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`prostate cancer progresses h) androgen mdependence,
`dmlops various ’pafiiways‘ allowing for gmth in the
`absence of beamstemne. Fm mph, cells may increase the
`syndxesis of androgen receptors, aflowmg them an flourish
`with very low levels of hesbosharm. Thix is known as the
`‘hypemexwfiiye pathway‘, In the ’prorniscuoua pathway‘, the
`axxdmgen recepfm mumms and is activated by a. broad range
`bf other circulatfing steroids, The ancimgen mm: is
`hmcfive nukes phdsphorylahed» In the ‘ontlaw pafltway‘, tbs
`temple:
`is
`abarrantiy phosphoryiamd afiang for
`cmfimfive receptor acfivaflon,
`In mattress: a bypass
`pathway“ allows for cell survival in the absence cf andrngen
`recepmr activation, allowingcells in- avoid apoptosis and an
`antiwmirogm environment {4}.
`
`Eackground to: the treatmam of MPG
`Wigws by Yagoda 3t l’etrylak [5} and Raghavan e: :11 [6E
`'acmramiy pdmayed the available cyboloxfc agents as
`ineffecfive in treatmg MPG Clinical
`trials evaluating
`anthracyciims alkylafing agmms, anfinwfabofim plafi‘nmm
`based agants and mpomm mhibiWrs was: reviewed
`{5,6}; Dvmall response rates {if 8.7% were notedin 2:3 clinical
`trials conducted between 198? and 1991. The bmad range: of
`xeporhed response mm and the lack of smnéaxdizeé
`objective: W cmtfabmied the
`reflewem, wlm
`dmribed the chemoflmerapeufic landscape? as cm {5}
`Subsequently the 9833; maponse was amped. as be
`standard Mpghzt’when‘ measuriflg the efimahy bf new
`chemadmapeuth: agents. A 1999 6W ,cenfexeme
`$2th a partial respmse in a clinical ma: ah a minimum
`I’SA decline of at least 50% cmxfirmed by a aecami E’SA
`value cal almflm' levels 4 03* mm wakes mar in the absent“
`
`(31; clinical at fadiogmphic evidwce of diseasb magma
`during this time perm {'3’}. This is what is typically mam"
`by a ’PSA mpanse‘ and is. used ad a measure of
`clemenstrable aefiviiy in phase ll clinical trzals
`
`Qiinlcal treatment with taxanes
`33062123er {Taxom} is a semi-synfltefic W, which
`disfiipm mrmal mim by bindmg to {Muhulin and
`premting ndcmmbuhz diambly Tins event: leads m an
`arrest m film cell cycle at the GM phase and ultimately
`apopizosis Varmus prwapophotic mechanisms 9f dccehaxei
`mludleg mahfivation of Bel-2 by phasphmylafinn,
`haduhtécn of p53 and overcommg multiémg resiam‘e have
`also» been proposed [4}. Initial phase II clinical trials with
`£1le revealed mate mam-aging response rams mart
`any previous agent it: AIPC and led to two large phase 311
`dials, bath ofwhich were mpmied it: 20%
`
`Docefaxe! plus ashamusfine versus mitoxantrone
`plus prednimm
`The randammed clitmal trial. Soumwesf: Omology Group
`(SW06) 9916 trial, compared docetaxel and estamusfine
`(DIE) with mmxanmne and prednjsone {M/P) in the
`
`JANSSEN EXHIBIT 2027
`
`Wockhardt v. Janssen |PR2016-01582
`
`W'Current chemotherapeutic approaches for androgen~independent prostate
`ancer
`
`539
`
`
`Jon A Rumohr & Sam 8 Chang"
`Address
`Vanderbilt University Medical Center
`
`99:13an of Umlogic Sargent
`A4302 Medial Center Non}:
`Nashville
`
`TN 37232«2735
`UsA
`Email: sam.chang@vanderbflt.edu
`
`‘Tao Wham mnespmdenm should be addressed
`
`current Oprah‘s: In Inmfigafloml Drugs 2606 1&me
`
`@Them Whoa [SEN 3472436”
`
`
`This review describes the current state of chemqflwmpy fa?
`
`' androgenéndependmt prosmte mixer. Landmark clinical trials,
`
`including TAX 327, a randomized trial whipping @le mm!
`
`preénisanz with mitoxahtrwe and predzdm and SW06 $93 6.;
`
`:2 madcmizad slim! Ma! 60ng 2305333le and esmmhtihe
`
`with mito‘mnfrm and pradyzisme,
`are reamed. Novel
`
`combination fizmzpies,
`involving Mane adminiséemi with
`
`campmlnds sud; as Mahdi and tlwlidamide, 1W mom
`
`agents vaccine therapies, and targéied ”Wishes are also detailed
`
`This revimv mlyfamses an agents with activity in phase xii/III
`iiiniczxi mm
`
`
`chemofitexapy,
`Aacimgeneindependence,
`Keywords
`hormmrefrachary, minamtic, prostaie CarmenW
`
`lniroducfion
`
`Admocamimma of the 913%th is‘the moat summonsalid
`tumor in 33 males, and is mend may m 11mg amt as, a
`cause» of swarm. In 2005, pmstam we: accmmd' for
`an estimated 33% of cancer cases and 16% ofcancer deaths
`in the US {1}. Wrap}? direcmd at pteshmahly leashed
`disease is successful in mg majority of cases, Wham“ by
`opmative means: at tadiaihm Despifse treatment myofvidg
`radical prosmmctomy, pmgmian rain: at five anti m years
`are estimated to E25322 and 25%, respectively, as measured by
`prosmte-specifib anfigmr (1553A)
`levels {2}. A3 with any
`metastatic malignancy, tlmapy for noanlohaiized disease
`requires system's treahnmt. Unlii madly, medical 03'
`surgical casuafion wa$ am only tenable systemic metapy
`available in mm With mmmtic prostrate meet The
`mailing} of mdmgan deprivation dams back in 1941, when
`Huggins 8:: Hodges separated the efficacy {if castratim am?
`esmgens in the armament of advmced Wyeth? came!" {3'}
`Unfortunately the gfficacy of 3116:90an depfivafim is
`limited by the pmgreshiozx to audmgen»mdependent
`prostate cancer (A132). 31:: men with memmfic probate
`cancer, this progression typically occurs within 12 {:0 18
`mondjs, mailbag in amedian sumivalof. two m-mteeywrss
`
`The progression to androgen independence is muififactofial,
`When prosmha camer is mdmgmrsensliive, Warm
`embers
`the
`EEK and
`is enzymatically (:0an t0
`dihydmbesmsmrone (BET), which warts its influence:2: the
`nucleus and activates genes involved in cell growth Ag
`
`
`
`JANSSEN EXHIBIT 2027
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`
`
`
`
` l
`
`l E
`
`to
`side-effect prafile
`similar
`anti had a.
`docetawsl
`mitoxanm 21ml pménmom {18“} The US Food anal Drug
`Administration (FDA) approved this
`regimen shortly
`thereafter for the treafment of ARC.
`
`Role of estramusfine in AIPC
`Results from the: SWCXZ 9916 and TAX 32? studies defined
`the role of ashamuafine in the: awkward: of ARC, anti
`altered the Seaman: paraciigm for this cancer type {116}. In
`comparable patient gopulations, a similar efficacy (48 b) 58%
`PSA response) was observed for patients W5;
`estramusfine and dacetaxei (SWOG 9916) and prééxfismre
`and docetawl (”EM 327). However, the boxisiw profiles in
`the two clinical trials fiiffered significantly; In the TAX 32?
`study, none of the patients reported grade 3 names and
`vomiting, compared with a 20% incifieme in lbs: SWCX} 9916
`estramustine arm Addfitionafiy, no patients in the TAX ‘32?
`study suffered grade 3 or higher cardiovascular or clotting
`ad‘s/rams Events, while a 15% madame was noted in €be~
`SWOG
`9916
`study.
`Nausea,
`vomiting
`and
`cardiovascular/clutfing
`evens
`are
`well
`Imown
`compficafions o£ estamustim admbxisttation became of its.
`high @5ng cement:
`{A}. Thus, ashamasfim, Wham
`afimfifisfiemfi with éocetaxel, {Elm not appear to nffer
`increased efficacy over preduisme and éoceiaxel, and is
`likely
`the muse of messed gasbbbmgiinai
`and
`cartilovascular madam. Therefore,
`it appears that the
`administration of estramustias with docetaxal for ARC is
`rWarr’anted, and possibly'hmmfui
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Damian! as sexism»? therapy
`Tit? benefits of adjuvant clmmofiwmpy OM is bit-as}: and
`vmbamerpafimiedmfixismbaMopflaang
`evaiuateémayhaseficmalfi‘iaiafdmmlafigr
`mammary. basinymsmwcmy 13356185433 :17?) with a high
`risk of Fromm earner resume reoeixmi am: {315
`nag/m?) on Says 1.. 3 and 150i: a 28-day gale. 0068133081 was
`Well whisked; howeven theWWMom of this study
`are pmcb‘ng. The ’E'AX 3501 study §S a phase Ill, randomised,
`{annulled trial comparing obsemfimt, androgen {leprivation
`therapy (ADT) and AET/doaetaxel in the 'adjuvant setting.
`Enrollmmt for axis cfixficai bial began in labe- XXIS. Those
`{am who progress in {he observation group wil} be
`mclomised to either AD? orADT/docetaseL The results of: file
`TAXSfiGiMabwimapmfecmdmflmeatofmm
`Wis, shmfld highlightme whenfhofix homonai therapy
`MWWmfimadjwmseflmgflfll
`
`
`
`
`
`
`
`
`
`Other taxana embinalion Mats
`Affler the meautagmg results from mvosiigafiom of the
`effect of skxgha—agent doceiaxe] m.
`the TAX 32'? sanity,
`haberest has turned in: W m combination tiwrapy
`
`pratocok The annihilation of cakitx'iol or thalidomide with;
`
`flocetaxei has gmemhed considerable mamas Calcitriob the
`
`most active metaboliae of vitamin D deem prosbabe
`canoes“ as}! proliferation and meteases thiscymmxiciw of
`
`taxanes btdepmdant of Bel-2 {13] Based on encouragmg
`phase II trials dam, the Andmgeandepemitmt Prostate
`
`Cancer Study of (Eskimo! Wing TMOW (WI)
`{gial was inib’afiad This mdomizaed, phoemonttofled
`
`clinical {371231 was dwigneci to: walnate the efficacy of high-v
`
`
`
`
`
`
`
`
`
`536 Current Opinion in Invesflgaflumt mugs 2006 V0: ‘3 No 6
`
`beamiwt of 6:51va mfmctoxy prosiam ems: {8“}. The
`M]? arm was bmluded beseci (m preview demonstrations
`of a pafiiative benefit, although this was without any
`observable survival benefit. In a prior stmiy conducted by
`T31ka 61: at, pain relief and a decline in average amigesic:
`consumption were greaher in patients receivmg M/P than
`prednimne alone {9.} In the SW05“: 9916 study, 770 men
`with progressive ARC receiveci one of two (ammonia, each
`given in 3wweek cycles: estramusfine {280 mg three times
`éaily) on days “IV to S, Swami (68 mg/m2} on day 2, and
`d'examathasons (60 mg)
`in three divitieé doses before
`doceiaxei; or mibaxaxfirone {12 nag/m2) on (lazy 1 plus
`paednmme (5 mg twice daily) Median survival rates in film
`D/B and M/F groups were 17.5 and 15.6 months,
`respectively (p m (L01). PSA response (59 versus 237%) and,
`fine objective response rate in paflmis with known 5on Same
`disease (17 versus 11%} watt: also significantly greatsr in the
`13/13 arm {8"} However; the {3/8 group had a statistically
`significant higher rate of gracie 3 or 4 neutropenic fawn; {5
`versus Eb}, cardiovascular mus {15 vemus 7%); nausea
`anti vomiting {26 vegans 5%}, membofic clismrbanms {6
`versus 1%) and neurologic events (’5’ mus 2%). Time was
`no obseweé diffierence in grade 3 or greafiar WWW
`batsmen the naabnm groups {8"}. Although the mefiian
`survival hmefit was oxfiy 2 months,_ fifis may set a new
`‘smndaré for firm efficacy of chemotherapmh‘x: agents in
`ARC.
`
`became! plus pmdnisone versus mitoxantrone
`plus prodnisom
`TAX 327 was a muIfi-insfimfional, prospective}, randomized
`ethical trial comparmg dowtaxei and pmdm‘sone with
`mama, and yrednisom {ifluL In fifia trial, 1086 men
`with ARCW prednisone (5 mg twice 63313;) and. were
`tandoaxbr assigm to fines moment groups: Manama
`(12 mg/m2) mm 3 weeks, {imam} (75 mgfmzj my 3
`weaks or fimtaxei (38 tag/m2) weekly for 5 of eve-2y 6
`weal-as. Overall survival was 11m pfimary endpoint, There
`was no mmfibafiy significanf difference in $119 weakly
`docetaxei group, but a diffarence was observed in 6:11:23»
`week am compared with mitoxanbfone (18.9 varsus 16
`monthszp * 0.009}. f’ainmclactionfrequemy, as a secondary
`endpomiz, was only significantly reduced in the 3»me
`dosabauxel arm when magmas, with mfmxamm {35 versus
`22%; 93601) The median duration of pain reduciion was
`{Emma acmafigmupsatSS toSémomha The mm of
`PSA W {A5 to 48$6; y < 0001) were significantly
`greabex‘
`111 patients mm docetaxel compared with
`miboxantrmre, mgardiess of
`the éosing schedule. A1:
`Mpmyemmt in quafity—of-iife was more 2&er in pafienis
`teceiving (iocetaxel compared Wifl'l mimxantrone {22m 23%
`warms 13%; p <1 om). The weekly doceizixel schaclule was
`included to determine whether a reduced dose adafiniahe’red
`
`woekly would result in fewer aéverse events or improved
`oukomes; however, this effect‘was not borne out in the data.
`:‘I’be adverse event mine in the Swab}; gimme! arm was
`2.6%. mpared with 29% whm admirfistered weekhr.
`‘Significanfiy more adverse-mm occurred in {112 time}
`imam: arms than with meantrom (20%), In mummy;
`an evexy Sweeb regimen of docsiaxei (7’5 mgfmz} with
`yrednisone (5 mg} mice ($21in was superior in weekly doseci
`
`

`

`
`
`in
`evale‘aiing deceiexei
`are eminently
`trials
`several
`eembi‘nafion with agents
`that
`interfere with minor
`aeovascalarization Mariette is a potent berategen with
`anfiangiegenh: gmpert‘ms, as evidenced by the skinned limb
`growth in engaged hm A ranéemizecl, phase ii clinical
`trial of docemxel pins thalidomide versus angle-agar:
`dmetaxel has been reported {15]. in this study; 75 patients
`with AIPC were randemized t0 receive doeetaxel {3t}
`mgfni’é , or hatidemide (2013 mg) daily pies deoetaxei (30
`nag/m2} ’I’be PSA response was 3?% in the doeeiaxel atom
`arm and 53% in the combinafian arm, although this did net
`reach statistical significance (p r» 0.32). Hewevet,
`the
`response rates did satisfy criteria far further evaluation The
`i$~month survival rate was 42.9 and 682% for the docetaxel
`alone and cembinatinn arms,
`respectively (p = i)11)
`Altimugh the ebsemed respense did not reaeh statistical
`aimfmanoe, finpmvement were demonstrated in all
`the
`standard eutmnre measures; PSA respense,
`fimewtm
`progression {HF} and overall survival Only a email
`number (if patimta were included in this study and it was
`net designed tn evalaete overall seminal; therefere, larger,
`randomized clinical Male are mceseary in better evaluate
`the etfitecy of this regimen in patients with AiPC.
`
`Future treatment modatittee
`
`Cytotoxic agents
`Sanapletin (CFC Biotech AG; Figure 1) is a Enrdwgeneration
`oral plafinquV) complex anticancer agent. with clinically
`demonstrated anfinmtor activity [16}. On the basis of
`promising phase II clinical trials dam, the Salvaplaiin and
`,P’t'ednisone Against Refractmy Cancer (SPARC) trial was
`initiated in 2603, and expanded in 2004 to exclude several
`more European sites, SFARC is a multicenter, randomized,
`doeblehlind, phase 331
`study desigmd to evaluate
`sanapiatin as a seednddine chemotherapy: in patients with
`metastatic AH’C that have area previous cytotexic
`chemotherapy [17E Currently there are no appmved agents
`for the meanddine treatment at hormonerw‘aetnry prostate
`cancer, and the US FDA has granted accelerated eppmval
`status to satraplafin in the SPARC clinical trial, which is
`currently ongoing.
`
`Current: chemthmpeuttc approaches for MPG Rumohr A Chang 531
`
`dose calaitrioi combined with docetaxel. Fatima; with AIPC
`(n “e 250) were rmrlomieed he remains either placebo and
`decennial, or a capsule tormenting: of caiciniel (BM-101
`{Norman his), 45 gig malty {men weeléy} and deceiaxel
`Wl was administered according to the Seeing/m?
`weekly dose schedule described in the TAX 327 sturdy,
`rather than the every-S-week regime. The primary endpoint
`of kids study was PEA respenae. Interim resales of this seedy
`have been reported in abstract farm [14}, PSA response within 6:
`mantle was 58% for patterns receiving cakitdel/doeeiaxel
`campared with 49% for those receiving placebo/decennial;
`' 21mm, this was mi; :1 stamixaily significant dififem {9 ==
`0.16) In patients with measurable disease, a band were
`improved objective respome rate was noted (28 versus 20%; p '2'
`. 0Oh”) Serious adveiae evems were less mm in the Drum
`gmufilélvereueafilfs; per {3638) Afullreportonthe ASCENT
`trialis pending,- partimflarly details of mndary endpomm and
`pregreeshmvfree semval
`
`‘
`
`Figure 1‘ me strumre of seventeen.
`
`
`
`Epothflenes are micrombule inlfibitore with an action
`similar to that: at We bet with the added advantage at
`activity in taxmeresismt more The epothflone B analog
`ixebepilene (326324-7550, BriefinbMyers Squibb; Figure 2)
`has demmtrated alihieel activity in a pbaseII clinical trial
`{18} PEA response was observed in 21 out {if the 44 patients
`reeeivfig habepilene, and in 31 out at the 45 patients
`'meeivmg habepilen'e pins estramvstine phosphate {28}
`Phase If and IE clinical trials are ongoing
`
`Figure 2.
`
`structure ofixabepflane.
`
` (Warhead-11>)
`
`
`
`Veceiees
`As cancer ishtereasingly behigwiewed, atvleaet'in part, as a
`breekdewn of'immune system euweillame, researchers we
`seeking ways in hicreaae the effectiveness ef the iramnne
`system. Thus, tamer vaccine therapyis a promising area and
`math
`
`GYM (Cell Genesys Inc}is a vaccine in which irradiated
`patient-derived emanate cancer cells are traxiadneed in
`elite with granaiocytemacmphage colenyeiimnlating
`facter. The role of this vaccine is in recruit and sfimnlete
`peripheral bleed monoeyies and macrepheges against
`malignant: cells A phase III cit-Lice! trial tempering GV-AX
`with docetaxel plus pmdnieone is undenvey Additional
`eemhinafien needles (if. docetaxel and GVAX are else being
`designed, {4]
`
`Fmvei'xge(AFCn8615;'Dendreon Corp) has been designed in
`help the body develop an humane respense to prostate
`tanner cells Auwlogeusantigen-presmmg cells (APCS) are
`loaded with a Easier: protein combining a pmsiatecspecific
`protein and e mohcule specifically targeting an AFC surface
`receptor Results {mm a phase II clinkal
`trial are
`montaghxg, with reports. of amedian lamehe pregressimiof
`118 days One patient with AlFC had a decrease in FSA
`from 221 ngfml to undetectable levels which remained
`undetectable fer four years [19} A randomwed pirate III
`are} in panama with asymptomatic, metastatic: AIM is
`underway, in which 275 patients will be randnmizad to
`Revenge or tractivezed APCS {2th};
`
`
`
`iz
`
`i
`
`

`

`in earnest. Encouraging rcsyonse fans have been obtained
`from lander clinical
`trick evaluating doceiaxel
`in
`cambinafion with estrnmusfine or predrfisona,» and would;
`from these studies have influenced firmre monument
`
`regimens for AIPC, Promising chemotlnrapenfic agonm,
`emerging tumor vaccines,
`targeind therapy, and naval
`comhhlation regimes are all under active investigation,
`These studies will hopefully play a role both in current
`mmfigotiml therapy and as a bridge to fuhxro modalities:
`
`References
`
`1~ WWWWWWM, GA. 03AM}
`Wilmwmnwmm
`
`2. Hmlfiw Remand Abbas? WW Kaganmw, We?!
`Came: contact mm W ’
`alone in mm
`mmullw Mums J Una! (2092) 16712 dd l}:528%
`
`31
`
`Huggins C, Hodges CV: Man on pruntaflc cm. i: Tim affect of
`:acwtlon, of Megan, and androgen lnjacflon on serum
`In We carcinoma of tho prostate. Gaacor Rec
`{1941} 22(4):232%“:
`I This was the angina! stupor to doscfibe androgen domino for More
`cancer maximum, and was“ the clearing path? for any discussion News to
`chemothmpy for Wmimmo 01’th: ‘Z’hc Irma! sensitivity to
`Wild mains cancer is: demsdaled via castration, W or
`'andmgor: mmmdm.
`
`4. MU,WBC:WWMMmoKWwA
`momma» Oil CW4 GM {2005) 55(5):390~318.
`
`5‘
`
`3,
`
`
`
`”WW
`YogodaA, Wk D: W10
`mmmm madammamnoocmu
`
`Regimen 0. Km 8 Jane Mt EvolvmgmtcgIn: all cytotoxic
`chemotheragy forMaxim promo: W Eur J Cancer (19$?)
`33“}WSW
`
`lama: WM WWWN. WI) SIWMFQQ
`wsrmwna manamnm—mmmanmnmw
`response: gumdm for can» 3 cmm inwwmm
`WWWRMWWMM
`WWW J£251! Oncdlm}17(11);366’l-3487.
`
`Pea-yank GR "ranger: on, Human: MK, Lara PN Jr‘ Jones at“: Tedd:
`ME Bunch Pkswyb Moinpomc Korma: EonwnMCofal
`mm and Muslim W with W and
`magnum-mam mmmm 515::me
`gm} 3S1£153zl$134520
`w) mmpermrdr W nromrewn whim dermal:
`medfcn mm! Wage of 2 mm with Wot—cow Worm;
`various mdcxcnfimna :‘n cations with mended: Ach:
`
`mummemmmmpc
`
`9,
`
`Tannock JFK 036135 CL SW 195R: Ernst 3% Neville Ad, Moore Mir '
`W96 GR Wis-ch J3, Vanna" PM, Coppln CM, Murphy KC:
`,
`filtemcmmpy with mltoxantmne plus prudnlsono or mdnlumu
`slam lot symptomatic hormwmm prostate cancer: A
`Canadian “Momma trial with Miami: andwindy J (311:: mm!
`(1996) we);wanna
`. This pupor {SW- 5 paidm benefit for momma madam”.
`Wash reported pad: and magnesia needs we noted in me
`Wm mzmazmwmcmdncammwwm
`busndonlfilrsdzdy;
`
`1
`‘
`
`10 TamockiF nmnmmma.mmn mm Marc
`3 Theodorcc 32mm Tumldnsammnalnocm
`Wmmwmmmmammmm
`Wm NErapIdeW) 351(15):?5924532
`I. MYMSZ?MWiamWWWWW
`ammpmwdmtosofruspomintemofpcm WPSA Icwimdqualdyv .
`and» 1%:- We! cm! mm comma Md: mmxama pics
`mmmmxymWWWWMWW>
`admimlrrrafloo and [mama the standardaroma
`
`11. modsmmc CamobelSand‘J mama? m1
`MG l-fiomoc mymsnmc SmmJAdi‘SomayofW
`WMwWWflmm
`«human»
`WWW (mangoes)193(1):11-31
`acmwmsmamcowgmmmm
`
`532 Currant Opinion in lmusfigafional brags 2cm Vol 1? No 6
`
`Onyvaxwl’ (0::wa Ltd) is a cell vaccinc compoced of three
`irradiated allogeneic cell lines Cells from primary and
`melaslalic disease are ‘mcluded in this vaccine, and
`
`dwarcfically, the broad range cf mfigdno will improve its
`efficacy and help avoid resistance. Based on encouraging
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