-. ...
`
`~ _.....,
`
`WIPO
`WORLD
`INTELLECTUAL PROPERTY
`ORGANI Z AT IO N
`
`CERTIFICATION
`
`It is hereby certified that the attached are true copies of the following documents
`contained in the file of international application No. PCT/US2011/064191, filed with the
`United States Patent and Trademark Office as receiving Office on 9 December 2011.
`
`record copy of the international application;
`statement concerning a sequence listing;
`fee calculation sheet (Form PCT/RO/101 (annex);
`notification of the international application number and of the international filing
`date (Form PCT/RO/105);
`notification concerning payment of prescribed fees (Form PCT/RO/102);
`notification of receipt of search copy (Form PCT/ISA/202);
`priority documents (2);
`notification of receipt of record copy (Form PCT/18/301 );
`notification concerning submission or transmittal of priority document (Form
`18/304);
`notification of Transmittal of the International Search Report and the Written
`Opinion of the International Searching Authority, or the Declaration (Form
`PCT/ISA/220);
`international search report (Form PCT/ISA/210);
`written opinion of the ISA (Form PCT/ISA/237);
`international publication of the application;
`notification concerning transmittal of copy of international application as published
`or republished (Form PCT/18/311 );
`amendment of the claims with letter and statement;
`notification concerning the filing of amendments (Form PCT/IB/346);
`communication in cases where no other Form is applicable (Form PCT/18/345);
`first notice informing the applicant of the communication of the international
`application (to the designated Offices which do not apply the 30 month time limit
`under Article 22(1 ))(Form PCT/1B/308 (First notice));
`re-publication of the international application;
`correction of the amendments to the claims;
`second notice informing the applicant of the communication of the international
`application (to the designated Offices which apply the 30 month time limit under
`Article 22(1))(Form PCT/IB/308 (Second and supplementary notice));
`notification concerning transmittal of copy of international application as published
`or republished (Form PCT/1B/311);
`request for recording of changes in the request;
`replacement sheets of the request form;
`transmittal letter and powers of attorney;
`notification of recording of a change (Form PCT/IB/306);
`
`3 4, ct·,ern1n de$ Gt1lornlic!tte~
`12 1 1 G(-movc1 20 , Sw(ti','l rlancl
`T +.l I::''.:' :3:38 91 11 F 1-4122 733 fi •I .-:H
`
`Miltenyi Ex. 1018 Page 1
`
`

`

`international preliminary report on patentabillty (Chapter I of the PCT) (Form
`PCT/1B/373); and
`notification concerning transmittal of copy of international preliminary report on
`patentability (Chapter I of the PCT) (Form (PCT/IB/326).
`
`By: The International Bureau
`. , .- -· r
`"' '-:( <f ~L ~
`Fabienne Gateau
`PCT Officer
`PCT Legal and User Support Section
`PCT Legal and User Relations Division
`
`March 15, 2022
`
`Miltenyi Ex. 1018 Page 2
`
`

`

`PCT
`
`REQUEST
`
`The undersigned requests that the present lnleniutional npplic111lon be
`processed according to lhe Patent Corporation Treaty
`
`11:~:;:~}!:~:::~:.
`
`09DEC 2011 (09.12.11)
`!lllema1i!loal Fili11!! D!!l!l
`RO/US
`Name of receiving Office and "PCT !J1ternntional Application"
`
`TITLE OF INVENTION
`Box No, I
`USE OF CHIMERIC Al\'TIGEN RECEPTOR-MODIFIED T CELLS TO TREAT CANCER
`·- - - - ·
`
`Applicant's or agent's file reference
`(if desired) ( I 2 clmmcters 111mlm11111)
`46483-6001-00-W0.601218
`
`-
`
`:
`
`111is person is nlso Inventor
`
`Telephone No.
`
`Facsimile No.
`
`Teleprinter No.
`
`1
`
`Applicant's registrntion No. with the Office
`
`llo.x No, ll
`APPLICANT
`-No-int n11J 0°ddrisi (Fnm/(1• ,,;;,,, fo//on'f,I by &fr.-11 nnm~: for "legal amlty,fi,/1 o.QM1/
`,r,slg,mlltm. The rukfff» tit/II( /11c/11tlo /lf>,1/(I/ cndt·IIIUI J>OIJlt of COWi/i)'· 11,e C'OtnH'}' of /Iii mkfM J$
`/iu/lrnltd Ill 111/1 811.1 Is l/10 opl'llt:mll '$ Sfalf (l//<1I I.I, t<1illllf)~ ofresilf,,,,e lf110 $/(I/If ~frcJlll,•t/f~ Is
`i11dlmted below.)
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Center for Technology Transfel'
`3160 Chestnut Street, Suite 200
`Philadelphia, PA 19104-6283
`United States of Amel'ica
`State (that is, counll')i} of residence:
`State (that is, cormllJi) ofnationallty:
`us
`us
`. ..
`all deslg1rnted States
`the United States of
`This person is opplicnnt for
`except the U11itcd
`X
`America only
`the pllljlO.le-s of:
`S!llleS of Am~1ka
`..
`·---
`FURTIIER APPLICANT(S) AND/OR (FURTIIERl INVENTORn
`Ilox No. JTT
`This person is:
`Name and address: (Family /1(1/Jre followed by g;m1 name; for o legal entily, ft,// of}lcla/
`desfguarlon, 77,e address mus/ 111c/11dc p,:)1111/ «itk WW 11m11e ofro1nl/l)', 77,e com11,yo/1ha address
`i11dl1'tllrrl f111M,· Dox Is 1/w <'PJfflro,11 's S1(1/e (l/1<1I fs, <V>ltlllr;~ efusldC11ce /ftJO S/016 o/rnidtnu Is
`i11dicmed below.)
`JUNE, Carl H.
`409 Baird Road
`Merion Station, PA 19066
`United States of America
`
`ull desigtwled Stutes
`
`tile States indicated in
`lhc Supplemental Box
`
`applicant only
`
`X applicun( and inventor
`
`inventor only (If this check-boJ is marked, do
`1101 !ill /11 below.)
`Applicant's rcr,istration No. with lhe Office
`
`I Stnte (Iha/ Is, country) of residence:
`us
`nil <blgillll~ S1aws X the Units'd SIPtcs of
`CXC<lpl the Un iled
`SIDtl'S of Americn
`
`America only
`
`all desigi10ted Stn1es
`
`Stale (Iha/ Is, co1111//J~ ofnntionnlit)•:
`us
`TI1is pcnon is arplicmn for
`lhc plllpOSes of:
`X
`Further npplicnnts and/or (fllrther) inventors am indicated on n contlnuation sheet.
`AGENT OR COJ\lt\lON UEl'llESENTA 1'1VE; OR ,\DD RESS FOR COHRESPONDl~NCE
`Dox No. IV
`!Kl agent
`The person identified below is hereby/has been appointed to act on behalf of the
`npplicmll(s) before the competent lntenmtionnl Authorities as:
`Name nnd address: (Family name followed by gil'ell name; for a legal entity, Jidl official
`Telephone No.
`designario11. 771c address 11111st include postal c:ode and ,wme of co1111II)~
`215.268,3888
`NGUYEN, Quang D,
`facsimile No.
`Riverside Law, LLP
`215.268.3871
`300 Four Falls Corpornte Cente1·, Suite 710
`Teleprinter No,
`300 Conshohocken State Road
`We.st Conshohocl,en, PA 19428
`Agent's rcgistn-ition No. with the Office
`Unltccl States of America
`52,066
`Address for cor1·espomlc11cc: Motk this check-box wlicrc no ngenl or conunon representative isn,ns been appoluted and the space above
`is used lnstcnd to indicnte a specfol iiddl'ess lo which correspondence should be sent.
`
`lhe Stntc-s indicnted in
`1he Supplcrnentnl Bo>-
`
`COllllllOll
`reprcscnlntive
`
`I
`I
`
`i
`
`Miltenyi Ex. 1018 Page 3
`
`

`

`Sheet No .. , !.~ .
`
`npplicant only
`
`X
`
`npplicnut 11nd Inventor
`
`inventor only (lj this check-box Is marked,
`do 11otj/ll /11 below.)
`Applicant's registration No. with the Oflicc
`
`all designated Stntes
`
`SIDie (tlml Is, co111111;1') of residence:
`us
`oil designated States X the United States of
`
`Amcricu only
`
`the Slllt~s Indicated in
`the Supplemental Bo)(
`
`... ...
`Continuation or Box No, m
`FURTHER APPLJCANT(S) AND/OR (FURTHER) JNVENTOR(S)
`If none ofrhefollowi11g sub-ho.res is med, this sheet sho11/d not be lnclrided i11 tlle request,
`Name ond address: (Family 1wmefollo11"ed by g/1•en 11ame: fol' a legal e1111ty,ji1/I oj}lclal
`deslgua//mt. 'nte address mus/ i11c/11de poslal code aud name of country, 1Jle co1111lr)' of1he <1ddress
`imlh:alerl ht lhii /Jc,t is 1he applirn111 's Slate ~lw i>, co11ntry) of residence if110 S1111e ofreslrlcnce Is
`indtmterl below.)
`LEVINE, Bruce L.
`1258 Libe11y Bell Drive
`Cherry Hill, NJ 08003
`United States of America
`Stole (tltar Is, co1111111~ of nationality:
`us
`Tl1is per.;on is npplk~ol for
`c.xcepl tlte Uni led
`the p\ll]loses of:
`S !ates of America
`Name and address: (FfWJI/)' 1m111efollowed by glw11 uame:for a legal e11tilyJ111/ of)1cia/
`des/gnat/011. T71e address /1111$/ /11c/11de postal C()jfe (l!ld11nme ofco1mtry. The corm/1;1' of the address
`imlirntecl /111/rls Bo., is the uppllm/11 's State (t/Ja/ Is, cowrlr):) of l'eside11ce tf110S1a1e of residence Is
`indirnlcd below.)
`PORTER, David L.
`821 Crum Creek Road
`Springfield. Pa. 19064
`United States of America
`
`applicru1t only
`
`X
`
`applicant and inventor
`
`hwentor only (if this check-box is marked,
`do 1101 fill in below.)
`Applicant's registration No. with the Office
`
`I Stnte (t//a/ Is, coJmhJ1 of residence:
`State (Iha/ is, COW/II")~ ofnAllonality:
`us
`us
`all dcslg11atcd Stntes X the United States or
`TI1is person is npplic.inl for
`c.~c~pt the United
`the purpose.s of:
`States of America
`Name and address: (F,111II1)' nmne.fo/Ja11•ed by gil•e11 name:for a legal emlty,ji1/I official
`designm/011. Tire address mus/ 111ch,de postal code mrd n11111e of count/)', Tire co111117;1• q(t/Je address
`indlc<11ed i111/1/5 Dox /5 rho applirnnt 's Stare (t//at Is, ca11111r,;) of1·eslde11ce lf110 Stale of residence Is
`i11rlic<11ed below.)
`KALOS, Michael D.
`716 Carpenter Lane
`Philadelphia, PA 19119
`United States of Amel'ica
`
`nil designated States
`
`:
`
`the Stntcs indicated in
`the Supplemental Box
`
`America ool)'
`
`applicant 0111)'
`
`X applicant und i111-e11tor
`
`inventor only (Jfiliis cl1eck-box Is mal'ked,
`do 1101 f/11 in below.)
`Applicant's registration No. with the Office
`
`Stute (that is, co111l/ry) of nationality:
`us
`This p<:)ISOTI is upplknnl for
`except the United
`the purposes of:
`Stntes of America
`Name und address: (Fam/{)' 11amcfol/owed by gh'c11 name;/01· 11 legal e111t1y,fi1// official
`desigllf1//ou. Tire address must lllc/11de posral code and 11r,111e of C<>JIIIII)'. 77,e co11111>y aftlte address
`it1dica1ed in this Dox is the applimm 's Stme (that Is, cowtnJ;) of residence lf110 State qfres/dence Is
`i11dicated below.)
`
`all dc5ignnted Stoles
`
`Amerirn only
`
`the Stales indicated in
`the Supplemental Box
`
`npplic:mt only
`
`opplicant and inventor
`
`I Stnte (Iha/ Is, cow1tt")') of residence:
`us
`all designated Sillies X the United Smtes of
`
`Stole (rhat Is, co11111/J~ of nationality:
`
`inventor only (If this check-box Is marked,
`do t1ot.flll (11 below,)
`Applicant's rcgistrollon No. with the O11\cc
`
`I S1!1tc (that is, cormlr>~ of residence:
`
`This per.;on is applicant for
`the pllljl0Sl'S of:
`
`all designated States
`
`nll designated States
`except the United
`Stat~s of Amerkn
`
`the United Slates of
`Amcrimonly
`
`the St~tes indicated in
`the S11pplcmentnl Box
`
`Fllrther applicants an<l/or (fttr1her) inventors are indicated on another continuntion sheet.
`
`Miltenyi Ex. 1018 Page 4
`
`

`

`~111ikme11lnl Box
`
`/fllrc Sttpple111c11l<1/ Bo.t Is IJlJt used, this sheet sl101dd ,rot be /nch;ded In tire reqwst.
`
`Sllt!tll N.o.
`
`').
`• .. 2. . . .
`
`I.
`
`(V
`
`(Ii)
`
`(III)
`
`(M
`
`Continuation of Box No. IV
`ALLEN, Justin
`DOYLE, Kathryn
`HAAS, Dennis
`LI, Yuql
`NGUYEN, Quang
`SILVA, Domingos
`Riverside Law, LLP
`300 Four Falls Corporate Center, Suite 710
`300 Conshohocken State Road
`West Conshohocken, PA 19428
`us
`Tel: (215)268-3888
`Fax: (215)268-3871
`the practitioners associated with Customer No. 10872
`
`If, fmmyojtlw Roxes, e.Yapt Bo.res Nos. VII/(/) toM/orll'h/ch
`t1.¥/J11Clnl cou1/111mt/011 box Is pro1'id~d. ll1esJN1cels /11s11/f/c/el/l
`to furut.rJ,oJI Mc il,forirto1lon: ills11rh,tt1.Se, u•ri. ''Crml'1muJloH
`of Bo.t NIA ... • , (1,/dkale die 111,uwcw of lltt! B».r) 11Ndf 11misb th.r
`h,for,nnlf,m Ill t/Je M/11/t /lltHIJler t/S l'tf/Uil~d IICC()n/lng IO ff/(!
`roplio11s of tile Bex /11 wliM1 the spm:e ,w,s l1is111flciMI, 111
`JXll'tlc11lar:
`if more flum 0I,e perso11 lsto be lmllcate1f as appJ/amt 11111Vbr
`/m<e11to, and no "comlmmt/011 £heel" is mTiilublc: in si,d,
`c'(lse, wrl/e "Co11/lmm//0110/Bo.r No. Ill'" ,111d1)11/icaIefaread1
`m/11/l/1111(1/fJi:'rstm Ifie /lb11,e lype of i11fmw11tio11111; 1w111/red /11
`I!w; No, II • 17,t co111111y q(the (l(k/l'f!ss f11dtra1ed i11 this Box Is
`the opp/lroll/'sSln/c (th{lf is, cowu,,~ ofres/d~1ice lf110 S1<1l>J of
`resld.•11ce IR /11dlroled bt/011•:
`1/. i11 IJ0.r No. JI oi· ill flllJ' of lite s11b-bo.:re.f of Rm No. JU, the
`b1dfrat/1m "Ille Stales l1111/r11te1/ /11 1/11: S11pple11 w11l11f ll o.\·" /1;
`cfredwd: i11 srw/r case, write "Crml/11uarl011 of &r l\'a. If" 01·
`"Co1t1/111mikmo/Oox No. Ill" or "C:0111/1111(1/i<mofllo.res No. II
`mid No. Ill'' ((,s fhe mse ma>• bt), ind/role the 11ame of the
`npplkm1J(s) f111'0h'td(l11d, mm to(each) s11tl11m11,e, tlwState(s)
`(1111Cllo1; 1,•ltcre r,pp{kablc, ARlPO, E11rMim1, ffor0J;ea11 01·
`01Jl'l pa/mt) for 1fre p11rposes of 11>hfc/l 11,e 1K1111cd per~~m is
`app/ical/1;
`ii. /11 Bo.r No. 11 01• /11 mp1 of the s11b-bo.w~ of Bo.\' .VG. fll 1he
`1,ivemor or lhe tin•e11tor/11ppl/('1ml /,\' 1ml lm'lmtvr for tire
`purposes of alf desigw,t"fl Stales or for lite Jlllrposts of tire
`U11l1ed Stores of America: in such cose, w1·//e "'l.'o11tf1111a//011
`of Bo.t No, II" 01· "Co111i111mlio11 o.f Bo.,· No. Ill" or
`"C:0i1fi111mllrm of Bo.ws No. JI 011d No. Ill" (<1s Ille case 1110•
`ba), luriimle the 11ame of tlw imVJ11flJr(s) and, ne.11 to (each)
`s11cli 11a111e, /he St!lft{II) {tmdlor, wlwtt! app{knhle, AR!PO,
`li11rnslmI, lf111-opee111 bl' OJIPJ JXl/r:111) foJ' thr: purposes of whid1
`tire nnmed person is /iJ\'c/1/or;
`ff, /11 Md/1/01110 ,r,e ogont(s) i,id/catcd /11 no.t No. II~ there m~
`111 such rose, wl'ile "Conlimm/1011 of
`fim//er 11,:11111s:
`Ho.Y No. IV" 1uld imJ/ca/e for eachfi111her ageul the same /)pt
`ojl11/0111mffo11 as 1-eq11i1wl /11 Box No. I/';
`M If, 11, /Jp.t No, VJ, 1l1erem·,n11orellu111 three l!l//'l/l!r11J1plleatlo1ts
`whose pr/01/ly Is d11l111ed.' ill s11cl1 cme, writ~ "Cimtilu//1//011
`of Box No. VJ" and /1,d/c{lfe for each e1dti//101ml f!arlfer
`applfration /he same /)'Pl of l11(01'111al/on as 1·eq11ired
`in Ho.T No. 1'1.
`If the applfca11/ intends lo 11mke rm /11d/m1/01I a/the wish Ilia/
`tire l111ematlo1ml aJJµ/lrot/011 bit l!'l'(ltl!d, i11 cerla/11 lksfg11(1ted
`States, 11smwppf/ca//011foN1 p11/e11/ of mldlt/011, cel'lljicate of
`addltfo11, l11m1/or 's cel'llf/rote of mid//io,1 01· 111111(1• cf rtljlmw
`()f tiddftlrm: ill suc/11:'(IJC, write /lie 11/111111 or hvo-t,mer c0tlo of
`enc/1 desl~1wted Stale co1wer1t1:d mxl lffll i11~lla11/o1t ''pr1te111 of
`arfdlt/011, '"cerr/jlc11Jer,fmldltlo11," "h11'e11tur'scert/j/c11teof
`add/I/011 "or ''1111/i(I' ,:e1/ijlcale i?f mfd/1/011, " tfw 111m1fn.r af lf,c
`pnrml aµplirol/01101· ,xu·em JJ(lfe//10/' 01!1e1· 1xweu1 gmm (11,d
`rile dme of im11t of /he 1x11·e,r/ pnre11/ or ollu.•r 1mre111 gm1// 01·
`1lre<k1te uffllll1g of the Jl(ll'fll/ app/lmf/011 (Rulr!s 4.1 l(a)(J)
`am/ .J9bii;. /(u) at (b)).
`Jf tlle app/lccm/ i111,m,Js to lll(lke mi f1idlwlio11 of 1/Je wish that
`tJ,e J11Iema//01m/ applicalio11 be 1m1l1!1/. i11 the U11/ted Sin/es of
`A111erlm, a ... lt co11timm1/on or c()l1/immli1m-i11-parl of 1111
`/11 51«:h r:a5e, w1·//e "U11/1ecl Stales of
`ear/ie1· a1,1plloo//011:
`,rmerlct1 ' or "US" and the i11diwI/011 •·co111/i11101/o11" o,·
`"co,1//111,af/011-/11-part" and the number and /he }lling date of
`1/1e f!ll/'ent 11pp/lca//011 (R11l11s 4. I I (<tj(li) and •!9his. J (d)).
`ff the t1pp//rr1111 wlslres /(I retJnest lhe 1"eCCM11g Office or /Ire
`li1Iermiliom1/ Bure,111 to obla/11 a priori/)' doc11111e111 from 11
`tligilol l;bmi)• //111 1/1{1[ docm11e1If Is 011/1• llrlr/ 111 11 d/,:llal
`flf,mr)' /!I t'0//11«1/o,1 with a11tJ1her 111ip/lmlia11 which 11/.m
`rt/led UJXlll llmt priority tloc111ne11I w s11µporl ,1 priq1'i(I• C'/11/111
`(,111,l 1111/ess that digiml /ibm1')• is ro be 11iwsse<I thror,gh the
`/Jlg/10/ ,ft:-ccss Servi~ for Prior/I)• Doc111111:111,;, In s11cl1 ooses
`Wl'ite "Comlm1at/011 of Bo.v No. Vf ", lncfleate for em:h f'i1r//e1·
`(,ppllrot/011 co11Mmed I/,esome (Wieofi1//ommr/c11111s1-eq11/red
`In Bm No. VJ and indicate fliv m1111b~r r,m/er ll'hich thr
`opp/ic{lfioll is stored ((Ind, If known, /he dlg/111/ 1/brm:,•
`coti<emed) (Seer/011 7 I 6(a)(i,J).
`
`2.
`
`3.
`
`4.
`
`fom1 PCT~O/IO I (s.uppleme1i11u! J1e ei1 ➔ (Jnrmary 201·.0)
`
`See Notes .to the req1.1es1for 11
`
`Miltenyi Ex. 1018 Page 5
`
`

`

`Sheet No ... f/.
`
`DESIGNATIONS
`8ox No. V
`·111c filing of this r~st t'fMlslihtt.11 11H.e1· ll•te "3(11), lbc dulgrintkm of 1111 Coatractlng Slates bound by the PCT on tho inlmllllionnl liling
`dale, for the gmut of every kind of protection available and, where opplicnble, tor tke gr~nt of lmlh n.-gionol nod 1llllkinol puleuts.
`However,
`DE Gemmny Is 11DI designated for any ki11d of nalionol protection
`KR Republic of Korea is 1101 deslgnnlcd for unr kind of national protection
`RU Russian Federation is nol designated for nny kind of national protectio11
`
`(l11e cl,eck-bo.res abo,·e may be used to exclude (lrre,·ombM th~ desig11alio11s cOIICfl'/ied /11 order 10 m·oid tlte ce11s/1Jg of the ~,-1, 11111fer 1/re 1111//()1/il/ law, of an
`earlier 11atio11a/ appllcatlo11from which priority Is claimed. See tile Notes Jo Bo.r No, Vas/() the coll!eq11e11ces of mc/1 1101/0110! /011· pro1·isions 1111/iese mrd certain
`other States.)
`Box No, VI
`
`PRIORITY CLAIM
`-
`The priol'ity of the follo\\1118 earlier appllcntion{s) is hereby clnimed:
`
`I
`
`File dulc
`of earlier application
`(daylmolllhlyemj
`item (I)
`09 December 20 I 0
`item (2)
`29 June 2011
`
`iceiii (3)
`
`Number
`ot' earlier applicntion
`
`61/421,470
`
`61/502,649
`
`1mtional application:
`counlry
`us
`us
`
`Where earlier appllculion is:
`regional n1iplication:•
`regional Oft1ce
`
`International application:
`receiving ~mce
`
`-
`
`Furlher priority claims are indicated in the Supplemental Bo:-..
`The receiving Office is requested to pNl)lre and mmsmit 10 lhe lntemalloonl llureau a certified copy of the enrlicr applicalion(s) ·(011/y if the
`enr/ler nppllca//011 was filed wilh /he Of/1ce which/or the p11rposei of this lmmiatlcn(I/ c1pplicalio11 fr the 1·ece/v/11g 0./Jlce) identified ubovc ns:
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`all items ~ ite111 ( I)
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`itcm(2)
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`item (3)
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`item(~)
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`item (5)
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`other, see Supplement.II Box
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`+wt,ere lite earlier app/icat/011 is 011 AR/PO appllcn1io11, indicate al /e(lsf one co1111fl')' party 10 the Paris Co11w111io11 for rite Protec:liM of
`!11d11stl'/al Properly or one Member of the World Trade Orga11/wtio11fo1· wh/c// /hat earl/er application 1msfl/ed (Rule./, IO(b)(iO}, .. .................
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`• • • " ' ... ••• • • • ••• . . . . . , , . , 111•11tn 11••n11••0, ••• ••• ,uu,..111 u , 111 •11 111 u , 111 ,., 11•111 "" ,., •••• "
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`•• • ••• ,. , ••• •• • ., •• u , u u t~ u , h l o j u ~H • ••• . . , ,,. • • • • u u , 11IU~•••u• ••• •• • •• • 111u1 ~u,u•
`-
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`Uox No, Vll
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`INTERNATIONAL SEARCHING AUTIIORlTY
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`Choke of InternallonAI Scarrhlng Aulhorll)' (ISA) (If h1·0 or more frJ1em111io11r,/ Search/11g A11rhorlties "re compete/II lo con)' 0111 lhe lnrm1atio11al .earch,
`illrlicate 1he A 111/rorfly cltose11: Ille h1•1r/e11er code nwy be used):
`l~A/US
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`Rcq11es1 to use resul I• of ml'llt1· sea 1·cll; rcfcrcucc lo 11ml sen reh (if m, r1rr/l,r search hos been cm·rlr<i 0111 by or req11r,red from 1/re ll1Jf/"lllllio110/ smrchl/Jg
`Amhm·II)~:
`D~tc (<1'1ylmomh')·em)
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`Country (or Ngio1rnl Of/Ice)
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`Number
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`-----
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`Box No. VTII
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`DECLARATIONS
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`The following declnrntions nre con1ained In Bo~es Nos. VIII (I) to (1•) (mr,rk /he applicable r!,eclr-bo.~es
`be/oll' and i11dica1e in tire rig/JI colu11111I1,e 1111111/Jer of rnch type of decl!lrat/011):
`Dedarntion as to the identity of the inventor
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`Ro~ No, VIII (i)
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`!:lox No. vm (ii)
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`Dox No. vm (iii)
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`Box No. vm (iv)
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`Box No. Vlll(\')
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`Declaration as to the applicnnl's entitlement, as at the in1emationnl filing date, 10
`apply for ond be granted a pn1en1
`Declnrntion as IO the npplicanl's c11titleinent, as nl the international filing dole, to
`claim the priority of the earlier application
`Decimation of invcntorship (only for !lie purposes of the designation of Uie United
`States of America)
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`Declaration as to non-prejudicial disclost1res or exceptions to lack of novelty
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`Declarations
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`Miltenyi Ex. 1018 Page 6
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`

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`C'
`Shee( No. ,.:,}, ..
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`Oo~ No, IX
`CHECK LIST; LANGUAGE OF FILING
`"t1i(s lnteniationnl nppllcntion cont11lns;
`This intcnmtional 11ppllcn1ion is 8cc-0m1»mlcd by the fol!owlng
`item(s) (,11(1/'k the oppllcob!e check-boxes: below ond Indicate /11
`the following number of
`(n)
`right colu11111 the 111111,ber of eoch /!em):
`5heets In pnpe1· form:
`request (Including
`declHralion sheets)
`description (excluding
`sequence listing part)
`claims
`abstract
`drawings
`Sub-Cotnl uumbcr of shccCs
`Sequence listing prut of
`Description f1cllm/ 1111mber
`Of silee/s If //led /11 f)(lper
`Form, whether or 1101 o/so
`Filed /11 co111pri1er reodable
`Form; ne (b) below)
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`5
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`93
`8
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`26
`133
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`18
`151
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`(b) sequence liscing part of description flied in computc1•
`readable form
`(i) D
`onl)' (under Section 80 I (.i)(i))
`(ii) D
`in addition to being filed in pnper form
`(under Section 80 l(n)(ii))
`Ty11c and number or carl'ie1·s (diskette, CD-ROM,
`CD-R or other) on which the sequence listing pnrt is
`cont11i11ed (odd///0110/ copies Jo be Ind/coled 1111der
`item 9(11), /11 righl cohm111):
`11-•+-11•r•&••••••••••1t,1+11,1••••1•••,•••1 • n••,.~••••••••••41
`
`Figure or the drawings which
`should accompany the nbstrnc{:
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`I
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`00 fee colculntlon sheet
`I.
`D origlnnl sepurate power of auomey
`2.
`D original genernl power ofatlomcy
`3.
`4. D copy of genernl power of altomey; reference number,
`if any: ....................................................... ............. .... ..
`5. 0 statement explaining lack of signah1re
`6, D priority document(s) identified in Box No. VI as
`item(s): ................................................... ,.,,,.,.,., ... , ...•..
`7, D translation ofintcnmtionnl opplicntion Into
`(la11g1111ge): ,,,,,, .................................................. ~,·······
`8. D scpnrntc indications concerning deposited
`microorganism or otl1er biological nmtcrial
`I!) sequence listing in computcl' rendable fonn (indicate nlso
`type and number of carriers (diskette, CD-ROM, CD-R or
`olher))
`(I} D copy submitted for the purposes of international
`search under Ruic I 3ter only (;ind not ;is pmi of
`the inh:mutionul uppllcation)
`(ii) D (on(v where check-box (b)(I) or (b)(Ji) is marked
`/11 left col11mn) additional copies including,
`where ~ppllcoble, the copy for the purposes of
`international search under Rule 131e1·
`(iii) 00 together with relevant statement ns lo the
`identity of the copy Dr copies with the sequence
`listing part mentioned in left column
`10. 0 other (specif>~:
`Language of filing of the
`lntemational application:
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`9.
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`English
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`N·umber-
`ofitems
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`SIGNATURE OF APPLICANT, AGENT OR COi\li\lON REPRESENTATIVE
`Ilox No. X
`ll'e~-11,, errch slg,wtr,r~, i11dlcflle the 11m11t ofrhe person signing rmd !he rapacity i11 wl,;clr the per,011 sig11s (if such capacily is JJOI obw"o11sfrom reudi11g
`,b, TMl/1~'1.
`~.,
`,9 )~~
`_yc'.,";y , ~~;,.0uang D., Agent for APl'>licant{s)
`/
`09-12-2011
`1. (.1~g(iual ~~elpt of the purported
`int 11 Iona! application:
`J, Corrected dale of actual receipt due to later but
`timely received papers or dmwings completing
`the purported inlernntion~l npplicntion:
`4, Date of timely receipt of (he required
`corrections under PCT Article 11(2):
`lnlem~tio1ml s;rn-J; Authority -----
`ISNUS
`(if two or more are competent):
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`Dnted: 09 Decembe1· 2011
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`, :~-
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`2.
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`D
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`Drawings:
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`received:
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`0
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`not received:
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`6, Transmitlnl of search copy dela)'ed until
`search fee is paid
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`Dy;
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`5.
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`Date of receipt of the record copy
`by the lutemnlional Bureau:
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`Miltenyi Ex. 1018 Page 7
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`

`

`Attorney Docl<et No, 046483-6001-00-WO,601218
`
`TITLE OF THE INVENTION
`USE OF CHIMERIC ANTIGEN RECEPTOR-MODIFIED T CELLS TO TREAT
`
`CANCER
`
`5
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`CROSS-REFERENCE TO RELATED APPLICATION
`
`This application claims priority to U.S. Provisional Application No.
`61/421,4 70, filed December 9, 20 I 0, and U.S. Provisional Application No.
`
`61/502,649, filed June 29, 2011, all of which are hereby incorporated herein by
`
`reference in their entireties.
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`10
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`l 5
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`25
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`30
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`BACKGROUND OF THE INVENTION
`The large majority of patients having B-cell malignancies, including
`chronic lymphocytic leukemia (CLL), will die from their disease. One approach to
`treating these patients is to genetically modify T cells to target antigens expressed on
`
`tumor cells through the expression of chimeric antigen receptors (CARs). CARs are
`antigen receptors that are designed to recognize cell surface antigens in a human
`leukocyte antigen-independent manner. Attempts in using genetically modified cells
`expressing CA Rs to treat these types of patients have met with very limited success.
`See for example, Brentjens et al., 20 I 0, Molecular Therapy, 18:4, 666-668; Morgan et
`al., 2010, Molecular Therapy, published online February 23, 2010, pages J-9; and,
`Till et al., 2008, Blood, 112 :2261-2271,
`
`Tn most cancers, tumor-specific antigens are not yet well defined, but
`in B cell malignancies, CD19 is an attractive tumor target. Expression ofCD19 is
`restricted to normal and malignant B cells (Uckun, et al. Blood, 1988, 71 :13-29), so
`
`that CD 19 is a widely accepted target to safely test CA Rs, While CA Rs can trigger
`T-cell activation in a manneJ' similal' to an endogenous T-cell receptOl', a major
`impediment to the clinical application of this technology to date has been limited in
`
`vivo expansion of CAR+ T cells, rapid disappearance of the cells after infusion, and
`disappointing clinical activity (Jena, et al., Blood, 201 0, 116: I 035-1044; Ucktm, et al.
`Blood, 1988, 71 :13-29).
`
`Thus, there is an urgent need in the art for compositions and methods
`for treatment of cE111cer using CA Rs that can expand in vivo. The present invention
`addl·esses tl1is need.
`
`1024333.doc
`
`Miltenyi Ex. 1018 Page 8
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`

`

`SUMMARY OF THE INVENTION
`The present invention provides an isolated nucleic acid sequence
`
`encoding a chimeric antigen receplor (CAR), wherein the CAR comprises an antigen
`binding domain, a transmembrane domain, a costimulatory signaling region, and a
`5 CD3 zeta signalil1g domain, wherein the CD3 zeta signaling domain comprises the
`amino acid sequence of SEQ ID NO: 24.
`In one embodiment, the nucleic acid sequence encodes a CAR
`
`comprising the amino acid sequence of SEQ ID NO: 12.
`In one embodiment, the nucleic acid sequence encoding a CAR
`
`IO
`
`compl'ises the nucleic acid sequence of SEQ ID NO: 8.
`
`In one embodiment, the antigen binding domain in the CAR is an
`
`antibody or an antigen-binding fragment thereof. Preferably, the antigen-binding
`
`fragment is a Fab 01· a scFv.
`In one embodiment, the antigen binding domain in the CAR binds to a
`
`15
`
`tumor antigen. In one embodiment, the tumor antigen is associated with a
`hematologic malignancy. In another embodiment, the tumor antigen is associated
`
`with a solid tumor. In yet another embodiment, the t1.1mo1· antigen is selected from the
`group consisting of CD 19, CD20, CD22, RORI, mesothelin, CD33/IL3Ra, c-Met,
`PSMA, Glycolipid F77, EGFRvITT, GD-2, NY-ESO-l TCR, MAGE A3 TCR, and any
`
`20
`
`combination thereof,
`
`In one embodiment, the costirnulatory signaling region in the CAR
`
`comprises the i.ntraceJlular domain of a costimulatory molecule selected from the
`group consisting ofCD27, CD28, 4-lBB, OX40, CD30, CD40, PD-I, ICOS,
`
`lymphocyte function-associated antigen-I (LFA-1), CD2, CD7, LIGHT, NKG2C, A7-
`
`25 H3, a ligand that specifically binds with CD83, and any combination thereof.
`In one embodiment, the CD3 zeta signaling domain in the CAR is
`
`encoded by the nucleic acid sequence of SEQ ID NO: 18,
`
`The invention also provides an isolated CAR comprising an antigen
`
`binding domain, a transmembrane domain, a costimulatory signaling region, and n
`CD3 zeta signaling domain, wherein the CD3 zeta signaling domain comprises the
`
`30
`
`amino acid sequence of SEQ ID NO: 24.
`
`The invention also provides a cell compl'ising a nucleic acid sequence
`encoding a CAR, wherein the CAR comprises an antigen binding domain, a
`
`1024333.doc
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`2
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`Miltenyi Ex. 1018 Page 9
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`transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling
`domain comprising the amino acid sequence of SEQ ID NO: 24.
`In one embodiment, the cell comprising the CAR ls selected from the
`group consisting ofa T cell, a Natural Killer (NK) cell, a cytotoxic T lymphocyte
`(CTL), and a regulatory T cell.
`ln one embodiment, the cell comprising the CAR exhibits an anti(cid:173)
`tumor immunity when the antigen binding domain of the CAR binds lo its
`corresponding antigen.
`The invention also provides a vector comprising a nucleic acid
`sequence encoding a CAR, wherein the CAR comprises an antigen binding domain, a
`costinrnlatory signaling region, and a CD3 zeta signaling domain, wherein the CD3
`zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 24.
`The invention also provides a method for stimulating a T cell-mediated
`immune 1·esponse to a target cell population or tissue in a mammal. 1n one
`embodiment, the method comprises administering to a mammal an effective amount
`of a cell genetically modified to express a CAR wherein the CAR comprises an
`antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling
`domain comprising the runino acid sequence of SEQ TD NO: 24, wherein the antigen
`binding domain is selected to specifically recognize the target cell population or
`tissue.
`
`The invention also provides a method of providing an anti-tumor
`immunity in a mammal. In one embodiment, the method comprises administering to
`a mammal an effective amount of a cell genetically modified to express a CAR
`wherein the CAR comprises an antigen binding domain, a costimulatory signaling
`region, and a CDJ zeta signaling domain comprising the amino acid sequence of SEQ
`1D NO: 24, thereby providing an anti-tumor immunity in the mammal.
`The invention also includes a method of treating a mammal having a
`disease, disorder or condition associated with an elevated expression of a tumor
`antigen. In one embodiment, the method comprises administering to a mammal an
`effective amount ofa cell genetically modified to express a CAR wherein the CAR
`comprises an antigen binding domain, a costimulatory signaling region, and a CD3
`zeta signaling domain comprising the amino acid sequence of SEQ TD NO: 24,
`thereby treating the mammal.
`In one embodiment, the cell is an autologous T cell,
`
`1024333.doc
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`3
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`Miltenyi Ex. 1018 Page 10
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`5
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`In one embodiment, the tumor antigen is selected from the gl'Oup
`consistingofCD19, CD20, CD22, RORl, mesothelin, CD33/JL3Ra, c-Met, PSMA,
`Glycolipid F77, EGFRvlll, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, and any
`combination thereof.
`The invention also pl'ovides a method of treating a human with chronic
`lymphocytic leukemia. In one embodiment, the method comprises administering to a
`human a T cell genetically engineered to express a CAR wherein the CAR comprises
`an antigen binding domain, a costimulatory signaling region, and a CD3 zeta
`signaling domain comprising the amino acid sequence of SEQ ID NO: 24.
`In one embodiment, the human is resistant to at least one
`
`chemotherapeutic agent
`In one embodiment, the chronic lymphocytic leukemia is refractory
`CD 19+ leukemia and lymphoma,
`The invention also includes a method of generating a persisting
`population of genetically engineered T cells in a human diagnosed with cancer, In
`one embodiment, the method comprises administering to a human a T cell genetically
`
`engineered to express a CAR wherein the CAR compl'ises an antigen binding domain,
`a costimulatory signaling region, and a CD3 zeta signaling domain comprising the
`amino acid sequence of SEQ ID NO: 24, wherein the persisting population of
`genetically engineered T cells persists in the human for at least one month after
`administration.
`In one embodiment, the persisting population of genetically engineered
`T cells comprises at least one cell selected from the group consisting of a T cell tlrnt
`was administered to the human, a progeny of a T cell that was admjnistered to the
`human, and a combination thereof.
`In one embodiment, the persisting population of genetically engineered
`T cells comprises a memory T cell.
`In one embodiment, the persisting population of genetically engineered
`
`T cells persists in the human for at least three months after administration, In another
`embodiment, the persisting population of genetically engineered T cells persists in the
`human for at least four months, five months, six months, seven months, eight months,
`nine months, ten months, eleven months, twelve months, two years, or three years
`aner administration.
`In one em!J,odiment, the