic
`
`to bone
`
`and
`
`iliac
`
`Id. Progressive disease was
`nodes.
`lymph
`
`noted after eight courses. Id.
`
`56.
`
`Mita states that the "preliminary
`
`antitumor activity
`
`reported"
`
`still
`
`"needs
`
`to be confirmed." Id. at 729,
`
`19
`
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`
`

`
`Sanofi Ref. FR2009/121 US CNT
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`US Application No. 13/456,720
`
`C.
`
`Tannock
`
`57.
`
`Tannock reports the results of a phase
`
`III study
`
`comparing
`
`docetaxel
`
`plus
`
`prednisone with mitoxantrone plus prednisone in metastatic hormone-refractory
`
`prostate
`
`cancer,
`
`also commonly referred to as mCRPC. Treatment with 75 mg/m2 of docetaxel e very three weeks
`
`plus 10 mg daily prednisone
`
`
`
`led to superior survival and improved rates of response "in
`
`terms
`
`of
`
`pain, serum PSA level, and quality of life"
`
`as compared
`
`to
`
`12 mg/m"
`
`of mitoxantrone
`
`weeks plus 10 mg daily prednisone. Tannock at 1502, Cabazitaxel is not mentioned in
`
`this
`
`publication.
`
`58.
`
`Eligible patients had histologically or cytoiogical
`
`confirmed
`
`adenocarcinoma of the prostate with clinical or radiologic evidence of metastatic
`
`disease,
`
`had
`
`disease progression during hormonal
`
`therapy,
`
`and were
`
`receiving
`
`primary
`
`androgen-ablation
`
`maintenance therapy. Id, at 1503. At least four weeks had to have elapsed between withdrawal
`
`of the antiandrogens, six weeks in
`
`the
`
`case
`
`of hicalutamide,
`
`and
`
`
`
`enrollment, to "avoid the
`
`so
`
`as
`
`possibility of confounding as a result of
`
`the response
`
`to
`
`antiandrogen
`
`Id.
`withdrawal."
`
`59.
`
`The primary endpoint was overall survival. Secondary endpoints included
`
`reductions in pain, improvement in
`
`
`
`the quality of fife, reduction in serum PSA levels of at least
`
`50% and objective tumor responses. Id. at 1504. In the discussion section, Tannock states,
`
`"[tnjore important, we found a significant
`
`improvement
`
`in
`
`overall
`
`survival
`
`for
`
`docetaxel
`
`as
`
`compared with mitoxantrone." Id. at 1511.
`
`III.
`
`Prior Art Treatment
`
`of
`
`Prostate
`
`Cancer
`
`60. mCRPC is an incurable condition. The goals of treatment emphasize
`
`symptom control and overall survival, Beardsley at 161. Docetaxel plus prednisone became
`
`the
`
`standard of care in
`
`large part because
`
`two phase-Ill
`
`trials
`
`20
`
`
`
`
`
`a demonstrated survival advantage over
`
`00183
`
`

`
`Sanofi Ref. FR2009/121 US CNT
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`US Application No. 13/456,720
`
`mitoxantrone plus prednisone. See, e.g., id. Mitoxantrone plus prednisone had been previously
`
`shown not to improve survival over prednisone
`
`Berry et ah. Phase HI Study of
`alone.
`
`Mitoxantrone Plus Low Dose Prednisone Versus Low Dose Prednisone Alone in Patients with
`
`Asymptomatic Hormone Refractory Prostate Cancer, 168 J. Urol. 2439-43, 2439, 2442 (2002).
`
`61.
`
`
`
`Unfortunately, as the ' 720 application explains, it was known
`
`that
`
`patients' cancer will eventually progress after docetaxel
`
`treatment because
`
`their
`
`cancer
`
`develops
`
`resistance to docetaxel therapy. Several mechanisms of resistance have been described in
`
`the
`
`literature. Cabral at 3-8; Dumontet & Sikic, Mechanisms of Action of and Resistance to
`
`Antitubulin Agents: Microtubule Dynamics, Drug Transport, and Cell Death, 17(3) J. Clin.
`
`Oncol. 1061-1070 (1999). Even today, the mechanisms of taxane
`
`resistance
`
`are not
`
`well
`
`understood, and it may be a combination of changes
`
`to cancer cells
`
`gives rise to the resistance.
`
`
`
`
`
`to exposed docetaxel that
`
`62.
`
`Beardsley noted in 2008 that
`
`there was an "urgent
`
`need for
`
`systemic
`
`treatment options for patients with castration-resistant
`
`prostate
`
`cancer
`
`who
`
`
`
`have after
`
`progressed
`
`receiving first-line docetaxel chemotherapy." Beardsley at 161. Beardsley describes a variety of
`
`treatments proposed for mCRPC
`
`in
`
`2008, including satraplatin,
`
`four epothilones,
`
`custirsen,
`
`sorafenib, sunitinib, abiraterone, and MDV3100
`
`
`
`(enzaiutamide). None of these treatments
`
`succeeded in meeting that clinical need before the earliest
`
`filing date of the ' 720 application.
`
`IV.
`
`The Treatment
`
`of mCRPC
`
`with
`
`Cabazilaxei
`
`63.
`
`The urgent need described by Beardsley was not met until
`
`the
`
`FDA
`
`approval of Jevtana (cabazitaxel)
`
`in
`
`
`
`
`
`a phase 2010, based on III clinical trial (the TROPIC study)
`
`that demonstrated a statistically significant
`
`improvement
`
`in
`
`overall
`
`survival
`
`compared
`
`to
`
`mitoxantrone plus prednisone.
`
`21
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`
`

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`
`64.
`
`As co-PI on the TROPIC study, I presented
`
`to
`
`the
`
`ASCO Genitourinary
`
`Cancers Symposium as the first public presentation of the mature phase
`
`
`
`III data. The response to
`
`the data was very positive. The results were unexpected, and many physicians
`
`expressed
`
`surprise given that there was virtually no data available
`
`prior
`
`to
`
`
`
`that For the
`
`time
`
`in
`
`mCRPC.
`
`
`
`first time, patients with mCRPC progressing on or after docetaxel treatment had an opportunity
`
`to prolong life.
`
`65.
`
`Prior to these results, the person of ordinary
`
`
`
`skill the art could not in
`
`
`
`reasonably predict whether eabazitaxei would provide a clinically meaningful benefit in
`
`palliation or survival in mCRPC patients, particularly not
`
`
`
`for those patients progressing after
`
`docetaxel treatment, based on
`
`the
`
`results
`
`reported
`
`in
`
`response was one of surprise at
`
`the positive
`
`results.
`
`Beardsley, or In fact, the typical
`Mita
`
`
`
`
`
`66.
`
`As the "720 application describes, metastatic prostate cancer
`
`is particularly
`
`
`
`difficult to evaluate because of the heterogeneity of the disease and the
`
`lack of consensus
`
`regarding the treatment response criteria. '425 Publication at
`
`[0007]; Mackumon
`
`et al.
`
`Molecular Biology Underlying the Clinical Heterogeneity of Prostate Cancer: An Update,
`
`133
`
`Arch. Pathol. Lab. Med. 1033-40, 1033 (2009) ("Mackinnon"); Armstrong & George, New Drug
`
`Development in Metastatic Prostate Cancer, 26 Urologic Oncol.: Seminars &
`
`Original
`
`
`
`Investigations 430-37, 430 (2008) ("Armstrong & George"). There are currently no biomarkers
`
`indicating which prostate cancer patients will
`
`respond
`
`to
`
`
`
`
`
`therapies. particular Many patients do
`
`not have measurable disease, and therefore alternative markers such as PSA are needed
`
`to
`
`evaluate response. '425 Publication at [0007]. However, even PSA is notorious
`
`for not being
`
`able to predict survival.
`
`22
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`67.
`
`A skilled artisan would have known
`
`that
`
`changes
`
`in
`
`PSA
`
`are not
`
`necessarily indicative of efficacy. Beardsley at 164 (noting ihai PSA may not be reflective of
`
`disease progression with vascular endothelial growth
`
`factor
`
`receptor
`
`targeting
`
`agents);
`
`see Berry
`
`at 2439 (reporting a significantly greater decrease in PSA levels without a statistically
`
`significant
`
`increase in overall survival for mitoxantrone); Tannock
`
`at 1502
`
`(reporting
`
`statistically
`
`significant
`
`improvements in rates of PSA response
`
`in
`
`patients
`
`taking
`
`docetaxel
`
`weekly
`
`compared
`
`to
`
`mitoxantrone, but no difference
`
`in
`
`overall
`
`
`
`survival), Susan Halabi, myself, and others found
`
`that
`
`"the benefits of cabazitaxel
`
`in mediating a survival
`
`benefit
`
`are
`
`not
`
`
`
`fully captured PSA
`
`by
`
`early
`
`changes." Halabi et al., Prostate-Specific Antigen Changes as Surrogate for Overall Survival in
`
`Men with Metastatic Castration-Resistant Prostate Cancer Treated with Second-Line
`
`Chemotherapy, 31(31)
`
`J. Clin. Oncol. 3944-50, 3944
`
`(2013).
`
`68.
`
`The primary endpoint leading
`
`to FDA approval of docetaxel
`
`for
`
`the
`
`treatment of mCRPC,2 and all post-docetaxel
`
`treatments
`
`has
`
`been
`
`D'Amico, US
`survival.
`overall
`
`Food and Drug Administration Approval of Drugs for the Treatment of Prostate Cancer: A New
`
`Era Has Begun, 32(4) J. Clin. Oncol. 362-64
`
`
`
`(2014). "[T]he only validated phase III endpoint
`
`in
`
`advanced prostate cancer, particularly CRPC,
`
`survival." Rami ah et al, Clinical
`is overall
`
`Endpoints for Drug Development in Prostate Cancer, 18 Curr, Opin. Urol.
`
`303-08,
`
`307 (2008).
`
`Accordingly, the person of ordinary skill was
`
`seeking
`
`
`
`a therapy
`
`that
`
`prolonged
`
`overall
`
`survival in
`
`
`
`a patient population with an acceptable side effect profile.
`
`69.
`
`But, as Rami ah et al. have emphasized, "[i]n phase 11 trials, however, it
`
`remains a challenge to select the
`
`
`
`ideal intermediate endpoint to gauge the efficacy of novel
`
`rate
`the
`to decrease
`for " The exception is denosumab, also approved osteoporosis, which is used
`
`
`of skeletal-related events
`in bone-metastatic CRPC patients. This
`is
`a palliative
`benefit and does
`not influence survival.
`
`23
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`
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`
`agents. The lack of proven surrogates,
`
`the
`
`heterogeneity
`
`of
`
`PFS definitions,
`
`the
`
`unknown
`
`of novel agents on PSA production, and
`
`the variability
`
`in
`
`patient-reported
`
`outcomes
`
`make
`
`of these endpoints problematic." Id. Indeed, Armstrong and George report
`
`
`
`that one of the
`
`
`
`challenges to drag development rnCRPC is "the in
`
`
`
`
`
`lack of established surrogates for overall
`
`survival." Armstrong & George at 430-31. Seeking to explain the high rate of phase
`
`III
`
`failures
`
`in mCRPC continuing in 2013, Antonarakis and Eisenberger
`
`also
`
`recognized
`
`that
`
`"there
`
`currently no established surrogate end points
`
`for overall
`
`survival
`
`in
`
`men
`
`with
`
`mCRPC,
`
`efforts should focus on identification
`
`and validation of
`
`alternative
`
`intermediate
`
`biomarkers
`
`of
`
`clinical benefit.
`
`. . ." Antonarakis & Eisenberger at 1711.
`
`70.
`
`It follows that phase I and II data, including
`
`responses
`
`in
`
`PSA
`
`levels
`
`and
`
`measurable lesions, would not have allowed a person of ordinary
`
`skill
`
`
`
`the art in to predict
`
`
`
`whether a patient would have ultimately lived longer or tolerated
`
`the medication
`
`long
`
`enough
`
`to
`
`see such a survival benefit.
`
`V.
`
`I nferoref afion of Cited
`
`Art
`
`71.
`
`
`
`As noted above, I have reviewed the references cited in the Office Action.
`
`In my opinion, these references, alone or in
`
`combination, would
`
`not
`
`give
`
`a person
`
`of ordinary
`
`skill at the relevant time a reasonable expectation
`
`that
`
`cabazitaxel
`
`could
`
`
`
`successfully treat
`
`mCRPC. Indeed, based on the evidence and experience in
`
`
`
`the field, such a skilled person would
`
`more reasonably expect failure
`
`than success.
`
`A.
`
`Phase i Data in Mita
`
`72. Mita evaluated twenty-five patients, eight of which
`
`had prostate
`
`cancer.
`
`This trial was not powered sufficiently to detect a survival or palliative benefit in
`
`prostate
`
`cancer.
`
`Nor did it report statistically significant
`
`results.
`
`24
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`

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`73.
`
`
`
`The 80 year old man with a partial response had previously been
`
`treated
`
`with bicaluiamide, an antiandrogen,
`
`in addition
`
`
`
`to other therapies. Prior treatment needed to
`
`
`
`have ceased 28 days prior to enrollment in this phase I study, but
`
`
`
`it was known that bicalutamide
`
`withdrawal could
`
`cause a response. Wirth & Frosehermaier, The Antiandrogen Withdrawal
`
`Syndrome, 25 (Suppl. 2 ) Urol. Res. S67-7L S67-68 (1997). This is why the phase III trial with
`
`docetaxel described in Tannock
`
`required
`
`least six weeks to have elapsed after bicalutamide
`at
`
`
`
`
`
`treatment before enrollment. Tannock at 1503 ("so as to avoid the possibility of confounding . .
`
`,
`
`the response to antiandrogen withdrawar).
`
`74.
`
`The 80 year old man had not been previously treated with docetaxel and
`
`was therefore not docetaxel-refractory. In addition, he declined further
`
`
`
`
`
`after treatment his sixth
`
`course, indicating thai the side effects might not have been
`
`acceptable.
`
`75.
`
`The 50 year old man with a partial response is the only
`
`docetaxel-
`
`refractory patient in Mita
`
`to have a partial
`
`response
`
`after
`
`
`
`treatment. cabazitaxel Progressive
`
`
`
`disease was noted after eight courses, A person of ordinary skill would not have
`
`
`
`found this result
`
`in a single patient sufficient
`
`to predict whether
`
`cabazitaxel would
`
`have
`
`provided
`
`a clinical benefit
`
`
`
`in palliation or survival for a population of mCRPC patients progressing after docetaxel therapy,
`
`or whether cabazitaxel would have had a risk-benefit ratio such that it would have been
`
`considered a treatment for the disease.
`
`76.
`
`These two patients are essentially a case
`
`
`
`study with cabazitaxel. The
`
`responses could be an anomaly, reflecting
`
`certain qualities
`
`in
`
`each
`
`
`
`patient's A
`
`particular
`
`
`
`
`
`person of ordinary skill would not take partial responses in two patients and extrapolate to
`
`predict the ability of cabazitaxel to provide a meaningful
`
`
`
`
`
`benefit, clinical e.g., prolongation of
`
`
`
`survival, for a patient population with mCRPC. In light of the voluminous phase III failures
`
`in
`
`25
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`
`

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`this indication, a person of ordinary
`
`skill would
`
`not
`
`
`
`in success expect a phase HI trial given this
`
`
`
`
`
`data, and indeed would predict
`
`that such
`
`a
`
`
`
`trial would more likely fail than succeed.
`
`Indeed, when I was on the faculty at Harvard in 2007 I had difficulty
`
`
`
`opening the TROPIC phase III study of cabazitaxel in niCRPC patients progressing
`
`after
`
`docetaxel therapy at the Lank Center
`
`for Genitourinary Oncology
`
`because
`
`the
`
`evidence
`
`of
`
`
`
`activity was considered too preliminary by those at the institution.
`
`B,
`
`Phase il Data in Beardslev
`
`78.
`
`Beardsley reports data from a phase II clinical trial of cabazitaxel
`
`in
`
`docetaxel-refractory breast cancer patients. A person of ordinary skill
`
`in
`
`the art would not
`
`assume that data in breast cancer patients would
`
`translate
`
`to
`
`distinct tissue types, and even within each
`
`type
`
`of
`
`cancer
`
`
`
`cancer prostate patients. They are
`
`
`
`
`
`
`
`is there heterogeneity.
`
`substantial
`
`Mackitmon at 1033; Wiechec & Hansen, The Effect of Genetic Variability on Drug Response in
`
`Conventional Breast Cancer Treatment, 625 Eur.
`
`J. Pharmacol.
`
`
`
`122-30 A person of (2009).
`
`
`
`ordinary skill would not have given weight
`
`to
`
`cabazitaxel for mCRPC.
`
`
`
`
`
`in results II these phase evaluating the use of
`
`
`
`
`
`C.
`
`Use of Prednisone
`
`in
`
`Tannock
`
`79.
`
`Tannock does not indicate whether the use of prednisone contributes
`
`to
`
`any palliative or survival benefit because docetaxel alone is not compared
`
`to
`
`docetaxel
`
`plus
`
`prednisone. Therefore it would not have suggested that prednisone
`
`improved
`
`
`
`therapy with
`
`docetaxel or that prednisone would have
`
`improved
`
`
`
`therapy with cabazitaxel. Consequently, a
`
`person of ordinary skill would not add prednisone
`
`to an oncologic
`
`agent,
`
`including
`
`a taxane,
`
`based on ihis article.
`
`26
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`
`

`
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`
`VI. Concljision
`
`80.
`
`A person of ordinary skill would not have had a reasonable expectation of
`
`success in using cabazitaxel
`
`to provide a clinically meaningful benefit,
`
`e.g., of life prolongation
`
`
`
`
`
`with acceptable toxicity , in patients with mCRPC in
`
`light of
`
`the
`
`
`
`breast cancer described above for several reasons:
`
`
`
`
`
`phase phase 11 data in I data or
`
`
`
`
`
`Anecdotal responses in particular patients can be, and often are, due to factors
`
`peculiar to those patients and do not represent a generalizable
`
`
`
`finding in a
`
`heterogeneous population of patients. As noted above, there are innumerable
`
`examples of patients in phase I
`
`or phase
`
`II
`
`studies
`
`showing
`
`significant
`
`responses
`
`
`
`with drags that go on to fail completely in phase TIT clinical
`
`
`
`studies.
`
`As the FDA has recognized, a meaningfully beneficial clinical
`
`endpoint
`
`(e.g.,
`
`improving survival in mCRPC patients
`
`refractory
`
`to
`
`docetaxel)
`
`is not
`
`typically
`
`predefined in phase I
`
`or phase II
`
`
`
`clinical Consequently, as a matter of studies.
`
`
`
`statistics and good clinical practice, a person of ordinary
`
`skill
`
`would
`
`draw
`
`no
`
`definite conclusions regarding the
`
`
`
`
`
`a efficacy of drug after a phase I or II trial
`
`unless those trials were exceptionally
`
`large or conducted
`
`in cancers
`
`where phase
`
`III trials are not feasible. Moreover, phase II studies are generally
`
`not
`
`sufficiently
`
`powered to determine whether
`
`the risk-benefit
`
`ratio
`
`justifies
`
`the use
`
`of
`
`a
`
`compound. Many drugs showing significant activity
`
`fail because
`
`the
`
`risks
`
`to
`
`patients outweigh the benefits of
`
`the
`
`(see. e.g., the discussion of the
`drag
`
`
`
`taxane
`
`Larotaxel above). This last point cannot be emphasized enough: a
`
`treatment
`
`that is too toxic to
`
`the
`
`
`
`patient no treatment at is
`
`
`
`ail. Finally, as phase II studies
`
`27
`
`00190
`
`

`
`Sanofi Ref. FR2009/121 US CNT
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`US Application No. 13/456,720
`
`are not usually designed
`
`to
`
`evaluate
`
`alternative
`
`therapies,
`
`one
`
`cannot
`
`that an experimental drug
`
`is
`
`
`
`superior to conventional
`
`therapy.
`
`Finally, cancers are biologically
`
`
`
`distinct. A drug that works
`
`for one
`
`tumor
`
`type
`
`will usually not work
`
`
`
`for another. A phase III study in the target tumor
`
`type
`
`(in
`
`this case prostate cancer)
`
`is
`
`typically
`
`
`
`
`
`before required any conclusion can be
`
`drawn
`
`regarding a compound's
`
`efficacy
`
`against
`
`that
`
`tumor.
`
`81.
`
`Indeed, prediction of a positive
`
`phase
`
`III
`
`study
`
`in
`
`mCRPC
`
`described as "an
`
`impossible
`
`
`
`endeavor." Antonarakis & Eisenberger
`
`at
`
`
`
`1711. A person of
`
`ordinary skill
`
`in the art would have understood
`
`that
`
`clinical
`
`
`
`development in oncology is
`
`the
`
`inherently unpredictable. In particular, they would
`
`have also
`
`understood
`
`that amongst
`
`level of late stage
`
`failures
`
`in
`
`oncology,
`
`
`
`mCRPC be a particularly difficult has proven
`
`
`
`
`
`to
`
`when
`
`indication to predict success. That understanding
`
`is as
`
`true
`
`today
`
`application was filed.
`
`
`
`it was as the patent
`
`
`
`82.
`
`I hereby declare that all statements made
`
`
`
`herein of my own knowledge
`
`are
`
`true and that all statements made on information and belief
`
`
`
`are believed to be
`
`true; and
`
`further
`
`that these statements were made
`
`with
`
`the
`
`knowledge
`
`that
`
`willful
`
`false
`
`made are punishabl e by fine and imprisonment, or both, U nder Section 1001
`
`of Title
`
`18
`
`of
`
`the
`
`
`
`may statements validity of the
`
`
`
`jeopardize
`
`United States Code
`
`and
`
`that
`
`such
`
`willful
`
`false
`
`application or any patent issued
`
`thereon.
`
`28
`
`00191
`
`

`
`Sanofi Ref. FR2009/12! US CNT
`
`'US Application No. 13/456,720
`
`/Vvl
`U&O
`^
`Alton Oliver Sartor, M.D,
`
`1
`
`E}ate:
`
`|
`
`IK4 n
`
`A
`( !
`V
`
`29
`
`00192
`
`

`
`EXHIBIT 1
`
`CURRICULUM VITAE
`
`PART I: Genera! Information
`
`DATE PREPARED:
`
`June 30, 2014
`
`Name:
`
`A, Oliver Sartor, M.D
`
`Home Address:
`
`1511 Dufossat Street, New Orleans, LA 70115
`
`Work E-Mail:
`
`OuSartor@tulaiie.edu
`
`Place of Birth:
`
`Shreveport, LA
`
`Education:
`1977 B.A.
`1982 M.D.
`
`Colorado College, Colorado Springs,
`CO
`Tulane University School
`of Medicine,
`
`New
`
`Orleans,
`
`LA
`
`Postdoctoral Training:
`of Hospital Philadelphia, University of
`
`
`Intern in Pediatries, Children's
`1982-1983
`Philadelphia,
`PA
`Pennsylvania Pediatrics Program,
`Intern in Medicine, Tulane University
`School
`of Medicine
`junior Resident, Internal Medicine, Tulane University
`School
`Medicine
`Senior Resident, Internal Medicine,
`Medicine
`Cancer
`Fellow in Medical Oncology, National
`Cellular
`Senior Staff Fellow, Laboratory
`of
`
`National Institutes of Dental R esearch, Bethesda, MD
`
`of
`
`Tulane
`
`University School
`
`1983-1984
`1984-1985
`
`1985-1986
`
`1986-1989
`1989-1990
`
`Institute,
`Development
`
`of
`
`Bethesda,
`and
`
`Licensure and Certification:
`1985-
`Louisiana Medical Licensure
`American Board of
`Internal Medicine Certificate
`1986-lifetime
`1989-lifetime
`American Board of Internal Medicine, Medical Oncology Certificate
`1986-1993
`Maryland Medical Licensures
`1988-1990
`Virginia Medical Licensures
`2006-2008
`Massachusetts Medical Licensure
`
`Academic Appointments:
`1990-1993
`Senior Investigator, Clinical Pharmacology Branch, National Cancer
`Institute, Bethesda, MD
`tenure), Section
`
`Associate Professor of M edicine (with
`of
`Medicine
`Hematology/Oncology, Departments
`State University School of Medicine,
`Shreveport,
`Patricia Powers Strong Professor
`of
`Oncology
`State University School of Medicine,
`New
`
`1993-1998
`
`1998-2006
`
`of
`
`and
`LA
`(with
`Orleans,
`
`Urology,
`
`tenure),
`LA
`
`00193
`
`

`
`
`
`Medicine, Tulane University School
`
`of
`
`Institu