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`Alan Yagoda, Bassam Abi-Rached, and Daniel Petrylak
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`ENAL-CELL CANCER (RCC) , as docu-
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`mented in prior (1967,1 1975,2 1977 3 and
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`19834) reviews has been a hormonally and cyto(cid:173)
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`toxic chemotherapeutically resistant tumor: It re(cid:173)
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`mains so today.
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`Since the present review spans 11 years, January
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`1983 through December 1993, it is of interest to
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`examine changes in cancer incidence and death
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`rates of 19835 and 1993.6 While the incidence
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`increased for all and for renal malignancies by
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`41.3% and 51. 7%, respectively, the percent of
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`RCCs remained rather constant at 2.1% and 2.3%,
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`respectively (Table 1). There was no change in
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`males (each 2.7% and only a +0.2% in females
`(1.6% and 1.8%, respectively).
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`The enormous increase in the number of pros(cid:173)
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`tate cases from 75,000 to 200,000 dramatically
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`impacted on the incidence of genitourinary tumors
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`(renal, renal pelvis, ureter, bladder, prostate, ure(cid:173)
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`thra, testis, and others) resulting in increase of
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`109.7% for such cancers; + 120.4% for men com(cid:173)
`pared with + 3 7 .3 % for women. The percentage of
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`kidney tumors within the genitourinary group actu(cid:173)
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`ally decreased by -3.7% to 9.6% in 1993 from
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`13.3% in 1983 (Table 1), with a decrease in males
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`by -1.8%, and an increase in females by + 5.2%.
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`Overall cancer mortality increased from 440,000
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`cases in 1983 to 538,000 in 1994, a + 22.3%
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`change, yet the percentage dying from renal tumors
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`remained about the same for all (1.9% and 2.1 %,
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`respectively) males and females (Table 1). The
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`change in the RCC death rate between 1983 and
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`1993
`in relationship to all cancers increased,
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`+32.9%, (8,500 to 11,300 cases) and although all
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`genitourinary malignancies had almost a similar
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`increase, +36.5%, (44,290 to 60.475 cases), the
`change was only + 1.1 % for the percent of genito(cid:173)
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`urinary to all cancers. The estimated death rate for
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`patients with RCC within the genitourinary group
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`From the Medical Oncology Division, Columbia-Presbyterian
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`Medical Center, New York, NY.
`to Alan Yagoda, MD, Division of
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`Address reprint requests
`Medical Oncology, Colwnbia-Presbyterian Medical Center, Atchley
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`739,161 Fort Wasllington Ave, New York, NY 10032-3789.
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`Supported by National Cancer Institute grant no. CA 13696, and
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`the I. Moradoff Fund.
`
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`Copyright © 1995 by W.B. Saunders Company
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`0093- 7754 /95 /220 1 -0009$05.00 (0
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`decreased slightly from 19.2% in 1983 to 18.7% in
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`1993; for men it was 11.7% to 11.2%, respectively,
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`and for females, it was 7.5% to 7.2%, respectively.
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`There was no definitive evidence that therapy has
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`favorably affected survival of patients with ad(cid:173)
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`vanced local and distant disease, and any marginal
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`improvement in survival, in fact, might simply be
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`due to patient selection factors-"stage migra(cid:173)
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`tion"-because of more patients being diagnosed
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`with lower stage disease that was treated success(cid:173)
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`fully by surgery alone.
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`MATERIALS AND METHODS
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`To assure consbLency in reporting results, ground
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`rules were set when reviewing the large number of
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`published studies. Differences in defining the catego(cid:173)
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`ries minor response (MR) and stabilization of
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`disease (STAB) (ie, a decrease of < 50% or < 25%
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`with an increase of > 25% or > 50% in either all or
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`selected parameters), coupled with varied patient
`selection (good risk factors 7), extent of restaging
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`used, tightening of criteria for patient entry (ie,
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`bidimensional parameters, absence of prior sys(cid:173)
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`temic therapy, better performance status, exclusion
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`of certain metastatic sites, etc), and introduction of
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`new diagnostic tests (ie, computed tomographic
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`(CT) scans, ultrasound), have led to more accurate
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`documentation of the extent of tumor regression.
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`Such refinements probably have resulted in decreas(cid:173)
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`ing the number of complete (CR) and partial (PR)
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`remissions while increasing the MR/ST AB group.
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`Without more accurate immunological or biologi(cid:173)
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`cal markers for this disease, attainment of MR/
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`STAB may be due more to the eye of the observer,
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`the absence of consistent restaging procedures, or
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`the biological variation of tumor growth and cell
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`death (so-called, "natural history").7 It remains
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`unclear whether STAB represents a true biological
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`effect of therapy on tumor growth, a lead-time bias,
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`and/ or intermittent periods of cell division(cid:173)
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`apoptosis. In older trials, many investigators fre(cid:173)
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`
`quently recognized STAB as evidence of an "objec(cid:173)
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`tive response" and thus, reported moderate to
`significant remission rates; others dismissed this
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`category altogether, failed to mention MR/ST AB
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`at all, or automatically placed it into the nonre(cid:173)
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`sponding/progression (PROG) category. The latter
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`view is now being questioned again because of
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`42
`
`Seminars in Oncology. Vol 22, No 1 (February), 1995: pp 42-60
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`NOVARTIS EXHIBIT 2034
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 19
`
`

`

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`Clltl'10THERAPY FOR RCC
`
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`43
`
`----------~
`
`Table I. Incidence and Mortality Rat,,, in 19113 and 1994
`
`
`Cancers
`
`1983
`
`
`Total
`
`
`Males
`
`
`Females
`
`1994
`
`
`Total
`
`
`
`
`Incidence
`
`
`
`
`
`
`Change Between 1983 and 1993
`
`Males
`
`
`Females
`
`
`Total
`
`
`All:
`
`Number
`
`Male:Female
`
`Genito-urinary:
`
`Number
`
`Male:Female
`
`
`Of All
`
`Renal:
`
`Number
`
`Male:Female
`
`
`Of All
`
`
`Of Genito-urinary
`
`All:
`
`
`Number
`
`Male:Female
`
`Genito-urinary:
`
`Number
`
`Male:Female,
`
`
`Of All
`
`Renal:
`
`Number
`
`Male:Female
`
`Of All
`
`
`Of Genito-urinary
`
`855,000
`
`
`422,500
`
`
`49.4%
`
`432,500
`
`
`50.6%
`
`1,20B,OOO
`
`
`
`137,350
`
`16.1%
`
`
`18,200
`
`
`
`2.1%
`
`13.3%
`
`
`119,800
`
`B7.2%
`28.4%
`
`
`
`11.400
`
`62.6%
`
`2.7%
`
`8.3%
`
`
`17,550
`
`12.8%
`4.1%
`
`
`6,800
`
`
`37.4%
`
`1.6%
`
`38.8%
`
`
`287,200
`
`23.8%
`
`
`27,600
`
`
`
`2.3%
`
`9.6%
`
`
`Mortality
`
`632,000
`
`
`52.3%
`
`
`263,100
`
`91.6%
`41.6%
`
`
`17,000
`
`
`61.6%
`
`2.7%
`
`6.5%
`
`576,000
`
`
`47.7%
`
`+41.3
`
`
`
`24,100
`
`8.4%
`4.2%
`
`
`10,600
`
`
`2B.4%
`
`1.8%
`
`44.0%
`
`
`
`+ 109.7
`
`+7.7
`
`
`+51.7
`
`
`
`+0.2
`
`-3.7
`
`440,000
`
`
`238,500
`
`54.2%
`
`
`201,500
`
`45.8%
`
`
`538,000
`
`
`283,000
`
`52.6%
`
`
`255,000
`
`
`47.4%
`
`44,290
`
`
`10.1%
`
`
`
`8,500
`
`
`1.9%
`
`19.2%
`
`37,550
`
`
`84.8%
`
`15.7%
`
`
`5,200
`61.2%
`
`
`2.2%
`
`11.7%
`
`6,740
`
`
`15.2%
`3.4%
`
`
`
`3,300
`
`38.8%
`
`1.6%
`
`7.5%
`
`60,475
`
`
`11.2%
`
`
`
`11.300
`
`
`2.1%
`
`18.7%
`
`52,325
`
`
`86.5%
`
`18.5%
`
`
`6,BOO
`
`60.2%
`
`2.4%
`
`11.2%
`
`8,150
`
`
`13.5%
`3.2%
`
`
`
`4,500
`39.8%
`
`
`1.8%
`
`7.4%
`
`+22.3
`
`
`+36.5
`
`
`+1.1
`
`
`
`+32.9
`
`
`+0.2
`
`-0.5
`
`
`Males
`
`(%)
`
`
`Females
`
`(%)
`
`+49.6
`
`
`+2.9
`
`
`
`+ 120.4
`
`+4.4
`+ 13.3
`
`
`+49.1
`
`
`-0.1
`
`0.0
`
`-1.8
`
`+ IB.7
`
`+0.4
`
`
`+39.4
`
`
`+1.7
`+2.8
`
`
`
`+30.9
`-1.0
`
`
`+0.2
`
`-0.5
`
`+33.2
`
`
`-2.9
`
`
`+37.3
`-4.4
`
`+0.1
`
`
`+55.1
`
`
`+1.0
`
`+0.2
`
`+5.2
`
`+26.6
`
`+1.6
`
`
`+20.9
`
`
`-1.7
`
`-0.2
`
`
`+36.4
`+1.0
`
`
`+0.2
`
`-0.1
`
`
`
`
`
`
`recent prospective randomized trials, particularly
`
`
`
`
`
`
`with immunological agents, describing modest CR
`
`
`
`
`
`
`
`
`
`-I- PR rates (about 18%) yet a statistically signifi(cid:173)
`
`
`
`
`
`
`
`
`cant increases in survival (about 2.5 times controls)
`
`
`for CR -I- PR + ST AB.8 In the present review
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(Table 2), MR/STAB, although listed, are ex(cid:173)
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`
`
`
`
`
`cluded from the final response rate which denotes
`
`
`
`
`
`
`
`
`attainment only of CR -I- PRo Response durations
`
`
`
`
`
`
`
`also were not reported because definitions varied
`
`(most lasted < 3 to 9 months) but mixed responses
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`always were included in the PROG category.
`
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`
`
`
`
`
`
`Many phase II trials used different initial and/ or
`
`
`
`
`
`
`
`escalated dosages, as well as schedule adjustments,
`
`
`
`
`
`
`sometimes based on so-called "good-risk" and
`
`
`
`
`
`
`"poor-risk" factors usually defined by prior treat(cid:173)
`
`
`
`
`
`ment with irradiation, immunotherapy or chemo(cid:173)
`
`
`
`
`
`therapy, poor performance status, renal dysfunc(cid:173)
`tion, anemia, metastatic sites, single versus multiple
`
`
`
`
`
`
`
`organ involvement, etc. 7 To simplify the multitude
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of changes, only the initial highest planned plus the
`
`
`
`
`
`
`
`highest escalated doses (in parenthesis) were re(cid:173)
`
`
`
`
`corded in Table 2.
`
`
`
`
`
`
`
`Particular attention was given to trace final
`
`
`
`
`
`
`
`publications of abstracts presented before 1990; in
`
`
`
`
`
`
`fact, some investigators were contacted concerning
`
`
`
`
`
`
`manuscript status. Numerous studies, which were
`
`
`
`
`
`
`
`presented as an abstract or preliminary report
`
`
`
`
`
`
`
`initially, sometimes were summarized as part of a
`
`
`
`
`
`
`review of multiple drug- or disease-oriented trials
`
`
`
`
`
`
`
`within a cooperative group or institution. Except
`
`
`
`
`
`
`
`where otherwise indicated by a double reference,
`
`
`
`
`
`
`
`
`only the last and/or updated study result was
`
`reported.
`
`
`
`
`
`
`
`Data are from phase II disease-oriented (not
`
`
`
`
`
`
`
`
`phase II drug-oriented) trials and almost all phase I
`
`
`
`pharmacokinetics/dose-finding studies were ex(cid:173)
`
`
`
`
`
`
`
`
`cluded because doses and schedules varied and, of
`more importance, response rates were absent. 9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`However, drugs evaluated in the time frame of this
`
`
`
`
`
`
`
`
`review that also had trials published before 1983
`
`NOVARTIS EXHIBIT 2034
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 19
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`

`

`
`44
`
`
`
`
`
`YAGODA, ABI-RACHED, AND PETRYLAK
`
`Table 2. Chemotherapy Trials from I,!nuary 1983 to December 1993
`
`
`Reference(s)
`
`
`
`Acivicin, CI
`
`
`Elson et al'°
`
`
`Aclarubicin (aclacino(cid:173)
`
`mycin-A)
`
`
`Decker et ai"
`
`
`Alanosine
`
`
`Elson et al lO
`
`
`Ametantrone
`
`
`Hansen et al"
`
`Aminothiadazole
`
`
`Elson et al'°
`
`
`
`Amonafide
`
`
`
`Higano el al"
`
`Ampligen
`Strayer et al 14
`
`
`
`
`No.
`
`Entered
`
`
`No.lnade(cid:173)
`
`quate
`
`
`No.
`
`Adequate
`
`
`No.
`Unpre-
`
`treated
`
`
`27
`27
`
`
`15
`
`
`15
`
`
`36
`
`36
`
`25
`
`25
`
`46
`
`46
`
`
`24
`
`24
`
`31
`
`31
`
`
`22
`
`22
`
`6
`
`
`6
`
`
`29
`
`29
`
`18
`
`18
`
`30
`
`30
`
`24
`
`
`24
`
`
`
`
`35
`
`35
`
`16
`
`
`16
`
`
`37
`
`37
`
`25
`
`25
`
`46
`
`46
`
`
`29
`
`29
`
`31
`
`31
`
`
`8
`
`o
`
`
`o
`
`
`
`
`o
`
`
`o
`
`o
`
`o
`
`
`
`
`
`
`No.
`
`
`
`
`Percent of Adequate
`
`CR PR CR + PR (95% CI)
`
`
`
`
`
`
`
`o
`
`o
`
`o
`
`
`
`
`4 (0-19)
`4
`
`
`0(0-18)
`
`0
`
`
`o
`
`
`o
`
`o
`
`o
`
`o
`
`
`o
`
`o
`
`
`
`
`0
`
`o
`
`o
`
`
`
`
`
`0
`
`
`0
`I
`
`
`o
`
`
`
`
`3 (0-15)
`
`3
`
`
`8 (1-26)
`
`8
`
`
`2 (0-12)
`
`
`
`0(0-12)
`o
`
`
`
`7 (1-21)
`
`
`
`
`o
`
`2
`
`o 0
`
`
`o
`
`
`0
`o
`I'
`
`o
`
`o
`
`o
`
`
`0
`
`
`0
`
`
`0
`
`
`
`MR/
`
`STAB
`
`
`
`*/*
`
`
`
`
`Initial (highest) Dose
`
`
`
`
`
`20 mg/m 2 d 1-3 Q3W.
`
`
`0/ I 2 65 mg/ m2 weekly for 4 weeks
`
`
`
`
`
`
`
`
`
`Q6W.
`
`
`
`*/*
`
`
`
`160 mg/m2 d 1-5QM.
`
`
`0/5
`
`135 (162) mg/m2 Q2W.
`
`
`
`
`
`*/*
`
`
`125 mg/m2 QW + Allopurinol
`
`
`
`
`
`
`
`300 mg QD.
`
`
`0/6
`
`
`
`
`
`
`300 (450) mg/m2 d 1-5 Q3W.
`
`
`*/*
`
`
`
`0/0
`
`0/5
`
`0/7
`*/*
`
`
`
`
`
`
`
`
`
`
`10 (120) mg BIW, or 200 (500)
`
`mgBIW.
`
`120 (180) mg/m2 Q3W.
`
`
`
`
`
`
`same (150).
`
`
`same (160).
`120 mg/m2 QM.
`
`
`
`0/2
`
`
`
`
`
`
`75 mg/m2 Q8H on d I Q5W.
`
`
`
`Amsacrine
`
`
`Schneider et ailS
`
`
`
`Van Echo et al 16
`
`
`
`Amrein et al"
`
`
`
`Earhart et al"
`
`5-Aza-2'Deoxycitidine
`
`
`
`Abele et al"
`Bisantrene
`
`
`
`Scher et al'°
`
`
`
`Myers et al"
`
`
`
`Evans et al22
`
`
`
`
`
`Spicer et al"
`Elson et aI"
`
`
`
`
`Carboplatin
`
`
`T ait et al"
`
`
`
`Trump et al26
`
`
`Cimetidine
`
`
`Inhorn et al"
`
`
`Cimetidine + coumarin
`
`
`
`
`Marshall et al'8
`
`
`Glynne-Jones et al29
`
`
`
`
`Vennok et apo
`
`
`
`
`Hermann et al"
`
`
`
`
`Dexeus et al"
`
`
`
`
`Kokron et al"
`
`
`Cimetidine + interferon
`
`
`
`Kotake et al34
`
`
`
`
`
`Cyclophosphamide +
`
`
`misonidazole
`
`
`145
`
`21
`
`16
`
`42
`
`66
`
`15
`
`15
`
`140
`
`27
`
`42
`
`24
`
`
`14
`
`33
`
`42
`
`22
`
`20
`
`42
`
`42
`
`202
`
`45
`
`
`12
`
`25
`
`31
`
`
`50
`
`
`39
`
`
`20
`
`20
`
`
`38
`
`
`5
`
`4
`
`o
`
`
`
`
`3
`2
`
`
`
`
`
`
`o
`
`o
`
`
`o
`
`
`o
`
`
`o
`
`
`
`140
`
`21
`
`16
`
`42
`
`61
`
`12
`
`12
`
`126
`
`26
`
`37
`
`20
`
`
`14
`
`29
`
`37
`
`19
`
`18
`
`38
`
`38
`
`198
`
`42
`
`II
`
`
`25
`
`31
`
`
`50
`
`
`39
`
`
`20
`
`20
`
`
`31
`
`
`63*
`
`17
`
`14
`
`11*
`
`21'
`
`12
`
`12
`
`94'
`
`16
`
`33*
`
`15*
`
`II
`
`
`19
`
`37'
`
`19*
`
`18
`
`38
`
`38
`
`172*
`
`40
`
`II
`
`
`16*
`
`31
`
`
`40
`
`
`34
`
`
`20
`
`20
`
`
`27
`
`o
`
`o
`
`o
`
`
`o 0
`
`
`I
`
`o 0
`
`
`o 0
`
`
`o
`
`
`0
`2
`0
`
`
`o
`
`
`
`
`19
`II
`
`
`
`o 0
`
`
`o
`0
`
`
`o
`
`
`
`
`
`
`
`
`
`
`o
`
`
`
`
`
`
`
`o
`
`
`
`
`1(0-5)
`o
`
`o
`
`
`
`2
`
`0(0-22)
`o
`
`
`
`5 (2-10)
`o
`
`
`
`
`o
`
`
`10
`
`
`0(0-8)
`o
`
`o
`
`
`
`5 (1-18)
`
`5
`
`
`12 (8-17)
`
`
`33 (20-50)
`
`
`
`0(0-24)
`
`0(0-11)
`
`
`7 (1-21)
`
`
`
`6 (1-17)
`
`
`
`13 (4-27)
`
`
`
`30 (12-54)
`
`30
`
`
`
`3 (0-17)
`
`
`0/2
`
`0/12
`
`0/4
`
`
`0/6
`*/*
`
`
`
`
`
`0/5
`*/*
`
`260 (300) mg/m2 Q3W.
`
`
`
`
`
`
`same (280).
`
`
`
`
`
`180 mg/m2 weekly for three
`
`
`weeksQ6W.
`
`
`
`150 (175) mg/m2 QW.
`
`
`
`
`260 mg/m2 QM.
`
`
`
`
`450 mg/m2 QM.
`
`
`
`
`400 (440) mg/m2 QM.
`
`
`
`0/4
`
`
`600 mg QID.
`
`
`0/2
`
`0/5
`
`0/5
`
`
`2/5
`
`
`
`
`
`
`
`0/ I 2 300 mg Q6H daily starting d
`15 + Coumarin 100 mg QD.
`
`
`
`
`
`same.
`
`same.
`
`
`
`
`same, except Cimetidine 400
`
`mgQ8H.
`
`
`
`
`
`same (400 mg), or with Cimeti-
`
`
`
`
`
`
`dine 900 mg QD (8 cases).
`
`400 mg QD + Coumarin
`
`
`
`
`
`
`
`
`
`
`100 mg QD starting d 7.
`
`
`4/6
`
`
`0/9
`
`200 mg QID + Interferon 5 mU
`
`
`
`
`
`
`
`
`
`
`
`
`1M twice in week I, three
`
`
`
`
`
`
`times in week 2, then QD.
`
`NOVARTIS EXHIBIT 2034
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 19
`
`

`

`
`
`
`CHn10THERAPY FOR RCC
`
`45
`
`
`--~----------
`
`Tab!e 2. (continued)
`
`
`Reference( 5)
`
`
`
`Glover et al 35
`
`
`
`IO-Deaza-amlnop-
`terin
`
`
`
`Scher et al36
`
`
`Deoxycorformycin
`
`
`
`Venner et al37
`
`Witte et al'°
`
`
`Diaziquone
`
`
`Nichols et al39
`
`
`
`
`Hansen et al40
`
`
`
`Decker et al41
`
`
`No.
`
`Entered
`
`
`No.lnade-
`
`quate
`
`
`No.
`
`Adequate
`
`
`No.
`Un pre-
`
`treated
`
`
`31
`
`
`12
`
`
`12
`
`43
`
`18
`
`
`25
`
`119
`
`20
`
`29
`
`15
`
`
`27
`
`
`10
`
`
`10
`
`43
`
`18
`
`
`25
`
`88
`
`18
`
`25
`
`15
`
`
`38
`
`
`14
`
`
`14
`
`49
`
`20
`
`
`29
`
`132
`
`20
`
`33
`
`22
`
`
`
`
`
`
`
`
`
`
`0
`
`4
`
`
`
`
`
`
`
`
`No.
`
`
`
`
`Percent of Adequate
`
`CR PR CR + PR (95% CI)
`
`
`
`
`
`
`
`
`0
`
`
`MR/
`
`STAB
`
`
`0/ I
`
`
`
`
`Initial (highest) Dose
`1.2 g/m' + Misonidazole 5
`
`
`
`
`
`g/m'Q3W.
`
`
`
`
`0
`
`
`0
`
`0
`
`0
`
`
`0
`
`0
`
`0
`
`0
`
`0
`
`
`0
`
`
`0
`
`0
`
`0
`
`
`0
`
`2
`
`0
`
`
`0
`
`
`
`0(0-22)
`
`
`0
`
`
`0(0-7)
`
`
`
`0
`
`
`2 (0-6)
`
`0
`
`
`0
`
`
`0/0
`
`
`
`37.5 mg/m' QW.
`
`
`
`0/4
`
`*/*
`
`
`
`
`
`
`
`
`4 mg/ m' weekly for three
`
`
`
`
`weeks, then Q2W.
`
`
`
`4 (8) mg/m' Q2W.
`
`
`
`3/7
`
`0/2
`
`0/8
`
`*/'
`
`
`
`27.5 mg/m' QM.
`
`
`27mg/m'QM.
`
`
`
`
`20 mg/ m' weekly for four
`
`
`weeksQ6W.
`
`
`
`40 mg/m' Q3W.
`
`
`
`Stephens et al42
`
`
`Didemnin-B
`
`
`Motzer et al 43
`
`
`
`Taylor et al44
`
`
`Echinomycin
`
`
`
`Marshall et al45
`
`Elliptinium
`
`
`Sternberg et .146
`
`
`
`
`
`Caille et al47 ; Droz
`
`et al48
`
`
`Droz et al40
`
`
`Eplrubicin
`
`
`Fossa et .149
`
`
`
`Benedetto et alSO
`
`
`Esorubicin
`
`
`Carlson et alSi
`
`
`
`VanOstrom et al52
`
`
`
`Kish et al53
`
`
`
`Braich et al54
`
`
`
`
`Hurteloup et al55
`
`
`Floxuridine, CI
`
`
`CiRCADIAN INFU-
`
`SION
`
`
`Hrushusky et al56
`
`
`
`57
`
`50
`
`23
`
`27
`
`49
`
`49
`
`70
`
`14
`
`
`40
`
`
`16
`
`41
`
`21
`
`20
`
`107
`
`25
`
`33
`
`15
`
`13
`
`21
`
`363
`
`290
`
`
`61
`
`
`
`Damascelli et al57
`
`Dexeus et a15•
`
`
`
`
`
`Huben et al"
`
`
`
`Clark et al60
`
`
`Budd et al"
`
`
`
`45
`
`42
`24
`
`
`6
`
`26
`
`
`
`
`6
`
`
`
`
`
`
`
`0
`
`
`
`
`
`
`
`
`3
`
`0
`
`0
`
`
`55
`
`43
`
`21
`
`22
`
`47
`
`47
`
`60
`
`8
`
`
`38
`
`
`14
`
`39
`
`20
`
`19
`
`97
`
`24
`
`27
`
`15
`
`12
`
`19
`
`330
`
`265
`
`
`56
`
`
`42
`
`40
`
`21
`
`
`26
`
`
`30
`
`43
`
`21
`
`22
`
`47
`
`47
`
`46"
`
`4"
`
`
`28*
`
`
`14*
`24"
`
`
`12"
`
`12
`
`92"
`
`24
`
`27
`
`15
`
`7"
`
`19
`
`273*
`
`227*
`
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`I
`
`0
`
`
`0
`
`I
`
`
`
`0
`
`
`
`
`
`0
`0
`
`
`0
`0
`
`
`0
`0
`
`
`0
`0
`
`
`
`
`0
`0
`
`
`0
`0
`
`
`0
`
`
`0
`0
`
`
`
`
`12 36
`
`
`10 30
`
`
`2
`
`
`2 (0-12)
`
`5
`
`0
`
`
`2 (0-11)
`2
`
`
`
`13 (6-25)
`
`
`0(0-31)
`
`
`
`21 (10-37)
`
`
`
`0(0-19)
`
`0(0-7)
`
`0
`
`0
`
`
`3 (1-9)
`
`0
`
`0
`
`
`0
`
`II
`
`
`15 (11-19)
`
`
`15 (11-20)
`
`
`47*
`
`
`4
`
`
`
`
`
`23(13-36)
`
`
`42
`
`33
`
`21*
`
`
`26
`
`
`3
`
`0
`
`
`0
`
`0
`
`
`3
`
`4
`
`
`0
`
`2
`
`
`
`14 (5-29)
`
`
`10 (3-24)
`
`
`43 (22-66)
`
`
`0(0-39)
`
`
`8 (1-25)
`
`
`
`
`
`
`0/0
`*/'
`
`"/.
`
`
`
`
`
`4.2 (4.8) mg/m' QM.
`
`
`3.47 mg/m' QM.
`
`
`
`
`1.25 mg/m' QM.
`
`
`
`0/0
`
`
`
`
`
`100 mg/ m' weekly for four
`
`
`
`
`weeks, then QOW.
`0/18 100 mg/ m2 QW.
`
`
`
`
`
`"/.
`
`80 mg/ m2 d 1-3 Q3W.
`
`
`
`
`
`
`75 mg/m2 Q3W.
`
`
`
`
`
`
`85 (110) mg/m2 Q3W.
`
`
`
`0/2
`
`0/0
`
`
`
`"/'
`
`
`30 mg/m2 Q3W.
`
`
`0/12 same.
`
`
`
`same.
`0/8
`
`
`same (32.5).
`
`I/O
`35 mg/m2 Q3W.
`
`
`
`0/9
`
`
`
`
`
`4/28 0.15 (0.325) mg/kg IV d 1-14, or
`
`
`
`
`0.25 mg/kg via hepatic artery d
`
`
`
`
`1-14 QM at 68% of the dose
`between 1500-2100 hours +
`
`
`
`
`
`
`15% between 2100- 0300
`hours + 2% between 0300-
`
`
`
`
`0900 hours + 15% between
`
`
`
`
`
`
`
`
`0900-1500 hours (51 cases
`
`
`IV+SIA).
`
`
`same (0.20).
`
`
`same (0.25).
`
`same.
`
`
`same (0.225).
`
`
`
`
`
`
`same (20 cases), or with minor
`modification ,(6 cases).
`
`
`
`
`0/ IS
`
`4/7
`
`0/2
`
`0/3
`"/.
`
`
`
`NOVARTIS EXHIBIT 2034
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 19
`
`

`

`
`46
`
`
`
`
`
`YAGODA, ABI-RACHED, AND PETRYLAK
`
`Table 2. (continued)
`
`
`No.
`
`Entered
`
`
`No.lnade-
`
`quate
`
`
`No.
`
`Adequate
`
`
`No.
`
`No.
`Unpre- - -
`CR PR CR + PR (95% CI)
`
`
`
`
`
`
`
`
`treated
`
`
`
`
`Percent of Adequate
`
`
`MR/
`
`STAB
`
`
`
`
`Initial (highest) Dose
`
`
`Reference(s)
`
`
`
`DeMarsh et al62
`
`
`
`
`Merrouche et al"
`
`
`Wilkinson et al 64
`
`
`
`Conroy et al65
`
`
`
`
`
`7
`
`
`20
`
`
`12
`
`30
`
`
`
`Poorter et al"
`
`
`
`17
`
`
`CONSTANT INFU-
`
`SION
`
`
`Hrushusky et al56
`
`
`Richards et al 67
`
`
`
`
`
`Wilkinson et al 64
`
`Floxuridine + inter-
`
`
`
`feron
`Falcone et al'8
`
`
`
`
`
`73
`
`
`7
`
`
`37
`
`29
`
`47
`
`
`16
`
`
`2
`
`6
`
`
`
`0
`
`2
`
`
`2
`
`
`0
`
`
`8
`
`0
`
`I
`
`
`5
`
`
`14
`
`
`12
`
`28
`
`4*
`
`
`
`14
`
`
`12*
`
`8
`
`
`0
`
`
`0
`
`
`0
`
`0
`
`I
`
`
`0
`
`
`0
`
`4
`
`
`
`20 (1-72)
`
`
`
`0(0-19)
`
`
`
`0(0-22)
`
`
`14 (4-33)
`
`
`15
`
`
`15'
`
`
`0
`
`I
`
`
`
`7 (0-32)
`
`
`65
`
`7
`
`
`
`29
`
`29
`
`39
`
`
`15
`
`
`46*
`
`
`2
`
`
`6
`
`
`
`12 (6-23)
`
`
`7'
`
`I
`
`I
`
`29 (4-71)
`
`
`
`
`29
`
`10'
`
`35'
`
`
`II
`
`
`0
`
`I
`I
`
`I
`
`
`0
`
`5
`
`8
`
`'4
`
`
`
`0(0-10)
`
`
`21 (8-40)
`
`
`23 (11-39)
`
`
`
`33 (12-62)
`
`
`1/6
`
`
`
`0/4
`
`
`
`0/5
`
`
`0/0
`
`3/5
`
`same, except minor mod inca-
`
`
`
`
`
`tion by 2%.
`
`
`
`same, except modified sinu-
`
`
`
`
`
`soidal peak at 1800 hours.
`
`
`same (0.4)
`
`
`
`
`same (0.4), except modified
`
`
`
`with 33% between 2300-
`1100 hours + 66% between
`
`
`
`
`
`
`
`
`1100-1 100 hours.
`
`
`
`
`
`
`
`0/10 0,15 (0.35) mg/kg IV d 1-14
`with 70% between 2000-
`
`
`
`0200 hours + 30% between
`
`
`
`
`
`
`
`0200-2000 hours.
`
`
`0/0
`
`
`
`0,15 (0.325) mg/kgd I-140M
`(5 cases IV + 2 IA).
`
`
`
`
`
`
`
`
`
`
`
`
`0/13 0.15 (0.20) mg/kg d 1-5 OM,
`
`
`
`
`
`
`
`0/12 0.075 (0.275) mg/kg d 1-14 OM.
`
`
`
`Dimopoulous
`
`et al"
`
`
`Saari et al70
`
`
`
`
`Floxuridine + Leu-
`
`
`covorin
`
`
`
`Raminski et al"
`
`
`
`13
`
`
`18
`
`
`23
`
`
`15
`
`
`0
`
`
`7
`
`
`0
`
`
`13
`
`
`II
`
`
`23
`
`
`15
`
`
`13*
`
`
`0
`
`
`4
`
`
`
`31 (9-61)
`
`
`3/0
`
`
`II'
`
`
`0
`
`
`0
`
`
`
`0(0-24)
`
`
`0/7
`
`
`17*
`
`
`0
`
`
`0
`
`
`
`0(0-12)
`
`
`15'
`
`
`0
`
`
`0
`
`
`0
`
`
`*/*
`
`
`
`
`Vokes et al72
`
`
`8
`
`
`0
`
`
`8
`
`
`2
`
`
`0
`
`
`0
`
`
`0
`
`
`1/2
`
`Floxuridine + Leu-
`
`
`covorin + Inter-
`
`
`
`feron
`Stadler et alll
`
`
`
`
`Floxuridine + Vinblas-
`
`
`tine
`
`
`
`Small etal"
`
`
`Fludarabine
`
`
`25
`
`
`25
`
`14
`
`
`
`14
`
`54
`
`
`
`5
`
`3
`
`
`20
`
`
`20
`
`II
`
`
`
`II
`
`45
`
`
`
`19
`
`
`19
`
`II
`
`
`
`II
`
`
`45
`
`a 0
`
`
`
`
`0(0-14)
`
`a a
`
`
`
`a
`
`
`
`0/0
`
`0
`
`
`2
`
`
`a 2
`
`
`
`18 (2-52)
`
`
`
`
`18
`
`
`0/4
`
`a a
`
`
`
`
`
`0(0-6)
`
`
`
`
`
`
`
`
`0.Q75 (0.200) mg/kg d 1-14 CI
`OM + Interferon 10 mU 1M
`
`
`
`
`
`
`TIW.
`
`
`
`
`
`0.125 mg/kg circadian CI d
`1-14 OM + Interferon 1-2
`
`
`
`
`mU/m2 OD.
`
`0.15 mg/kg CI d 1-14 + Inter-
`
`
`feron 3 mU/m2 SOTIWOM.
`
`
`
`
`
`
`
`
`
`
`
`
`
`100-2000 mg/m2 d 1-5 given
`
`
`between 1800-2 I 00
`hours + Leucovorin 200
`
`
`
`
`mgt m 2 IV day 1-5 between
`
`
`
`
`
`
`
`
`
`1900-2100 hours OM,
`0.1 (0,375) mg/kg CI d 1-5
`
`
`
`
`
`
`hours 03W + Leucovorin
`
`
`
`
`
`
`
`
`
`
`
`100 mg PO OH for four
`
`
`
`
`
`
`doses, then 04H d 1-5 03W.
`
`0.1 mg/m2 CI d 1-5 + Leu-
`
`
`
`
`
`
`
`
`
`
`
`
`covorin 100 mg PO every
`
`
`
`
`four hours for 36
`doses + Interferon
`
`
`
`30xmU/m2 SC d 1-6.
`
`
`
`
`
`
`
`
`
`O.Q7S (0, 125) mg/kg CI d
`1-14 + Vinblastine 0.7 (0,8)
`
`
`
`
`
`
`
`
`
`
`mg/m2 CI d 15-28 OM.
`
`
`NOVARTIS EXHIBIT 2034
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 19
`
`

`

`
`
`
`CHFf'10THERAPY FOR RCC
`
`
`47
`
`.--.-------------------------------------------------------------------------------.---~.--.--------
`
`Table:t (continued)
`
`-.------------------------------------------------~------------------------------~
`
`No,
`
`
`
`
`No,
`Percent of Adequate
`Un pre-
`
`treated
`
`
`
`
`
`
`
`CR PR CR + PR (95% CI)
`
`o 0
`o
`
`
`
`
`o 0
`
`
`I 8
`
`
`
`
`o 4
`
`
`o 0
`
`
`
`o 0
`
`
`
`o
`
`
`
`10 (5-17)
`
`
`9 (2-25)
`
`
`7 (9-25)
`
`
`II (3-27)
`
`
`0(0-19)
`
`o
`
`
`
`Reference(s)
`
`
`No,
`
`Entered
`
`
`No, Inade(cid:173)
`
`quate
`
`No,
`
`
`Adequate
`
`
`
`Shevdn et al75
`
`
`
`
`Balducci et al 76
`
`
`
`5-Fluorouracil, CI
`
`
`
`Kish et al 77
`
`
`Schulof et al70
`
`
`
`Ahgren et al"
`
`
`
`5-Fluorouracil + leu(cid:173)
`covorin
`
`
`
`
`Zaniboni et al80
`
`
`
`5-Fluorouracil +
`
`interferon
`
`
`Romero et al"
`
`
`
`
`Murphy et al"
`
`
`
`
`Sella et al83
`
`
`
`
`Schuth et al04
`
`
`
`18
`
`
`36
`
`103
`
`36
`
`31
`
`36
`
`14
`
`
`14
`
`
`66
`
`
`10
`
`
`15
`
`
`20
`
`
`21
`
`
`57
`
`
`15
`
`
`30
`
`94
`
`32
`
`27
`
`35
`
`14
`
`
`14
`
`
`63
`
`
`
`
`14
`
`
`20
`
`
`21
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`15
`
`
`30
`
`94
`
`32
`
`27
`
`35
`
`14
`
`
`14
`
`
`63
`
`8
`
`
`
`14
`
`
`20
`
`
`21
`
`
`39
`
`
`MR/
`
`STAB
`
`
`
`
`Initial (highest) Dose
`
`
`
`
`
`20 mg/m2 IVP d I + 35 mg/m2
`
`
`
`
`Cld 1-2Q3W
`0/14 25mg/m2d I-SQM,
`
`
`
`
`
`
`
`
`0/9
`
`
`
`
`
`0/13 Low dose Ct.·
`
`
`
`
`0/17 300 mg/m2 CI QD.
`
`'/*
`
`same.
`
`
`
`
`0/8
`
`
`370 mg/m2 d 1-5 + Leucovo(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`rin 200 mg/m2 d 1-5 QM.
`
`
`
`
`
`7'
`
`
`
`19 (10-31)
`
`o
`
`
`
`
`13 (0-53)
`
`
`0/2
`
`o 0
`
`
`
`
`
`0(0-19)
`
`0/ I
`
`
`
`
`
`5'
`
`
`
`
`
`
`
`
`30 (12-54)
`
`
`
`24 (8-47)
`
`
`3/0
`
`0/7
`
`
`
`18 (8-34)
`
`
`
`
`
`
`10 mg/kg (Tegafur"') PO daily
`
`
`
`
`
`for six months + Interferon
`
`10mUIMTIW.
`750 mg/m2 CI d 1-5, then 750
`
`
`
`
`
`
`
`
`
`
`
`mg/m2 QW + Interferon 9
`
`
`mUSCTIW.
`
`750 mg/m2 CI d 1-5 + Inter(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`feron 5 mU 1M d 1-5 QD,
`500 mg/m2 d 1-5 in weeks 2, 6,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10, 14 + Interferon 5 mU SC
`
`
`
`
`
`
`d 1-5 weekly for 14 weeks.
`
`
`
`5-Fluorouracil +
`
`uracil
`
`
`Esteban et alBS
`
`
`
`Niijima et al"
`
`
`Flutamide
`
`
`Ahmed et al87
`
`
`
`Flutamide + inter(cid:173)
`
`feron
`
`
`Hartlapp et al88
`
`
`
`Fosquidone
`
`
`
`Kaye et al'"
`Fotemustine
`
`
`
`Chevallier et al'o
`
`
`
`
`Lasset et al91
`
`
`
`Gallium nitrate
`
`
`Schwartz et al"
`
`
`
`Vugrin et al93
`
`
`Gemcitabine
`
`
`Weiss bach et al'4
`
`
`
`
`Mertens et al95
`
`
`ICRF-187
`
`
`Brubaker et al"
`
`
`
`Idarubicin
`
`
`Scher et al97
`
`
`
`
`Ifosfamide ± mesna
`
`
`DeForges et al98 /
`
`
`
`Droz et al 48
`
`
`
`
`Fossa et al99
`
`
`Bodrogi et at' 00
`
`
`
`16
`
`41
`
`28
`
`28
`
`52
`
`
`52
`
`
`26
`
`26
`
`90
`
`74
`
`
`16
`
`47
`
`12
`
`35
`
`56
`
`38
`
`
`18
`
`40
`
`40
`
`21
`
`21
`
`
`43
`
`19
`
`
`15
`
`9
`
`
`
`16
`
`
`
`
`
`
`
`12
`
`
`
`
`
`
`10
`
`
`
`o
`
`
`o
`
`
`
`
`
`
`
`4
`o
`
`
`
`14
`
`25
`
`25
`
`25
`
`52
`
`
`52
`
`
`21
`
`21
`
`76
`
`62
`
`
`14
`
`35
`
`10
`
`25
`
`48
`
`30
`
`
`18
`
`40
`
`40
`
`
`19
`
`19
`
`36
`
`16
`
`II
`
`
`
`
`39'
`
`
`14
`
`25'
`
`15
`
`15
`
`52*
`
`
`52'
`
`
`21
`
`21
`
`48'
`
`38
`
`
`10'
`
`30'
`
`5*
`
`25
`
`48
`
`30
`
`
`18
`
`23
`
`23
`
`
`14
`
`14
`
`31
`
`14
`
`II
`
`
`
`
`
`o 0
`
`
`
`
`2
`o
`
`o
`
`I
`
`
`2 12
`
`
`
`0(0-19)
`
`
`28 (12-49)
`
`
`4 (0-20)
`
`4
`
`
`27 (16-41)
`
`
`0/4
`
`1/8
`
`400 mg/m2 PO QD.
`
`
`
`
`
`600 mg PO QD.
`
`0/2
`
`
`
`
`
`
`250 mg PO TID.
`
`
`
`
`12
`
`
`27
`
`o 0
`
`
`o 0
`
`
`I
`
`I
`
`
`o 0
`
`
`o
`I
`
`
`o 0
`
`
`o
`
`
`
`
`
`
`o
`I
`
`
`o 0
`
`
`o 0
`
`
`
`o 0
`
`
`o 0
`
`
`o
`
`I
`
`o 0
`
`
`
`o
`
`o 0
`
`
`
`
`0(0-13)
`o
`
`
`
`5 (1-13)
`
`
`o
`
`
`
`3 (0-15)
`o
`
`4
`
`
`8 (2-20)
`
`10
`
`
`6
`
`
`0(0-7)
`o
`
`
`
`
`0(0-15)
`o
`
`
`
`3 (0-15)
`o
`
`
`
`o
`
`
`
`
`
`
`
`
`11/97S0mgPOQD+2ImUSC
`
`
`TIW.
`
`0/3
`
`
`
`
`
`
`120 mg/m2 d 1-5 Q3W
`
`0/19 100 mg/m2 d 1,8, 15, then
`
`
`
`
`
`
`
`
`
`
`
`
`from d 42 Q3W.
`
`same.
`
`
`0/4
`
`
`0/0
`
`200 mg/m2 CI d 1-7 QM,
`
`
`
`
`
`
`
`
`700 mg/m2 Q2W.
`
`
`
`
`
`
`
`0/17 800 mg/m 2 weekly forthree
`
`
`
`weeksQM.
`
`
`0/16 same (1250).
`
`
`0/0
`
`3.8 (4.75) g/m2 weekly for four
`
`
`
`
`
`
`
`weeksQ6W,
`
`0/ I
`
`
`*/*
`
`
`
`
`0/1
`
`0/3
`
`
`
`17.5 mg/m' Q3W,
`
`
`
`
`
`
`
`
`3 g/m' d 1-2 + Mesna 3.6
`
`
`g/m'd 1-2 QM.
`
`
`
`
`50-60 mg/kg d 1-5 QM,
`
`
`
`
`40 mg/kg d 1-5 QM.
`
`NOVARTIS EXHIBIT 2034
`Breckenridge v. Novartis, IPR 2017-01592
`Page 6 of 19
`
`

`

`
`48
`
`
`
`
`
`YAGODA, ABI,RACHED, AND PETRYLAK
`
`
`
`
`
`
`
`
`
`Table~. (e(Jllt/flue<!)
`
`Reference(s)
`
`
`
`
`Iseador (mistletoe)
`KjaerlOI
`
`
`Lomustine + ampho-
`
`
`tericin-B
`Presant et aP 02
`
`
`
`
`
`
`No.
`Entered
`
`
`No,lnade-
`
`quate
`
`
`No.
`
`Adequate
`
`
`No.
`
`No.
`
`Unpre- - -
`treated
`
`CR PR CR + PR (95% CI)
`
`
`
`
`
`
`
`
`Percent of Adequate
`
`
`
`
`14
`
`14
`
`
`5
`
`
`5
`
`
`63
`30
`
`
`33
`
`16
`
`16
`
`8
`
`8
`72
`
`15
`
`57
`
`212
`
`
`45
`25
`
`14
`
`
`95
`33
`
`
`16
`
`0
`
`
`0
`
`
`II
`
`
`8
`
`0
`
`0
`
`
`0
`
`0
`
`I
`
`
`
`15
`0
`
`0
`
`
`8
`2
`
`
`2
`
`
`14
`
`14
`
`5
`
`
`5
`
`
`
`44
`19
`
`
`25
`
`16
`
`16
`
`8
`
`8
`71
`
`15
`
`56
`
`187
`
`
`30
`25
`
`14
`
`
`87
`31
`
`
`14
`
`14
`
`14
`
`5
`
`
`5
`
`
`
`42
`19
`
`
`23
`
`14
`
`14
`
`8
`
`8
`71
`
`15
`
`56
`
`136'
`
`30'
`17
`
`9
`
`
`62
`18
`
`
`II'
`
`0
`
`0
`
`0
`
`
`0
`
`0
`
`0
`
`
`0(0-19)
`
`
`0
`
`0(0-45)
`
`
`
`0
`
`
`0
`
`
`0
`
`
`
`I
`3
`I
`I
`
`
`0
`2
`
`
`
`0
`I
`I
`
`0
`
`0
`
`0
`0
`0
`
`
`3
`0
`
`
`0
`
`0
`
`3
`0
`
`
`2 9
`
`
`
`
`0
`3
`I
`3
`
`
`0
`0
`
`
`
`
`I
`3
`
`'0
`0
`
`
`
`0
`0
`
`
`
`9 (3-22)
`
`II
`
`8
`
`
`6 (0-30)
`
`6
`
`
`0(0-31)
`0
`
`4 (1-12)
`
`
`0
`
`
`5
`6 (3-11)
`
`
`
`10 (3-31)
`16 (5-36)
`
`
`0(0-19)
`
`
`
`5 (I-II)
`0(0-9)
`
`
`
`
`0(0-19)
`
`
`0
`
`
`0
`
`MR/
`
`STAB
`
`
`
`'/'
`
`Initial (highest) Dose
`
`
`
`
`I (+escalation*) mL SC Q2D.
`
`
`
`
`
`
`0/0
`
`
`
`120 mg/m2 + Amphotericin 7.5
`
`
`
`
`mg/m2d I + 30mg/m2d2Q6W.
`
`
`
`
`0/12 350 mg/m2 QD.
`
`
`
`
`60 (450) mg/m2 QD.
`
`
`
`
`0/9
`
`
`
`0/8
`
`1000 mg/m2
`
`
`
`
`0/1
`
`
`30 mg/m2 IV QM.
`
`
`
`
`
`'/'
`
`
`'/'
`
`
`0/11
`0/9
`
`0/5
`
`
`0/4
`3/1
`
`
`
`200 (220) mg/m2 QM.
`
`
`
`same (240).
`
`
`
`
`500 mg/m2 QW.
`
`
`same (825).
`
`
`600 mg/m2 QW.
`
`
`
`same (700).
`same (700).
`
`
`
`
`Lonidamine
`
`
`
`Stahl et aPOl
`
`Weinerman et al"M
`
`
`
`Mafosfamlde
`
`Schomberg et apos
`
`
`
`Melphalan
`Falkson et apo,
`
`
`
`Menogaril
`
`
`Long et aP07
`
`
`Stephens et apoa
`
`
`
`M Itoguazone
`
`Child et apo,
`
`
`
`Todd et ai lio
`
`
`
`Fuks et aPIl
`
`Knight et al1l2
`
`
`
`
`Zefferin et aPIl
`
`
`
`
`
`Mltoguazone + mel-
`phalan
`
`
`Guimares CI et aPI4
`
`
`
`
`Mitolactol
`
`
`Mischler et aPls
`
`
`
`
`Brubaker et aPI'
`
`
`Mitolozomlde
`vanOss tram et al l17
`
`
`
`Mitoxantrone
`
`Gams et ai lia
`
`
`
`
`Taylor et alII'
`
`
`
`
`
`VanOsterom et
`
`aP20
`
`
`
`Dejager et aP2I
`N-Methylformamide
`
`
`Sternberg et aP22
`
`
`Abrams et al i23
`
`
`
`Navelbine
`
`Canobbio et aPH
`
`
`
`Wilding et al12s
`
`
`
`PCNU
`
`
`Elson et al'4
`
`
`Harvey et al 12'
`
`
`
`
`Pirarubicin
`DeVassal et al 127
`
`
`
`
`Roche et al12a
`
`
`
`Piroxantrone
`
`
`Allen et all29
`
`
`
`
`Shevrin et aPlO
`
`
`
`
`16
`
`
`44
`
`13
`
`31
`
`23
`23
`
`177
`
`
`58
`53
`
`
`43
`
`
`23
`
`36
`18
`
`
`18
`50
`
`
`15
`
`35
`
`84
`
`47
`37
`
`
`40
`16
`
`
`24
`
`
`68
`34
`
`34
`
`
`
`14
`
`44
`
`
`13
`
`31
`
`17
`17
`
`146
`
`48
`
`49
`
`
`29
`
`
`20
`
`30
`16
`
`
`14
`38
`
`
`14
`
`24
`79
`
`
`45
`34
`
`
`39
`16
`
`
`23
`
`
`63
`32
`
`31
`
`
`
`II'
`
`31
`
`
`0
`
`31
`
`17
`17
`
`102
`
`31
`
`28
`
`
`29
`
`
`14
`27
`
`13
`
`
`14
`
`38
`
`14
`
`24
`
`50'
`
`33
`17'
`
`
`39'
`
`16'
`
`23
`
`63
`
`32
`
`31
`
`
`0
`
`
`3
`
`I
`
`2
`
`0
`0
`
`0
`
`0
`
`0
`
`
`0
`
`0
`
`
`0
`0
`
`
`0
`0
`
`
`0
`
`0
`I
`
`
`0
`I
`
`
`2
`I
`
`
`I
`I
`0
`
`I
`
`I
`
`0
`
`I
`
`0
`0
`
`0
`
`0
`
`0
`
`
`0
`
`
`0
`
`0
`0
`
`
`0
`I
`
`
`0
`I
`0
`
`
`0
`0
`
`
`0
`0
`
`
`0
`
`0
`
`0
`
`0
`
`
`
`9 (3-22)
`
`
`8
`
`10
`
`0(0-16)
`0
`
`0(0-2)
`
`
`0
`
`0
`
`
`0
`
`
`0
`
`0(0-10)
`0
`
`
`0
`3 (0-14)
`
`
`
`0
`4
`
`I (0-7)
`
`
`
`0
`3
`
`
`
`5 (1-17)
`6
`
`
`4
`
`2 (0-9)
`
`
`0
`
`3
`
`
`
`0
`
`0
`
`
`6
`
`10
`
`4
`
`
`14
`
`
`3
`
`2
`
`
`4
`
`I
`
`II
`
`
`2
`3
`
`
`•
`
`I
`
`2
`
`3
`
`
`0/6
`
`
`500 mg/ m2 d I, 8, 22, 29 + Mel-
`
`
`
`
`
`
`
`
`
`
`
`
`phalan 0.5 mg/kg d I Q6W.
`
`
`0/5
`
`"/'
`
`200mg/m2d I-IOQM.
`
`
`
`
`
`
`180 mg/m2 d 1-10 QM.
`
`0/3 No dose given.
`
`
`
`
`
`
`
`*/.
`0/15
`
`
`0/14
`
`smg/m2QW.
`
`12 mg/ m2 Q3W.
`
`
`
`
`
`
`
`15 (19) mg/m2 Q3W.
`
`0/10
`
`
`14 mg/ m2 Q3W.
`
`
`0/3
`
`
`0/4
`
`1000 mg/m2 d 1-5 QM.
`
`
`
`same.
`
`
`0/5
`0/12
`
`
`
`
`
`'/'
`0/3
`
`
`'/'
`
`
`'/'
`
`30 mg/m2 QW.
`
`
`same.
`
`100 mg/ m2 Q6W.
`
`
`same.
`
`50 mg/ m2 Q3W or 40 mg/ m2
`
`
`
`
`
`
`d 1-3 Q3-4W.
`
`
`20 mg/m2 d 1-3 Q3W.
`
`
`
`
`
`0/1
`
`0/17
`
`
`150 (180) mg/ m2 Q3W.
`
`
`
`
`same.
`
`
`NOVARTIS EXHIBIT 2034
`Breckenridge v. Novartis, IPR 2017-01592
`Page 7 of 19
`
`

`

`CHEMOTHERAPY FOR RCC
`
`
`
`
`49
`
`
`,---------------------------------------------------------------------------------------
`Tabl .. 2. (continued)
`
`Reference(s)
`
`
`Poly IC:LC
`
`Droller et al" l
`
`
`
`
`
`
`
`Sparfosic acid (PALA)
`
`
`Earhart et al"
`
`Natale et al'll
`
`
`
`
`Spirogermanium
`Saiers et al ll3
`
`
`
`Schulman et al'14
`
`
`
`
`Streptozotocin
`
`Licht et al llS
`
`
`
`Sulofenur
`
`Weinerman et al' J6
`
`
`
`
`Suramin
`
`Iverson et al '37
`
`
`
`
`Motzer et al'38
`
`
`
`
`laRocca et aI'''
`
`
`
`
`No.
`
`Entered
`
`
`No. Inade(cid:173)
`
`
`quate
`
`No.
`
`
`Adequate
`
`
`II
`II
`
`
`
`74
`59
`
`15
`
`
`68
`
`32
`
`36
`
`20
`
`20
`
`19
`
`19
`
`
`
`44
`
`
`26
`
`12
`
`
`
`
`
`
`67
`52
`
`15
`
`
`62
`26
`
`
`36
`
`18
`
`18
`
`18
`
`18
`
`
`41
`
`
`
`25
`
`
`10
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`No.
`
`Percent of Adequate
`
`
`
`
`No.
`
`Unpre-
`treated CR PR CR + PR (95% CI)
`
`
`
`
`
`
`
`
`o 0
`
`
`o 0
`
`
`
`
`7'
`
`7*
`
`
`
`0(0-35)
`o
`
`
`
`
`3 (0-10)
`4
`
`o
`
`
`
`0(0-5)
`o
`
`o
`
`
`6 (0-27)
`
`
`6
`
`0(0-15)
`
`o
`
`
`10 (3-23)
`
`50
`
`
`
`o
`
`
`
`33
`25
`
`
`8
`
`33'
`
`IS'
`
`18
`
`
`IS'
`
`IS'
`18
`
`18
`
`
`
`40'
`
`6'
`
`25
`
`
`
`o
`
`
`o 2
`
`
`o 0
`
`
`o 0
`
`
`o 0
`
`
`o 0
`
`
`
`o
`
`o
`
`o 0
`
`
`o 0
`
`
`
`o 4
`
`
`o
`
`
`
`o
`
`
`o 0
`
`
`
`
`
`
`
`MR/
`
`STAB
`
`
`
`0/0
`
`Initial (highest) D