Dr. Howard A. Burris, III
`
`Novartis Pharmaceuticals Corp., et al. v. Roxane, Breckenridge and Par
`
`Case Nos. 14-1196, 14-1043 and 14-1289 (D. Del.)
`
`Plaintiffs'
`Presentation
`On Validity
`(RCC And Breast
`Cancer)
`
`PDX 5001
`
`

`

`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5003
`
`

`

`Person Of Ordinary Skill In The Art
`
`• Medicinal chemist
`
`• With access to a medical doctor with
`several years of experience treating patients
`with malignant or benign tumors and/or
`
`• A Ph.D degree in oncology or a related
`discipline and experience evaluating
`antitumor compounds in preclinical assays
`
`PDX 5004
`
`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5005
`
`

`

`RCC Treatment Options In October 1992
`Had Serious Side Effects And Problems
`
`WARNINGS
`PROLEUKIN@ (aldesleuk.in for injection) should be
`administered only in a hospital setting under the super(cid:173)
`vision of a qualified physician experienced in the use of
`anti-cancer agents. An intensive care facility and spe(cid:173)
`cialists skilled in cardiopulmonary or intensive care
`medicme must be available.
`Proleukin administration has been associated with cap(cid:173)
`illary leak syndrome (CLS). CLS results in hyp0tens1on
`and reduced organ perfusion which may be severe and
`can result in death.
`Therapy with Proleuk.in should be restricted to patients
`with normal cardiac and pulmonary functions as de-(cid:173)
`fined by thallium stress testing and formal pulmonary
`function testing. Extreme caution should be used in
`patients with normal thallium stress tests and pulmo(cid:173)
`nary function tests who have a history of prior canhac
`or pulmonary disease.
`Proleukin administration should be held in patients
`developing moderate to severe lethargy or somnolence;
`continued administration may result in coma.
`
`Problems with IL-2:
`• Very toxic, severe side effects in
`over 70% of patients
`• Black box warning (capillary leak
`syndrome, death)
`• Positive effect in only a small
`subset of patients
`
`“IL-2 treatment was associated with severe side
`effects”
`
`Stahl 1992 at p. 73
`
`IL-2 alone is “only marginally active in RCC”
`
`Wersall 1992 at p. 71
`
`PTX 597 (IL-2 (Proleukin®) PDR 1993), 607 (Stahl 1992), 618 (Wersall 1992)
`
`PDX 5006
`
`

`

`RCC Treatment Options In October 1992
`Had Serious Side Effects And Problems
`
`Problems with interferon-alpha (IFN-α):
`• Not FDA approved
`• Small subset of patients responded
`• Toxic, severe flu-like symptoms
`(fever, fatigue, headache)
`• Toxicity limited dosage and efficacy
`
`PTX 551 (Belldegrun 1992), 596 (IFN-α (Intron A®) PDR 1992), 607 (Stahl 1992)
`
`PDX 5007
`
`

`

`PDX 5008
`
`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5009
`
`

`

`

`

`

`

`Others Tried And Failed To Develop New
`Therapies For Advanced RCC Before October 1992
`
`PTX 582 (Merimsky 1992)
`
`PDX 5012
`
`

`

`Everolimus Satisfied The Need In Advanced RCC
`
`RECORD-1 Phase III Clinical Trial Design
`
`• Double-blind, randomized, placebo-controlled, multi-center
`phase III trial
`
`• Enrolled 410 patients after failure of sunitinib, sorafenib, or
`both
`
`Afinitor® (everolimus)
`
`(n = 272)
`
`Crossover to Afinitor®
`(everolimus) upon
`disease progression
`
`Placebo
`
`(n = 138)
`
`R A N D O M I Z A T I O N
`
`2:1
`
`Metastatic RCC
`
`Prior treatment with
`sunitinib, sorafenib,
`or both
`
`(n = 410)
`
`PTX 583 (Motzer 2008)
`
`PDX 5013
`
`

`

`Everolimus Satisfied The Need In Advanced RCC
`
`RECORD-1 Phase III Clinical Trial Results
`
`PFS after progression on sunitinib or sorafenib1
`
`100
`
`~
`>
`~
`.c
`"' .c
`~
`a..
`en
`u.
`a..
`
`80
`
`60
`
`40
`
`20
`
`67%
`
`reduction in risk
`of progression
`or death
`
`0 -+----..!,,.--------------!.------,.-----!=;;==~-------.-----.....--------,
`14
`2
`10
`12
`4
`6
`8
`0
`
`-
`-
`
`AFINITOR: (n=277) 4.9 months (95% Cl, 4.0-5.5)
`Placebo: (n=139) 1.9 months (95% Cl, 1.8-1.9)
`
`Time (months)
`
`HR=0.33 (95% Cl, 0.25-0.43) Log-rank P<0.0001
`
`• 6 month PFS rate: 25.7% for everolimus vs. 2.1% for placebo
`• Everolimus lowered the risk of tumor progression by 67%
`
`PTX 583 (Motzer 2008), 591 (NPC02181740-745)
`
`PDX 5014
`
`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5015
`
`

`

`Breast Cancer Treatment Options In October
`1992 Had Serious Side Effects And Problems
`
`Problems with hormonal
`therapies (tamoxifen):
`
`PTX 569 (Greenberg 1991), 579 (Macheledt 1991), 598 (Nolvadex® PDR 1992)
`
`PDX 5016
`
`

`

`Breast Cancer Treatment Options In October
`1992 Had Serious Side Effects And Problems
`
`Problems with chemotherapy
`(cyclophosphamide,
`methotrexate, 5-fluorouracil,
`doxorubicin):
`
`PTX 569 (Greenberg 1991)
`
`PDX 5017
`
`

`

`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5019
`
`

`

`Others Tried And Failed To Develop New Therapies
`For Advanced Breast Cancer Before October 1992
`
`•
`
`•
`
`Interferon-alpha did not
`overcome tamoxifen resistance
`
`Interferon-alpha caused
`additional toxicity
`
`PTX 579 (Macheledt 1991)
`
`PDX 5020
`
`

`

`Everolimus Satisfied The
`Need In Advanced Breast Cancer
`
`BOLERO-2 Phase III Clinical Trial Design
`
`• Double-blind, randomized, placebo-controlled, multi-center
`phase III trial
`
`• Enrolled 724 patients after failure of letrozole or anastrozole
`
`Metastatic Breast
`Cancer
`
`Failure of
`letrozole or
`anastrozole
`
`(n = 724)
`
`Randomization
`2:1
`
`Afinitor® (everolimus)
`+ Exemestane
`
`(n = 485)
`
`Placebo +
`Exemestane
`
`(n = 239)
`
`PTX 621 (Yardley 2013)
`
`PDX 5021
`
`

`

`Everolimus Satisfied The
`Need In Advanced Breast Cancer
`
`BOLERO-2 Phase III Clinical Trial Results
`
`100
`
`Hazard Ratio = 0.38 (95% Cl: 0.31-0.48)
`Log-rank P value: < .000 1
`
`., 80
`C
`Q)
`
`> w -0
`
`..0
`ro
`..0
`0 .....
`0..
`
`Kaplan-Meier medians
`Everolimus + exemestane: 11.0 months
`Placebo + exemestane: 4.1 months
`
`60
`
`40
`
`20
`
`....,_ Everolimus + exemestane (n/N = 188/485)
`....,_ Placebo + exemestane (n/N = 132/239)
`
`0
`
`0
`
`6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
`Time (weeks)
`
`• Everolimus increased PFS from 4.1 months to 11.0 months
`• Everolimus boosts the effectiveness of hormonal therapy
`and overcomes resistance to hormonal therapy
`
`PTX 621 (Yardley 2013), 1068 (BOLERO-2 Kaplan-Meier)
`
`PDX 5022
`
`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5023
`
`

`

`In Vivo Activity of Rapamycin Against Tumor Models
`
`PDX 5024
`
`

`

`PDX 5025
`
`

`

`

`

`The NCI Tumor Models Used Before October
`1992 Did Not Predict Antitumor Activity In Humans
`
`No correlation between activity
`in an in vivo model of one tumor
`type and activity in human
`tumors of the same type
`
`PTX 552 (Benvenuto 1992), 581 (Marsoni 1987), 602 (Schilsky 1991)
`
`PDX 5027
`
`

`

`In October 1992 Rapamycin’s In Vivo
`Antitumor Activity Was Unpredictable
`
`I«t .c;l l,JS.N rn ~Offll)(lll-M!!- i n hnnaan tu.v>r ~ra:fu. r• Vff/8
`
`Appl_i cation
`
`Compound
`
`Rapamyci n
`
`Dose
`mg/kg/day)
`
`Schedule
`(days)
`
`R o ute
`
`Tumor
`
`Histo ogy,
`carcinoma
`
`Growth
`delay
`
`RTS (%)"
`
`Activity•
`
`100
`100
`100
`100
`100
`100
`LOO
`
`1-4
`1-4
`1--4
`1-4
`J-4
`1-4
`1-4
`
`i.p.
`i.p.
`i.p.
`i.p.
`i.p.
`1.p.
`i.p.
`
`GXF97
`LXFA 629
`LXFL 529
`LXFS 538
`LXFS6i0
`MAXF401
`MAXF449
`
`Gastric
`Lung, ad4:no
`Lung, large-c.ell
`Lung, SCLC
`Lung, SCLC
`Br ast
`Breasl
`
`2.75
`2.96
`4.80
`5.'20
`1.83
`4.49
`3.20
`
`120.2
`122.3
`119.7
`91.5
`201.3
`122.2
`74.4
`
`No change
`No change
`No change
`No change
`Progress.ion
`o change
`Minor rcgrei.siun
`
`• Rehnive tumor !.i:t.e at day 2 1 or d ay 28.
`b Progressjon, 125% < RT S; no change, 75% < RTS ~ I 25% · minor regression, 50% < RTS ~ 75%; partial remission, 10% < RTS ::;;: 50%; complete remission,
`RTS ~ 10%.
`
`•
`•
`•
`
`In vitro: selective for small cell lung cancer (SCLC)
`
`In vivo: no change/tumor growth in SCLC models
`
`In vivo: one breast tumor shrank 26%, the other
`breast tumor grew 22%
`
`JTX 168 (Fiebig 1990)
`
`PDX 5028
`
`

`

`In October 1992 Rapamycin’s
`Mechanisms Of Action Were Not Understood
`
`Antitumor Activity vs. Immunosuppressant Activity
`
`Mechanism of antitumor activity
`
`~•bit ~). The rn~~;rn.,rn 1olt.-;11t'd <.koK ""' 100 "'II k1,r.fay gi,·m on d111 l,8 and I)
`,.p. A h>lh 1n1inoopb.cif tffir:.(\· .,._~.-.·.-d ;., 111 !"m()f) !nlnl. I n the p.mi,c C-•l>Cc~
`,·- --~'--rl ,hl--1nnrrrmodrl MAX •"401rqi~
`(.'{f<l7 ,-,,~I
`. "
`!1rg,-..-~Ul11nicc1ncn l-X H. ):1'9,1
`-.J:,i:;:~1i::7"" ... ,icu,i,·i1r .... ,,..
`
`~ -
`
`1ografts in N ude M ice as
`
`1 SVl.\"A M Jl l ll,l. f:T1 and OOSAI.D E, 5LAC:1!:l.l
`
`. ,.....,., _.., •. T~w
`IU~l)w" •
`.....,
`
`ppressive Agents
`
`Rapamycin “inhibits DNA synthesis by interference
`with thymidine incorporation” Fiebig 1990 at p. 116
`~========================================================================================================================================~"=======================;::.::.:~~~.:::::,.~:~=:";;."'~~~1:
`_,, ... ,.,.~ .. ,~~-
`..,.,_ ........ , .......
`~,.,.... ......... ,., .. .,
`“In human tumor xenografts, rapamycin showed a high
`::~.::i;--~!"t'!:
`_.,,~.-.... ...,
`.. ,., ur,_.,.. .. .,.,
`·~2!~?=~~~~
`cytotoxic potency in the clonogenic assay in vitro”
`Fiebig 1990 at p. 116
`
`.. ..icJ1haol~•-,nook<dfn,mlfflpn,,11:,
`
`... ~ .... ..,,.,., ... ,( ... i .... ~ ... ,Jultl><"' ...... s. ....
`bolhJ,.._,_,.,.,.,...i..,,-arc11oL1M(aoo:U'll1!1Cnp(cid:173)
`,-•11hofllff)' .... afMl•~bd1'ffT-«il
`a<I"'•'- IC,. IG G, lfllMII- af Ml <yt"I<), n •1n ••·
`.. ,..,,..,.,~..,.,. ,..,.,.. r..,~.,.,.r ,n 11,, ,..,....., .. .,,.
`-« ... 1<W1Wn ..... d1..,,_~r-,,.,,.latt)'p,ara"••
`- - , ,..., ,._. .. ,.,,u-req,,ftd111C_,,...11CU¥ioy
`of"'->ch~'Tho,11on<1..,...i,...,;i..;,,,...,
`.,.,,.,. .. p,plo,;lyl•p,dyl N,,,,....,
`,1><-t..-lM~1ilh.. 1rw!~"•1·. . i -.' Ju,ddi"""
`"'k•-•••-•,lbl ...... Nlt!lnotol1nJi<a,-.CyA
`- " " - bY '"" """""'' ,.., l><Mh •~~ - ...i
`FKOP.
`,...,,
`~ollh<_,,,,._, • ....,,,,,..._1om,_.
`n.t.o .. odclyc.....,)'al.,..,upnftllllllO>lfo,kw
`._....,._ a..t Illa! 11,.,. a<11>MV WM fllo>Cbd br cM
`,.._11.•J•""""ncknl....._ ....... ,nnwtuc,;_,-ob•
`-,-.w,.. ....... -1 ,,,,,,.;wn,...r,,, ~
`r.iw•or • .........,;,;,,,oo ... .......,...ar...1r.....,.._
`inl..-."ffll-.'
`llarlyim.,........,,.,,1111;.,,..,_,n1n1 ,11a1CrAbkl<l•
`..-,;.-.,.,.. J T <><lb and d"" ,1,.,, "' ,..1, "'"'h' rm.,
`w.-- ut,~- of ly,.,...,.__ -
`_..,,,.
`ililfflnll,.,.-1 t ll.-l). lM ..... -·ch flOCI.,,. r ... Ttell>."
`
`::·~-:. ~.'::1::::: ~::.= ==
`
`Mechanism of immunosuppressant activity
`
`-t,yC,A_,i,1i..t.bylMibirli,all..-lr>p«>ioa1n
`Tcdl>,C'yA p<<•CO•h h<lpaTcd, f"""on:k>•~ ...
`
`11ic~1.-q,1oftllc-.... of---•
`=~~:,.':::'~_:',..'!::,"_ori.,1; •• ~=
`Rapamycin suggested to be cytostatic to immune cells
`Baumann II 1992 at p. 4
`
`-=.=-...E::::===
`Rapamycin “block[s] downstream events leading to
`T-cell proliferation, e.g., … G1 to S phase”
`
`~~&-.:IN.UI03tt.CH-<ICIIR--
`
`:i!~:w~~oi..-oo
`
`Baumann II 1992 at p. 4
`
`JTX 65 (Baumann II 1992), 168 (Fiebig 1990), 183 (Houchens 1983)
`
`PDX 5029
`
`I
`
`_,,,..,....,noploili,,(fKlll').b,fl<llna_"',..r..,n
`;,~lw:tfrt't1>l"K"6•n.:l...,..,.,r<irl,Md 111df,,c1<•
`........... -
`.. ,.,..;1',cfo,b<,ct,dnop,''
`Stl'&loSlr, 1ho _,,. d........,_• ~ Ila, -
`F"'"' ____ LII, __ ,
`
`ll.-Z """""""''°"' n,;, do.,lr -.,,a1u ,._, tho
`irlubil""'dlh<P<POdyl-p,,:,l)"lril-,r-•.-.Cnwac,;..
`ioyoff/KIIP i, ..,-.ullk,t1ff ...,..,IO-.i..,c1he~
`,.-.,., ufFK • " 1• -11.-. k""" bcffl - - • bY
`a,mpdio"""ol'<"""""'' 1M l'K"°6 ..... ~yc;,,....,-,
`llnJlo•-•-ctldofr«c,-o,,....,c.._)'C>ft
`cana<:1•••-ao....,....,ofFK"°6."Tbe-,.•1
`~-•"""boohd,_a.:c_,,..,....,..,..,.
`
`_,.,ofT.,:ct1!nh;t,it;,.,nb)'CrA-.lf K 50!,,
`Am:.,iof.-cptio<ool-.,c.,.._ h dota""°"'y-c,
`-i-;.......,-,r,rrn....,,.,i.. .......... ,_,,,yt" ...
`wlnok.,...nob,1«lfrom.\,,,p,,-,,.,,.,.,.......,,..-.,,
`n,;,,.......,,...iintih,T<da<l"'Mioftot~UIOC(cid:173)
`~•uthuo<.,{1i.,>0,"<hnllrrcl'"l«lfK"°6,but
`..... ~ ~ ~-;.,., ,,..,, n •"~r .i,11<,ttt11 r.- 11111,
`-•INlbyul><rt'K:!Ol,otCyA"~r<in<loo""'
`....... 11><1_......,.._or...,.yT-<dl..,,, ... '°"_•
`""'llldmt. U,1. i... _ . , . in"tad ,oblod, do¥•n•l.rO!II
`• .....,.,ln<l ... hlT-alpn,lif"91-,<••'""..,...,...,,.
`J....-.- ,,.,h-r •"""""lllf fn,m Ir..,._ N«fMor-.,
`,uc!,a,oho 11..-l_,...,..(G, ,.,s~,....,..,._,
`~ - - -1<>FKKl' -inlllboo,11>tpc:plNl)I•
`p«>lylril-ll,....,_,.n ...... lY.y.butildunlllllil'lllit!ol
`
`

`

`Oral Cancer Treatments Were Available In October 1992
`
`Oral cancer treatments
`available in October 1992:
`
`• Chlorambucil: blood cancer
`
`• Tamoxifen: breast cancer
`
`• Altretamine: ovarian cancer
`
`PTX 569 (Greenberg 1991), 598 (Nolvadex® PDR), 626 (Hexalen® Approval
`
`History), 658 (Leukeran® Drug Details), 659 (Leukeran® PDR)
`
`PDX 5030
`
`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5031
`
`

`

`Everolimus’s Unexpected
`Combination Of FDA Approvals Is Unique
`
`PDX 5032
`
`

`

`Temsirolimus Is Inactive In Small-Cell
`Lung Cancer And Soft Tissue Sarcoma
`
`PTX 666 (Okuno 2011), 668 (Pandya 2007)
`
`PDX 5033
`
`

`

`Not All Analogs Were Expected To Have Similar
`Activity Or Toxicity To Their Parent In October 1992
`
`Several Analogs Were Failures
`
`c,...-oJ""•"uu,O..ulofy/lfmtalllloty, 1991 :L l:4)-(l,4
`•') 19'1!F.LM-.,,..,Sacr:ocl'llb!iJ.'1im9V. 1°"°""'?8/JI/U.SO
`
`Doxorubicin Analogs:
`
`New anthracycline antitumor antibiotics
`
`Franco M . M uggia 1 a nd Michael D. Grccn2
`'IJ;,-,--., t,fM,diri,,t. u111..,.,.,, ofS,,,.,,,.,,,~ (MifonW. Lo, ,..,...,i., •. CA -4:0,,,.,,,,-
`
`,.,__ n-. Vol U . "'· ll-4&. 1991
`l'mNol ia 0 - &.,1-. Aft "'IIK• -IWllll
`
`• 4’ deoxydoxorubicin: clinical studies
`“universally disappointing”
`
`THE CLI NICAL PHARMACOLOGY AND
`ANTIMICROTUBULE AGENTS IN CA
`CHEMOTH ERAP EUTICS
`
`Eit!C K. R OWTNSK Y and Ross C. (}ot,,'Qf()W(a
`DiriJ'- of,._"""""°":, -.II b,-.,_u,1 n,,,.,,..,in, n.t Jo,luu H~ ,.,
`6()0 Norill w.q, S1tttl, &lltlMot~, "'°''"°"" 2110.S. u.s
`
`A~- Althoui)I theft bu botn a rapid «pt.n.tioft of 1k ll'lti1rnbe1 of dU1.
`bll~IICli\'1l7.kwba\'\'{)Q)'cdamott'1\alrol.cintbeCW11liYean.dpulia1
`than. lbc antirnicrotwbulc t,,mt1. AltbcM,Jb I.ht rioct 1lkaloicb U-..e bccft !he Ofli
`tubl,lle ql!IIU that bl\'\' hid bo-oad upcrilllfflUJ Ind diaic:al app&.UON ia oao
`the Jut M"Troll dealdct,. the ll.UOC,, led b)'ffle l)fOl«ypicac,ml w ol. ~ ClnefJI"
`cU of 1111iffiicrot11buk a,mn. Ark, bridty rnxwi,q the rncdu.nisms of ..,
`~occ. thlt utkk comprdw.nw<o'tb' ~1 !ht chllkal p~ ay. \ku1
`dinical 10>.ic:i1ia of XS!cd an11mK'ro1ubulc ag,mu.
`
`CONTENTS
`
`I . l111roduc:1-
`l. Vi.:a Albloi~
`?.I. Cmv,a\
`2.2. Medu,nmn:11 ofKtk,a.
`2.l . M«ban.iuru of r-nutaace
`2.4. Vincmtinc
`2.4..1.0iaicslpharll'lK'Oloo
`2.42.DDR:andte:bcdulc
`2.AJ. OilllCll applkatiON
`:u.4. ToJiriria
`:U. Vinbla.t,nt
`2.5 I ainbl pb,.rmac:ok,ff
`2.5.2. ~•ndtclwdid,
`2.5J. Cliak:&lappliar,lion.
`?.5.4. To.iirit>tt
`l .6 Vinckwtw
`2.6.1.Ctiaicllc,llannaco~
`2.6.l. OolC and xhcdulc
`2.U. Clillic:lltrialt
`2.6.• Toxiri1W$
`l.1. Vmon!buw ( Na.vclbulc)
`2.11 Prec::lrnic:al
`2.7.l. Oiaical phannacoloo
`1.7.l. Dotcal)dtehc,dwlc
`2.1;l. Ctiiucal trials
`!.l.$. ToAkitin
`) Tau.na
`J . l. Tuol
`)11 Me,;Mni...u o(aa,on
`l .1.2. Pn!tlln.ical anlineoplutic Ktlril)'
`) . J . ) . Mo;:hani,nu of muta.«
`) .14. Oiu:11 pharmaeolol)'
`J.I~. Dow .nd schedule
`ll .6. 0i11kal1ril.b
`
`'·" , ... _.
`
`NY
`lllt)'of
`M.D.
`0.. 0
`
`"""" "-
`
`AlbbnTOll1,0,U . ALL • &C\ltc l)·mphOqtlc: kulcmia; ANLL • KIIIC -iympboq,k
`ume-~u-nlrahon c11n,c: ONA -4coxyribosc: nuc~ .ad: G M-CFC-sr.-nw«
`cdl; OTP • 1uaaos1nc
`lriphosphatr. HSR • b)y.nrm.i1lvily
`rnc:tion; MAP, •
`
`NCI - Na tional C•- lnM.1t11ir. NV8 • WIOJclbuw; (NaVi'lbin,J: SlAOH - tyndt
`
`anudiwttic homtonr.
`
`- half-bl'r. V81. - vinbln1i11e: VC R - ....:riMine:; VOS • rink\
`
`• Aclacinomycin: “without significant activity”
`in most solid tumors
`
`• Carminomycin: “significantly inferior to
`doxorubicin” in breast cancer
`
`• Epirubicin: “No objective response” for
`stomach and colorectal cancer
`Muggia 1993 at pp. 56-57, Vorobiof 1989 at p. 564
`
`Vinca Alkaloids:
`
`• Vinleurosine and vinrosidine: “abandoned due
`to their exceptional toxicities”
`
`Rowinsky 1991 at pp. 36-37
`
`JTX 169 (Muggia 1993), 171 (Rowinsky 1991); PTX 684 (Vorobiof 1989)
`
`PDX 5034
`
`

`

`Comparison To Everolimus RECORD-1 And BOLERO-2 Trials
`
`PDX 5035
`
`

`

`PDX 5036
`
`

`

`Temsirolimus Has “Little Activity”
`In Neuroendocrine Cancer
`
`PDX 5037
`
`

`

`Temsirolimus Does Not Have The
`Same Clinical Efficacy As Everolimus
`
`PTX 686 (Wolff 2013)
`
`PDX 5038
`
`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5039
`
`

`

`PDX 5040
`
`

`

`Current Advanced Breast Cancer Treatments
`
`Treatment
`
`Approved Line Of Therapy
`
`Nolvadex® (tamoxifen)
`
`Arimidex® (anastrozole)
`
`Femara® (letrozole)
`
`Aromasin® (exemestane)
`
`Faslodex® (fulvestrant) (alone or in
`combination with anastrozole)
`
`Ibrance® (palbociclib) plus letrozole
`
`Chemotherapies (Xeloda®
`(capecitabine), taxanes)
`
`Afinitor® (everolimus) plus
`exemestane
`
`First-line
`
`First-line
`
`First-line
`
`First-line
`
`First-line
`
`First-line
`
`First-line
`
`Second-line
`
`Labels: JTX 155 (Afinitor®); PTX 536 (Arimidex®), 538 (Aromasin®), 560 (Faslodex®), 567
`
`(Femara®), 575 (Ibrance®), 841 (Nolvadex®), 869 (Xeloda®), 1069 (BC Treatments Summary)
`
`PDX 5041
`
`

`

`Summary Of Opinions
`
`Renal Cell Carcinoma (RCC) And Breast Cancer Indications
`
`• No reasonable expectation of everolimus’s clinical
`efficacy
`• Objective evidence of nonobviousness
`• Everolimus satisfied the long-felt but unmet
`medical needs
`• Others tried and failed to develop new therapies
`• Everolimus has demonstrated unexpected
`properties
`• Everolimus has received industry praise
`• There is a nexus between everolimus and the
`commercial success of Afinitor® (everolimus)
`
`PDX 5042
`
`

`

`Everolimus Has Received Praise For Its Efficacy And Use
`In The Treatment Of Advanced RCC And Breast Cancer
`
`Everolimus “considered standard of care for 2nd
`line” RCC treatment with study results described as
`'\)\.ooes\. a:
`“solid” and “profound” RCC ATU Waves 2, 3, and 5
`Y
`Y,ieas\ ('J).\\cei (liui eveio,\11\us ""
`fus ;.s 'oe;.niuai\eo.as =---:-:,:-:-::----=========-----
`mat'nas fue \lo\en\ia\ toe:
`t,.new'o,eas\. can~e, orut
`==========------
`Everolimus “importantly offers women an effective
`ao.'lances ;.n ,ea1? ·
`,ifu ao.'lanceo. &sease 'o~ \1\on
`alternative to a chemotherapy regime”
`Prof. Stephen Johnston
`
`Reasons tor Anticipated \nc
`for 2°d-Line Treatment of A
`
`Adams 2012
`
`(cid:141) ASCOlntormat\Oflw.lSpro10Uod
`.,_ Jus\ s1.ortlng to use rne dru9
`'; Pat1entspceferort1I
`; More referral,
`; e.11ectNe ,ncreased
`> 1tonlY ree•n•Y earn• ou\, and I am ge1\in9 rnor• e,oenenceusin9 ii
`> Gu,celinesand would Ilk• ••P
`using \\W drug
`> n,ere .,. ,1udi••
`olhel dN9S and If \hes& ...
`
`pe>Sit\ve my use ol
`., convenient sod well tolerated
`; Mucntietter to\ef8\eC1thantorisel
`(cid:141) New ageot with good 8Cfr,iity in 1KI failures
`> Reeent lavorable eltpenence with the dtU9
`> -;ng rnOf• 1arnllia"''"· since apl)<O"ed· or.ii ,s. IV m10R
`., t,AoreellectNe
`
`\nl'\ib\\Of
`(cid:141) t oterence and ethcecv
`(cid:141) ~cc11ent tolerablll"..Y
`; 1hl• •oenl nas emca<Yin ,..., 2nd \in& end lits rnY ueaunen\ pa\\L
`> Good 1o1erdflCO, eon,eni""'- sa\isfac\OIY resP"" .. •"d PfS dac.
`
`7 Good tolerance and ellic<IC'J
`'.i' N~Y 8\'ai\able
`,. since
`AlsO I
`gett\"'9
`; Well toteroted,ccal
`
`“Everolimus is one of the biggest advances in
`breast cancer treatment in many years”
`Dr. Rachel Greig
`
`Adams 2012
`
`“Everolimus is the most important advance in
`breast cancer since trastuzumab”
`Dr. Fabrice André
`
`Chustecka 2011
`
`PTX 521 (Adams 2012), 526A (RCC ATU Wave 2),
`
`527A (RCC ATU Wave 3), 528A (RCC ATU Wave 5), 556 (Chustecka 2011)
`
`PDX 5043
`
`

`

`Dr. Howard A. Burris, III
`
`Novartis Pharmaceuticals Corp., et al. v. Roxane, Breckenridge and Par
`
`Case Nos. 14-1196, 14-1043 and 14-1289 (D. Del.)
`
`Plaintiffs'
`Presentation
`On Validity
`(RCC And Breast
`Cancer)
`
`PDX 5044
`
`