throbber
.(Q,01\liE\:$
`llQJA'DIS,'llQ)\W,QMf'l .llliES~~~SE~i!l~ ~
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`
`March 18, 2022
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THIS OFFICE OF:
`
`PATENT NUlVIBER: 9,46.J,1.J0
`ISSUE DATE: October 11, 2016
`
`By Authority of the
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office
`
`Certifying Officer
`
`Miltenyi Ex. 1001 Page 1
`
`

`

`I 11111 11111111111 11111 111111111111111 IIIII IIIII IIIII IIIII 111111111111111 IIII
`US009464 I 40B2
`
`(12) United States Patent
`June et al.
`
`(JO) Patent No.:
`(45) Date of Patent:
`
`US 9,464,140 B2
`*Oct. 11, 2:016
`
`C /2N 15185 (2013.0J): A61K 2039/505
`(2013.0 1); A6JK 2039/5/56 (2013.01): A6/K
`103915158 (2013.0J ): A61 K 2039/585
`(2013.01); C07K 1317/611 (2013.01): C07K
`1317/ 80 (2013.01 ); C07K 13/9/00 (2013.01 ):
`C07K 1319102 (2013.01): C07K 2319/03
`(2013.0 1); Cl2N 250//515 (2013.01); ,cnN
`2510/00 (2013,()1); Cl 1N 2740/1'5034
`(2013.01 J; crm 274f/lJ5043 (20 t3 .0J)
`(58) Field of C lassification Starch
`None
`Sec application ille for complete search hls101y.
`Refereuccs C ited
`
`(56)
`
`(54) COMPO SITIO1"S ,\.','D METIIODS FO R
`T REATl\mNT O F CANCER
`
`(71) Applicam: T he Tr ustees of the University of
`Pennsylvania. Philadelphia, PA (US)
`
`(72)
`
`Invcnh)r$: Car l B. Ju ne, Merion Station, PA (US):
`Bruce L. Levine. Cherry l lill, NJ (US);
`David L. Portct-. Springfield. PA (US);
`M ichael D. K atos, Phlladelpliia, PA
`(US): M ichael C. M ilo ne, Cherry Hill.
`NJ (US)
`
`(73) As~ignee; T he 1\-ustel?S uf the Un iversity uf
`Pennsyh,aniu. Philadolph.i:i. PA (US)
`
`( "J Notice:
`
`Subject lo ,my disclaimer. (he (erm l1fthis
`patent is extended or adjusted under 35
`U.S.C. 154(h) by 0 days.
`
`·Th.is pateut is subject to a ten11iual dis(cid:173)
`~laimcr.
`
`(21) Appl. !No.: 14/996,95:l
`
`(22) Piled:
`
`.Jan. JS, 20.16
`
`(65)
`
`Prior P ublication Data
`us 2016/0130355 '\1
`
`May 12, 2016
`
`Related U.S. Applic~tion Data
`
`U.S. PATENT DOCUMENTS
`
`5,359,046 I\
`5.686.2St A
`5,712, 149 /\
`5.S74,240 I\
`5.906.916 A
`6.103.521 A
`6,J JC/.494 Bl
`(i,355,779 BI
`6.4I0.319 Bl
`6,569,991 Bl
`7,049, 136 132
`7,052.906 BL
`7 ,070,995 132
`7,265,209 !32
`7,319,143 !32
`7 .320,787 B2
`7,402.43 1 B2
`7 .446.190 132
`7,446.191 82
`
`1011994 C'npon ct 3f.
`ll/1997 Robeti:s
`t 1998 Robcns
`2/1999 Ni <!l al.
`5/J 999 Eshhar ct al.
`lV:!000 Capon ~I al.
`J 111001 Capon ct al.
`312002 Goodwin ct al.
`6/2002 Raubitschek cl al.
`5/2003 Kwon
`512006 Seed c1 al.
`5/2006 l awson d al.
`71W06 Jensen
`912007 Jensen
`1•2008 Gross el al.
`li200li Seed el 111.
`7 12008 l lar-Noy
`1Ji2008 S:tdclain t'f al.
`( 112008 Jensen
`(Continued)
`
`FOREJGN PATENT DOCUMENTS
`
`0574512 13 I
`2/2003
`l 226244
`712004
`(Contiu11c.xl)
`
`OTHER PlJBI ,TCATIONS
`
`A NCBJ Direc1 Submission NP 000725 dnJcd i'iov. :!l. 2()1().
`A NCBI Oirecl Submission NT• 932 170.1 dated Nov, 21. 20 I 0.
`Backsgaard el al.. "Acute tumor lysis syndrome in solid rurnOJ1'-a
`case report Md review of the liicr;,ture." 2003, C,ioccr ChcrnoHier
`!'hannacol., 5 l, lt.7-92.
`Romla11za ct al .. "Suicide gene I herapy o f g.rnf1-versus-hoSL d.isease
`iJJdl1ced by conlntl memo1y buman T lymphocytes," 2006. B lood
`107: 1828- 1831\,
`
`(Continued)
`
`Primar.i• Examiner - Michael Burkhart
`(74) Allvrne_i'; Agent, or Firm - Saul Ewing LU';
`Kathryn Doyle
`
`A BST RACT
`(57)
`·n1e present invention provides compositions and methods
`for treating cancer in a human. Th" invcmlion inc:ludcs
`relates 10 admi nistering a genetically modified T c,e.Jl to
`express ,i CAR wherein the CAR comprises ru1 autigen
`binding domain, a lr.:lllslllerubrane domain, a costimullatory
`signaling region. and a CD3 zeta signaling domain.
`
`28 C laims, 2 6 Drawing Sheets
`
`(63) Contiou(1tinn nr application No. 13/992.622 . .filed as
`applic;:1tion No. PCT/US20 1 l/064191 on Dec. 9.
`2011.
`
`(60) Provisl1011al applic.ition No. 61/421.470. filed on Dec.
`9. 2010, provisional applica1ion No.61/ 502,649. filed
`on Juu. 29, 2011.
`
`EP
`llP
`
`(51)
`
`(52)
`
`(2010.0l)
`(2010.01)
`(2006.01)
`(2015.01)
`(2006.0l)
`(20 15.01)
`(2006.0l)
`(2006.01)
`(2006.0 I)
`(2006.01)
`(2006.0 l)
`(2006.0J)
`(2006.01 )
`(2006.01)
`(2006.01)
`
`l nt. CII.
`C12N 5/071
`C12N 5/0783
`C12N 5122
`A61K JS/14
`C07K 161'28
`A61K 15117
`A61K 39/(}0
`A61K 191395
`C/2N 15185
`Cfl7K 14/705
`A 61 K 48l()(J
`C(J7K 141525
`C(J7K 141725
`Cll7K 16/3()
`CJ2N 7/fl(J
`U.S. Cl.
`ere ........... Cf/7K 16/1896 (2013.01): A6/K 35/17
`(2(H3.0J); A61K 39/(l(}JJ (2013.01); A61K
`.l9/39558 (20 13.01); A61K 481005 (2013.01);
`C07K 14/525 (2013.01); CfJ7K 1417051
`(2013.0J ); C(l7K 14/711517 (2013.0l ); C() 7K
`14170578 (2013.01): C07K 14170596
`(20 13.01)~ C07K 16/3061 (2013.01); C12N
`5/(1636 (2013.0 1 ): CJ2N 710/J (2013.01):
`
`Miltenyi Ex. 1001 Page 2
`
`

`

`US 9,464,140 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PAJENT DOCUMENTS
`
`7.514.537 [l2
`7.74 1.46:i Bl
`7,994.298 82
`8,2 11,42:! B2
`8,252,914 82
`8,389.282 82
`8,399,645 B2
`8.465,74:l Bl
`2003/0060444 A I
`200310077249 A I
`2()(JJ/O 14898:! A I
`200410038886 /\ I
`200410043401 Al•
`
`4100!1 ,k-nsen
`6!2010 1: shhar et al.
`81.201 1 Zhang cl al.
`l~ hhar d :ti.
`7120 [2
`8,120 [2 ?Jiang el al.
`312013 Sa.lelain el al.
`'.\ '20 lJ Campana et al.
`611013 Roscnoc1-g ct a I.
`3/ 2003 Finney c1 al.
`4 12003 Bebbington el al.
`S 2003 13renner et al.
`212004 Finney et al.
`'.lt.2004 Sadelain ......
`
`200510 113564 Al
`2005'012967'1 Al
`200810131415 Al
`20091025 7994 A I
`201()10.233200 A I
`201110052554 Al
`lOll/014855:! ,\I
`2013 007141•1 Al
`20131014933'1 AL
`
`51W05 Campana <'l nl.
`6.12005 Cooper 01 al.
`6,·wox Riddell ct al.
`1011009 Jensen
`9120 [0 Medin
`312011 Zakrzewski e t al.
`612012 Jensen
`312013 Dolli el al
`61201) Cooper el a.I.
`
`C071 l 2 l 104
`43516 ,]6
`
`FOREIGN PATENT DOCUMJ1NTS
`
`r,p
`871495
`JP
`2003-5.1730J
`2004-529636
`JP
`WO'/11 I 5322
`WO
`\VO
`W0/9513 0014
`WO
`\\1096/238 14
`W096/2467 I
`WO
`W0/97115669
`WO
`W<),'971236!3
`WO
`WO
`W09$/ l 8809
`W099100494
`WO
`WO
`W099l 57268
`W0/00/ 14257
`WO
`WO 01134841
`WO
`WO
`W 0 102/33 I O l
`WO 02:077029
`WO
`W<;)l021077029
`WO
`WO
`WU '021088334
`WO
`W02005l0 19429
`WO WO 2 00S1044996
`WO
`W0200610G0878
`WO
`\V0200ll,045437
`WO
`W02009/09 l 8,6
`WO W0/20101025(77
`WO wo,20 w. 085660
`W020 L 1/059836
`WO
`WO
`W02012/0J3885
`WO
`W02012/0.58460
`WO
`W02012.'08284J
`WO
`W02012/127464
`W020121 I 35k54
`WO
`WO
`W020l2/ U885S
`WOl O 13/033626
`WO
`WO
`WOlOIJ.1040371
`WO
`W020131059593
`
`6 12005
`512003
`912004
`9119i>2
`IJ/[995
`$11996
`8i1996
`5 · 1997
`7, 1997
`5, 1998
`111999
`1111999
`J /2000
`5 •2001
`4/2002
`l0/2002
`l012002
`11 /2002
`312005
`5,2005
`6 ·2006
`4,200s
`7tl009
`J120IO
`712010
`5 2011
`3 120 12
`.512012
`6/ 2012
`9120 12
`1012012
`10120 12
`312013
`3 ·201J
`4'20 13
`
`OTIIER PUBLICATIONS
`13,~nljens et al ... "Eradicntlun o r systemic B-cdl lumt>rs by geneti(cid:173)
`cally ta.rge1ed lhum:in T lymplwcytes cu-stimulated by CD80 and
`inlerleukin-1 5." 200'.l. Na111re Medicine. 9(3): 279-286
`Brent_jens et al.. "Crendically tars,eted ·1 cells era((icale sys1emic
`acute lymphohlastic lcukc,mia .xcnogrnfis." 2007, Clin Cancer Res
`I 3:54i6-5435.
`Brenljens cl al., .. Safely and persistence of adopli vely transferred
`m11ologo11s CD l9-targeh .. -d 1 cells in paticms with i·elapsed or
`leu.h·mias," 20 I J
`chomothcrnpy
`rcfracwry 8-cul l
`131ood
`1 IS(18);4817-41S2~.
`
`Bn,nljcns Cl al .. "Trealmenl uf ch.rook lymphocytic lcmkcmia wiih
`genetically target<-.! aulologous T coils; Ctl.SO repur1 or a.n u1l10:res~en
`adverse <!Vent in a phase I clinical trial." 20 I 0, M9I Ther, I$, 666-8.
`Brent,iens. cl ,tl. '";\ Pba"" l Trial for the rreaurn.•nl of C'hemo(cid:173)
`refracto,y Chronic l,ymphocyl ic Leukemia wilh Ci) IQ."fargeiet.1
`Aulologou, 1 Cells.'" Mol. fherapy. 200~. p. S 15, vol. l6, Suppl I.
`Brocker and Karjalaincn . .. Sig,1mls Uuouglt T cell receptor-!; chain
`alone ore insufficicnl to prime resting T lymphocytes." 1995. JI. Exp.
`Moo .. !Sl: 1653-1659.
`Call. el al., ·'The T cell t<.'Ccplor: critical rol<: or the membrane
`environ111enl in receptor assembly and funciion." 2005, An nu Rev
`lmmunol . 2005, 23:JOJ-125.
`Campana et al .. " ]'-Cell lmtmmc,Lh~rapy for l:l-Linengc Acute
`Lymphoblastic Leukemia Csing Chi111erk Anlii;en Receptors fha_l
`l)~livcr 4-188-Moointed Coslimulaio,y SigMls'' 200J Blood
`J 02( 11 ); abstmct 112:!'.I.
`Oupenilo el aL. --conlJ'ol ot' la.rg.c. established tumor xcnografls
`with gcnclicitlly rcl/lrgct<XI human T c0lls containing C'D28 am!
`CDJJ7 domains." 20()(). Proc Natl Acad Sci US A 106;3360-3365.
`Davila et al.. "B Cell Aplasi.i in a Patient with Relapsed 13 Cell
`/\cute Lymphoblaslic Leukemia followi ng Rc-rnductio n and Con(cid:173)
`solidation with Aulologous I Cells Genetically l;ugeled tu the
`CD l9 Antigen." 2010 ASH Meeting Abstract No. 3268. presented
`Dec. 6. 2010 (posh,r abstract).
`Davila et al., '"f Cells Genetically Tru·getcd 10 C'l:>t!) P.ra.clii;.11c
`13-J\Il in 8 No~cl Syngcneic Mouse Discas<1 Model." 20W ASII
`Mceling Abstract No. 17 J. pi~scnteo Dec. Ci. 20]() tposlcrabst.rnct).
`l)ohncr el nl., "p53 gene deletion predicts for poor survivl!ll an,I
`non-response tu therapy with purine ,l.Jlnlogs in chronic B-cell
`leukemias." 1995, Blood. 85: ISR0-9.
`Dropulic el al., '"Genc-ba~cd 1mmunot.hcrapy for human i1111111uno(cid:173)
`delicicncy virus infccllo n and acquired ,mmunodeliciem:y Syn (cid:173)
`d.romc." 2006, Human Gene Therapy. 17; 577-88.
`l)ul l el al .. "A rhird-generation leni-ivims vector w ith ~ con/1 itiomtJ
`packaging syslcnL·· 1998. J ViJol, 72: l!46J-7 l.
`6shb:u e t al.. " Specific activatiun and targeting of cytotoxi<: lym(cid:173)
`phocyte~ through chimeric si1tgk chains consisling <>[ antirbody(cid:173)
`b inding domains aud lhe Y or!; subunits uf I.he immun()globul in and
`T-cell rccoplors." 1993, Proc Nall Acad Sci USA 90;720-724 .
`FiMey el al .. "'Activation of resting human primary T cells with
`cltimeric r<-ceplors: coslimulaJion from CO2~, inducible cosliunula(cid:173)
`lur. CD l34. and C0 l 37 (4-IBBJ in series with signals from the
`TCR zela chain." 2004, J. lmmunol 172: 104-113.
`Finney et al.. "Chimeric receptors providing both primnry and
`cos1i111ulatory signaling in r cells from a single gene pmducL"
`1998. J lmmunol 161 :2791-2797.
`FricdmnM-Morvinski cl at.. "Rcdirecl'cd pr1m:uy T cdls harboring
`a chimeric receptor .rcquin; co~limulnlion for lhdr anl1gc11-,;pecuic
`aclivalion." 2005, Blood 105:3087-3093.
`Geiger a11d Jyolht, ''Devclopmenl and applicalfon of rnc.cplor(cid:173)
`lymphocytes for adoptive 1mmunotherapy." 200 I,
`modifietl T
`Transfusion Mcd.icine Reviews. IS(l): 21-34 .
`(icigcr cl al .. ·'tntcgraloo src kinase aml constimulntory a,ctivity
`enhances signal transduction through single-ch;un chimeric rec~l'(cid:173)
`tors in T lymphocytes." 2001. Blood 98lS):2364-7L
`Gilham et al .... Primruy Polydonal lluman T lymphocytes tugclcd.
`l.o carcirlo-cmbry,mic anligens ;md neural cell adhesion mo•kcule
`tumor a11ligens by CD31;-bas~d chimeric immune receptors." 200 I,
`J, ln111m11ology, 25(2): 139-151.
`Gong el at.. "Cancer p,1lienl T cells genet ically liirgetetl Lu prostale(cid:173)
`spoeifit 111<\mbrfiocJ ruili!;~n specifically ly,;e pro~tall! c:1necir cells
`and release cytokincs in re.,;ponse 10 prostnlc~spccific memhmne
`antigen.'' 1999,Ncoplasia, 1(2): 123-127.
`Uribben cl nl., '"Siem cell tmnsplantation fur inclo!e nl lymphoma
`a.od chronic ly mphocylic leukemia:· 20 11 , Biol Blood Mlarmw
`Tmnsplnnt. 17: Suppl :SCi3-S70.
`Grilliri el al., "Development itnd appUcalioo of ~llrface-linkcd single
`chain antibod.ies against T-cell antigens." 200 I. J . l.mn11lIJologica.l
`M~'llloJs. 248: 77-'JO ..
`Gross and F.shha.r. 1992. "F.,ndowing T cells with a_ntibody speci(cid:173)
`tidty using chimeric T ,ell receptors." 1992, FASEB J. 6; JJ70-
`JJ7$,
`
`Miltenyi Ex. 1001 Page 3
`
`

`

`US 9,464,140 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTl-1.ER PUBLICATIONS
`
`I l:,llek et al., .. (,~iddincs for the diagnosis Md trcatmenl of cluo oic
`Jyrnpboc)'l.ic lc1ukcmia: a report fro,n Lhe lnlemmionalWork~bop on
`Chronic Lymp,hocytic Loukllmia updating the Nalionnl Can<:er
`lnslitule-Working GroLLp
`1996 guidelines."
`2008, Blood
`11 1 ( 12):5446-5:456.
`lkkclc cl 11L, "1(1foW1h retardaJion ofl\llllOfS by adoptive tmnsfer of
`<..-ytotoxic T lymphocytes reprogrammed by CD44v6-specific
`~cl'v:zcw-chimcra." 1996, Int J Caneer 6k:232-2J8.
`llo ct al., "Ado'[llive lmmunolhempy: 11nginecring 'I .:ell rcsJ)(" nses
`as biological \\lc:,pons for tumor mass destniction.'' 2003, Cancer
`Cell 3:43 l-437.
`Hollyman c t nl .. ··Manufocluring Valiclalion of Biologically flunc(cid:173)
`tional T Cells Targeted to CD19 Antij!,en for Aulolog1,us Adoptive
`Cell lnerapy." .I. ln1111uno1her .• 2009. pp, 16!/- 180, vol. 32, ~o. 2.
`Hornback ~~ aJ., -~rhe Recomblnanl T Cell Recep(or Slralei;y:
`Insight~ inlo StnK·l11rc nnd Function ofRccombinnnl lmmunorecet,(cid:173)
`lors on the Way 1owards an Op<imnl Reccplor Design for Cellular
`lmmnnothcrapy," 2002 Currcnl Gene Therapy 2.2 11-226.
`Lmai ct al.. "Chimeric recl-;.,tors with 4-IBl3 sigualing capacity
`provoke pokol cylotoxlci1y against acute Jymphob(agtic leukemia."
`2004. Leukemia 18(4):676-684.
`Imai el al., 2005, Genetic modificntlon of primary MlLU'al killer cells
`overcomes inh:1bi101y signals and induces specific killing of leuke(cid:173)
`mic cells. Bloc,d, 106:376-383-
`JntcmaJiona.1 S•Nuch Report for PC'flUS20 J l,0li4191 tlaled May l,
`2012.
`Irving & Weiss. ·"lb" cytoplasmic doma.iit oft.be I' coll receptor zcli!
`chain is i;utficie ot 10 couple to r~-ccpto r-asst1ciaK'<l signal transduc(cid:173)
`tion pathways." 199 1, Cell 64:891-901.
`Jena cl al., "R<:d.irecl.ing T-cell sp~cilic il)' by introducing a ILUnor•
`s pecific chimeric antigen rccep1or." 2010, Blood. 116: 1035-44,
`Jensen el al.. ""Anlilra.nsgene Rejection Responses Con1ribulc to
`Altenualed Pe,rsistence or Adorlivcly Transferred CD20/CI) 19-
`Specific Chimeric An ligcn Receptor Reclirccted T Cells
`in
`Humans." 20 10 Biol Blood MnrrowTransplMI 16;1245-1256.
`Johnson et al.. "Gene lherapy wilh hum.to :md mouse 'f-cell recep(cid:173)
`tors mediates cancer rcgrc:,,~ion Md targcls normal Ussues c.-<press(cid:173)
`ing cognate antigen." 2009, Olood. 1 l4: 535-46.
`June et al.. "Engineering lympho,ytt: subsets: tools. trials and
`1.rib11lalions.'' 2009. Nat Rev I.Jllll1llno l. 9: 704-16.
`Kalos, ct ,ti., "T Cells with ChimcricAnligen Receptors Have Potcnl
`Anlitumor l'!Jfocls and Can l:,s1ablish Memory in l'a!ienls with
`Advanced Let1lkcmia." 101 1, Sci Transl Me<l 3(95):95ra73.
`Kcr.ahaw <:I at, "A ph:1sc 1 study on adoplive i1rm1unollmrnpy using
`gene-modified T cel ls for ovaria/J cancer.'' 2006, Cli n Cancer Res
`12:6106-611~.
`Kim et al.. --111um,1n 4-IBB regulates CD28 co-stimulntion to
`promote Tbl cell responses," 1998, fau· J 1Jiun1,mol 28:8~1-890.
`Kochenclerfor c,t al.. "Cons1.ruction and Pre-clinical Eva.luation of an
`Anli-CO19 Chimeric Antigen Receptor." 2009, J IJ11munothcr
`32(7)6il9-702.
`Kochenclerler, d nl., "A PhaNc r c'linicnl ·1ri,tl of rrentmenl or
`B-Cell Malignancie.~ wi1h Autologous A.nti-CDl9-CAR(cid:173)
`Tran5dllc~-d T Cells.'' 2010 ASJ-1 Mccling Ahslrnd No. 2~65,
`prcSWllCd Dec. 5, 2010 (p():\l<'r nbslracl).
`Kochcndcrfor, ct al ., "Adopliw lrnnsfcr of syngeneic T cells
`lians<luced with n chiJl'lefic nntigcn receptor IJrnl recognizes murinc
`CD 19 can cradjcate lympl1oma and normal 8 cells." 20 I 0, l31oo<l.
`J J 6(9)3875-38:&6.
`Koehcnderfor. •et al., "Etadicat.lon o f B-li neagc cclJs and n:gn:s~ion
`of lymphoma i n a pa1jenl treated with aulologous T cel ls scnetI(cid:173)
`ca.lly--cnginecrnd lo recognize CD19." 2010. Blood l 16:409!/-4102.
`Kocbcnderfer, ,21 al,, '·Novel l\ntigcn-Sp<..>cific 11-cpnnsioo ofT Cells
`'l'ra.nsduced willh a ('1) 19 Ch imeric Antigen Receptor." 2010 ASH
`Mectln_g Abstracl No. 3262. pn.,.ented l)ec. 6. 2010 \poster
`abstract).
`Kohn, cl' al., ''C,\Rs on trnck in the clinic ." 201 I, Moleculru· Thcr
`19(3 ):432~3l:i,
`
`Krause el a.I .. "Anligen--dcpend.cnl CD28 signaling sel<-"<:ti~ely
`0nh1U1ces s urvival and rroliJcra1ion in g.:ncti,ally mod.i.fied acti(cid:173)
`vated h uman pri111nry ·1 lymphocytes: · 1998, .I. fap. Med., I 88(4):
`6 IC)-626.
`l runanna et al" "l'cntostalin, cyclophosphamide, and ril'lLximab is
`an active. wdl-toleraled regimen for patients wilh previously
`treated chronic lymphocytic leukemia." 2006, J Clin Once,!, 14:
`1575-$1.
`Lamers er :ti .. ''Trea1,n~nt oJ' metastatic renal cell carcinom:1 with
`aulologous T-lymphocyles genetically retargcted against carbonic
`anhydmsa IX: first clinical e.~p<'rien~e." 2006, .l ( lin Oncol 24·e20-
`e22.
`f.apo1t el al., "Ad<lpl.ivl.' lransl<>r of costimulated I ~ell~ induces
`lymphocytosis in p;lLienlS witl1 relapsed/refractory non-Hodgkin
`lymphomn following CD:.4+-sdedcd hcm,1lopoietic cdl lransplnn(cid:173)
`tation." 200;1, nlood 102, :?004-2013.
`lee ct a.I.. "In vivo inhibilion of human CDl9-targcted clfoctor T
`cells by nan,rnl 'l' regulatory cells in~ xenolransplanl m11rinc model
`of B cdl mali!].llllllcy," 20 11. Cancer Res 71 :2871-2881.
`Le1ourn<lur & Klausner, ''l'-ccll and basophi l activation through the
`cytoplasmic tail ofT-cell-rcceptor zcta family pl'Oteins.'' t \)9 ( _ Proc
`Nnll Acad Sci US A 88:8905-8909,
`Levine el a.I.. "Ot.'ne lransler in humans usin!,?. a cMditionally
`replicat ing lcnlivirnl vector." 2006. Proc ~nil J\catl Sci ll S A
`J 03: I 7372- 17377.
`Maca.llan cl al., "Measurement anti modding. o f human 'T cell
`k1J1ctics:· 2003. Eur J lmmunol , 33: 2J 16-Ui,
`Maher ci al., "I lutmn T-lymphocytc cytotmdcity and pro Ii fm11ion
`d.lrod~'<I by a single dwneric TCR:re1a / CD28 rtlceptor:• 2002, Ka.t
`Biotcchnol 20(1 ):70-5.
`McGuinncss. el al.. "Ami-tumor ac11vily of human r cells express(cid:173)
`lng the CC-IIJ-ze~1. chimeric Immune receptor." 1999, Hull11.Gene
`Ther JO: 165-l 73.
`Milone et aL, "Ch imeric receplors cootaining C-DIJ7 signnJ
`lransductioo do nL'J.i ns iued ialc enhanced survival of 1 cellls anti
`increased
`itntilcu.kemic efficacy
`in vivo.'' 2009, Mot
`!'her
`17(8): 1453-64-
`Molina. "A decade o f riluximab: improving survival outcorn<'s in
`non-Hodgkin's lymphoma." 200$. Ann Rev Med. 59: 237-50,
`Morgan ct al .. "Case repprt of a seriol!S adverse ev'-'nl following the
`admin istrnlion ofT cells lmns1lu<:ecl with a c himeric antigen recqJ(cid:173)
`tor n!cog.ni:ting ERBB2." 2010. Mol Ther. 18: ll43-51.
`Morit-z &. Umncr, ''A s pacer region hdwccn lhc single .:hain
`antilxldy- Md the CD3 ✓.cl'n-ch:iin domain of chimeric T cell
`recep1or compone nts is required for .:tlicient lignml bindin.g and
`signnling activity," 199~. Gene 111cmpy, 2:539-546.
`Moritz cl nl.. "Cytoto:(tC T lymphotyles with n gralled rccog:nition
`specificity for E RJ3B2-e:<presslll~ tumor cells" 1994, Proc. Natl
`Acnd. Sci. 91:4318-4322.
`Naldini el al.. "In vivo gene deliv.:ry and slable transducl ion of
`nondlviding cells by a J.:ntiviral vector." 1996, Science. 272: ,263 -7
`Nic holson, cl a.I .• ··coastrnclicms :Ind Cha.radtlrizniion of a Punc(cid:173)
`lion;u (1)19 Specific Si ogle Chain Fv Frngmcnt for lnununolhorapy
`ofB Lineage l.eukcrni3 and Lymph oma.'' .\,fol, lr,11mu10I., 1\197, pp.
`11.57-J 165, vol. 34. ~o. 16-( 7,
`Ochoa ct al., lmmunc Defects Ln T Cells From O mccr Pa.tie nls,
`Parallels In lnl<'Clious Diseases, from: Crulccr Jmmunolhc~~py 11t
`thl' Cwssroad.s: how 11uno1·s evade immunity and what ~-,U) "1: done
`{curren t clinical oncology), ~clilc'(( by James H. Finke, Romdd M.
`Bukowski 2004 •~1ilion.
`Park and Btenljeng. "A<lopliV<' lm1i1unothM1py !br B-cell Malig(cid:173)
`nancies with Autologous c himeric Anligcn Rcccplor Modified
`Tumor rargcte<I 'I' Cells," 2010, l)iscov Med 9(47):277-2~8.
`Pnrk el 11I.. "Adoptive tnmsfer ol' chimeric antigen receptor re(cid:173)
`dlrcclcd cytolyttc T
`lymphocyte clones
`in pntlco1s with
`neuroblastoma .'' .2007. Mol lnc.r 15:82.5-833.
`Patel c1 al .. "Impact of chimeric immune re.:ep(or cxtrac,ollulat
`protein doma.Uls on T ceU fum;tion." I 998. Gene Th.:rapy. 6,
`412-419.
`Portl!r el al. ·•A phase I trial of do no r lymph ocyte inflisions
`expanded and aclivaled t:X vivo -via CDJ,CD28 eostimulillion."
`2006. 131011d, l07; 1325-J J.
`
`Miltenyi Ex. 1001 Page 4
`
`

`

`US 9,464,140 B2
`Page 4
`
`(56)
`
`References Cited
`
`OTHER PUBLJCATIONS
`
`Portor e( al ,, Chimeric Antigcu Receptor 1 herapy for B-ccll M3lig(cid:173)
`nancies. 10 I I , J Cancer 2 :33 l -332.
`Porter. "Chim<!fic an1igcn r,-ceptor-111odi6ed r culls in chronic
`ly mphoid leuJ«,mia." 2011 New England J Med 365(8):725- 73:l.
`Pul~ et al,. " Virus-specific T cells engineered to C\>CXpress tumor(cid:173)
`specific Jcccpt<1rs: pcn;islcncc and :mtilumor ru:fivily in individual s
`with neuroblastoma," 200l!, Na1 Med 14: 1264-1270,
`Rapopon er aL. "Restoration of immunity in lymphopenic individ11-
`nls with cancer by v:icdnalion and ndortive T-ccll lr:lllsfer," 2005,
`Nal Med ll: 12:30-1237.
`Rocdcrer, "T~,:11 dynamics ofinununottdi,;i,;ncy," 19'15, Nat Med,
`.I : 621-7
`Romeo & Seed. "Cellular [m:munity to 1IJV :iclivnlctl by CD4 fo,.,d
`lo TceH or Fe r.c~p1orpolypeptidcs.TI L991.Cell 64: L037- J046.
`Sabbagh el al., "11':F (iunily ligamls tlefwe oiches for ·1 cell
`memory.'' 2007, 'frends lmmur\ol 28:333-339.
`S3dcl:tin cl ~1" ·•targeting 11.u110111s w ith gcoelie,11Jy enhance~ l
`ly111phocy1es:· 2003,Nal Rev Cancer J(l):35-45.
`Smklain L1 al., "The promise and poteoti;J pitfalls of chimeric
`antigen recL"J)[Clrs." 2009. CtuT Opin Immunol. 11; 215-:!3.
`Savoldo cl al.. "CD28 cos1im11lation impiovcs expansion and pcr(cid:173)
`Kistenceof chirneric antigen receplor-mo11ifietl Teells in lymphomn
`patients.'' 201 1. J Cliu Inwsl 12 1(5): 1$22-6.
`Sebestyen, cl al .. "Human TC'R lhnl in<'oll"oratc CDJzetn induce
`highly pn•fem·d pairing between rcRnlpha and beta ch.tins fol(cid:173)
`lowing gene tmnsfer." 2008. J lmmunol. 2008. 180( I i ):7736-46.
`Song. cl al. ''C'D27 costimutation nugments lhe survival and anti(cid:173)
`tumor Bl'livi1y of redirected human T cells in vivo." 2011 Blood
`119:696-706.
`Sorror el al., "<Outcomes after ollogcncic bcm111opoiclic cell trans(cid:173)
`pl:tnrnlion with nonmycloobla1ivc or myeloablalivc conditioning
`n!timens for i.reatmcnl of lymphoma nnd Chronic lymphocytic
`leuk<:mia." 100,s. Blood. 111: 446-51.
`Tammnna Syarn et al., "4-1 HB nnd CD28 signaling plays a syner(cid:173)
`gislic role in redirecling u:mbillcal cord blood 'I cells ag,'1insl B-cell
`malignruJcics." 2010 lluman Gene Tl1crapy 21 :75-l\6.
`Till ci al., ''Adopiive immunolhcrapy for i11dl'lcnl 11on-l lodgkin
`lymphoma and mn.nlk cell lympbomu using gcMticnlly 1nodilkd
`autologous CDZO-~~iecific T cells: · 2008. Blood. ll1. 2261-2271.
`Uckrn1, el al, "Dc1ailed stuu.ies on cxprc-ssion and funclion ofCDl9
`surface delcm1.inan t by using 843 monoclonnl anlibody and the
`clinical polenti:Jl of ant·i-CD 19 immunotoxins." 1988. Blood. 7 l; 13-
`29.
`Vinny and Kwon, "Role of 4-1 BB in immune responses." 1998,
`Seminars in Immunology, l0:481-489.
`Willemsen et ul .. "GeMtic Engineering of T Cell Specificity for
`lmmunolhcrnpy of Cancer.'' 2003.1 luman Immunology, 64: 56.f,$,
`Zu1fctey et al.. "M1JLiply altcnuated lcntivtral ViMOr ncbieves
`efficient gene delivery in vivo." 1997, Nature Biot,schnology
`J 5:87 l-S75.
`ChTncsc Patenl Appllcation No. 20 t 1800671 73.X- Office Action
`dated Oct. 22. 20 l4.
`Chinese Palcnl Application No. 20 I [80067173.X- Secontl Ofljce
`Ac11on tlaled J1ul. IO, 10 15,
`Colombia l'al~nl Application No. 13-137636-Colombian resolu(cid:173)
`tion No. 8 176 dated reb. 27, 20 15.
`Colombia l'alcnl /\pplic,ition '\io. n-117636 English lranslatio11
`of Ollice Action of Sep. 5. 2014.
`Cuba Patent Application :Ko. 101310079 00:il-c Action of Apr. l,
`2014,
`Cuba P:11ent A1pplica1ion No , 1013100'79 O llice Aclion of Ocl, 28,
`2014.
`Ft1rasian Region !'ntenl Application No. 201390$47128 omce
`Aclion tlnled Mar, 11. 2015.
`European Paten, Appl 11846757.0 European Search Repon of Dec.
`2. 20 14.
`
`l'inal Office 1\Ction mailed Mnr. 28.
`
`European Pal<:nt Application No. ll846757.0-0.IliceActioo dated
`Aug.. 17.2015,
`Guatemala Pa1enl Applicatlon No. A-20J3-150 E ngli~h lrnnsla.(cid:173)
`liM of Observer's comments of Sep. 17. 1014 .
`. lnpanese Patent AppHcation No. 20 I J -S43J80-0llice Acliorn dated
`Oct. 15, 2015.
`Mexican Pall'nt Applicalion Ko. MXla/201~ '006570 Office
`Action ,falctl Oct. 9. 20 IS.
`New Zealand Pnlenr Applic:il i0n No. 612512 - Firs! E:<Ml Report
`of Nov. 20, 2013.
`rhailand Patent Application No. 1301003 120 Ollice Action of Jul,
`2014,
`U.S. Appl. No. 14'107.302- Fi nal OfticeAction of'Mar. J I. 20 15,
`U.S. Appl. No 141107 .. 102- non-finul Ollice Action of Ser . 30.
`2014,
`U.S. Appl. No, J41567.426-non-final Olli<Je Aclion of Jan, 16,
`20J 5 .
`U.S. Appl. No. J4 '568. l95 non-6nni Ollic.c ,.\ction of Jan . :Jll,
`1015.
`U.S. Appl. No. 14'568,569 non-final Otlkc Action of Jan . 15,
`2015.
`U.S. Appl. No. 13'992,622- non-fina.l Office Aclio n of Jun. 19.
`2015.
`U.S. Appl. No. 13•992,622- Final Office Aclfon of Jan. 5, 2016.
`U.S. Appl. No. 14/465.952- non-tinal ()Dice Aclion of No,v. 20,
`2014.
`U.S. 1\ppl. No, 131938.923
`20)4,
`U.S. Appl. No. 131938,91.3- Finul Ollice Action malled Oci. 8.
`2014,
`U.S. Appl. No. 13/9:18.923-nou-lioal OHicc -\ccioo of Sep. l 9.
`2013.
`U.S. Appl. No. 131938.947- Final Ollice Acti1>n of Sep. l I. 2014.
`U.S. Appl. No. U /938,947- non-final O llicc Acli<>n of Ike. I(>,
`2013.
`U.S. Appl. No . 14/466,096-non-!inul OlficeAction ofCJcl. 8. 1014.
`/\ustm lian Application No. 2011338200 Paten! E.'<ami nnlion
`Rcpor1 No. I. ,L11cd /\pr. 11. 201G.
`Chinese Patent Applicatlon No. 20118006717JX- Third OOke
`Action dated Mat. 28, 2016.
`U.S. Appl. No. 141984.371 non-fuial Ofl:keAction elated Mat. 11 ,
`2016.
`U.S. Appl. No. 141997,042- non-final Ollie" i\dion dated i\ip1'. 13,
`2016.
`U,S. Appl. No. 141997.13(,,_non-final Oflice Action dated Apr. 21 ,
`2016,
`Colombian ra1cn1 Application No 15-80418- 0 .flicc /\cti,m issued
`Dec. 23. 2015.
`Colombian Patent Application No.
`issued Nov, 23. 2015.
`Eumsiru, Palen! Applirntion No, 201390847--00ice Action issued
`Feb, 14. 2016.
`U.S. Apr l. N'o, 131992.622- Final OOice Action i~sued Jan, 5,
`2016.
`"G,mctic1tlly Engine.:red Lymphocyte Therapy in rreating [';1tienls
`with ll-C'ell Leukemia or Lymphoma That is Rcsislanl or Rcfrncto.ry
`lo C'hemolherapy" C'lini,nlTri:ils.gov ltlcntificr NCTO I0:!9366:
`Retrit!vcd from the iotcmeL on Jnn. 29. 2016. l'ound at hltp~:i•\V\\I\V.
`clinicaltrials.gov/ct2/sl1ow1NCTOl029366'/term
`=NCTll 1029366
`&rank- I.
`·"PJl01 Si11dy for Pnlfonts with C hemolherapy Resislnnl or Refrac(cid:173)
`tory CDl9 Leukemia and Lyrnph01na (CART-19)" C linkaJTrials.
`gov Identifier: NCT00891215: Retrieved from the inlemct on Sep,
`2, 2015. Found al hllp://web.archive.org,web,200909030023041
`http:/icli nica ltria ls.govicr;vshow/J\CTOOS9 n 15.
`Apt>liC'hem prod11ct shco1 for RPMl-1640. 1 pages, downloaded
`[)cc. 28. 2015.
`Milone, M. Ill al., Supplementary Matciials and Melhods. Moll Tuer.
`vol. 17. 2009. 7 pages.
`
`:-<\>, 13-t 3 7536- 0llicc ,li.ction
`
`" cited by eJ<amioer
`
`Miltenyi Ex. 1001 Page 5
`
`

`

`"'y J
`I i~
`. I
`Bacterial
`repli.cadon ----i,
`orig:in
`
`.R region
`
`.~
`,<0_1/r
`
`;i:;:,.LT· .. ·R
`. ,.
`
`pELPS 19~:BB--{
`1155.6: hp
`
`,, RRE
`
`·, Trum:::ated
`e.nv
`
`.._EF~lct
`
`~~=
`<i,
`~~
`
`'t
`";\, 3 \LTR {truncateq)
`•:<'(~
`'.
`Bovine GH Poly A
`·<:,\~&"tr .
`.
`... .
`R r,ea-ion 1truncated)~~i<,.,. , __ ~ -....
`~
`\.
`
`''co lg BB.t
`
`'
`
`_..,,
`
`_.,..
`
`v.VPRE
`UJ ltruncatedl
`t
`•
`FMC6:3
`Human CD8a
`Hin~:~nc:f J:M 4~188
`
`Figure 1A
`
`c= .
`~
`--= ~ ;-= !"+-
`
`0 ..,
`....
`:"'°
`r
`0 ....
`
`N
`
`0\
`
`tri =(cid:173)~
`~ ....
`....
`0 ..,
`N
`0\
`
`c:::
`VJ
`--.,.
`',el
`O'I
`~
`""'"' ~
`0
`i:,:;
`N
`
`Miltenyi Ex. 1001 Page 6
`
`

`

`U.S. Patent
`
`Oct. 11, 2016
`
`Sheet 2 of 26
`
`US 9,464,140 B2
`
`l1l
`~ -
`~
`
`.s
`.....
`g~
`
`0.:.
`
`'
`
`t;, .. - ·
`
`Cl) w ~i
`-g
`<.l §
`~ ....
`s:f. ....,
`l5
`p;;
`'
`~i
`~ @
`~ -- &! 1 lt.'!J
`?:
`~£
`8'
`fj
`
`~ I
`
`£.-
`...,.N
`rt,:· .. ,
`<l)'
`>~
`m
`
`!::-
`
`t
`
`_.
`co
`
`OJ
`~
`:::J
`bJJ
`u..
`
`lt1
`>-,
`~-
`0
`
`~~
`
`ID
`::,, ~.g
`,., .
`~m
`r U
`jffi
`t
`'$. ,· k~
`(,:J-~i
`i 01%1
`:cy ·mi
`,I e s:ll'
`::,,
`'
`1
`·~ee
`0 ~ 9l.
`> a
`t
`. - ll :
`ffiz i :,,
`~ ~ %l
`.•
`t;g·i-
`~· ' fl'~
`,: ~ co
`~@J;
`Q ~i'.11~0
`t- ~
`.-a .~~
`€~!
`._,.,(iji
`j •~ ·E
`~S~J .
`~"a!ij~
`~- .
`~ ~~ . j
`·-.. t::: .. ' ·
`_.j ft.
`0
`t;(J .(/) ft.
`(;f:l~-
`(~) if~
`Cl I Ci
`Pi,,...o
`t
`t :i g ,JI· ~· ;
`;j ,(;, ~l'
`
`~
`
`~
`Q ·
`
`"7
`,;::,,·
`>;
`ell
`
`0
`
`- ~
`
`'
`
`'
`
`Miltenyi Ex. 1001 Page 7
`
`

`

`U.S. Patent
`
`Oct.11 . 2016
`
`Sheet 3 of 26
`
`US 9.464,140 B2
`
`.J~Jtl.i8Jl •Mfi◊~P.$l~!llJ $~\f ~A~~p
`JOJ Su!,~HWll-l JOJ na Jl_gl;}~ s~ .;OJ
`lb~~.Jd t:it.i!}~O!lW3:p ~ J~o JP¥
`
`ZJll~oJ.
`&.I jJ~ll,UtlW/1.li>~f>\l~ ,¼J~lltrt:}
`
`UO\~U! ~od '>l;l)UOUi 9
`il.fc!~UOW.; VOO~MJ~qo Al(,flJ.lOfJ
`
`u
`
`~
`(1)
`'--::::,
`tlO
`LL
`
`-5uia~~o}! 1own1.
`AtlfQiQ!!J
`
`Miltenyi Ex. 1001 Page 8
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 4 of 26
`
`US 9,464,140 B2
`
`t ._ tJii.J i
`
`I
`
`jPill\ I
`
`)li,Slj 1 Ji/. I
`
`jCl\i
`
`Jctlil ,
`
`i ,..
`
`co
`N
`OJ
`I,...
`:J
`tl.O
`u...
`
`<(
`N
`
`~ .,.
`/lit .., ....
`... tl
`i ~ ·,;
`';ii
`~ ~
`.,. .5
`(:;, ~
`$
`
`¥1
`.II')
`Q
`
`i t
`Q
`
`0,. -·
`
`Miltenyi Ex. 1001 Page 9
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 5 of 26
`
`US 9,464,140 B2
`
`I
`I J
`
`jihfil j I.
`
`►()Iii i !
`
`fll,11, ij. l
`
`I
`
`jliliil!
`
`jiklii I 4-
`
`0
`N
`(lJ
`~ Ill i
`
`LL
`
`~ I
`
`u
`N
`(lJ
`'(cid:173)
`::l
`tlO
`LL
`
`Miltenyi Ex. 1001 Page 10
`
`

`

`U.S. Patent
`
`Oct. 11, 2016
`
`Sheet 6 of 26
`
`US 9,464,140 B2
`
`LL
`N
`OJ
`!....
`::J
`b.O
`LL
`
`UJ
`N
`OJ
`i...
`::J
`b.O
`LL
`
`,
`
`. I 1
`
`\I( 11$\ • MIiii I
`
`(
`
`j,lh i i I
`
`l,hilid i
`
`I
`
`!iiii¥1;
`
`t;
`!
`~-
`0
`
`e.
`""
`
`ij'
`i
`
`<':,
`~
`
`';,,r,r '
`"'''' ''
`,,.
`
`Miltenyi Ex. 1001 Page 11
`
`

`

`U.S. Patent
`
`Oct. 11, 2016
`
`Sheet 7 of 26
`
`US 9,464J40 B2
`
`;,,,
`~
`
`.__ ......... = Cl ·;
`~ ~
`~ ,!E
`it
`0
`~ ·
`::I>. a
`
`·t
`
`~
`
`co
`M
`Q)
`~
`:J
`bD
`LL
`
`tau-H~Q iu~1i ~Jrueu~ mnil
`~QJ.~!fWMS
`
`<C
`M
`Q) ~
`"(cid:173)
`:J
`bD
`LL
`
`,..
`~
`{~ll~~q lt.i!QJJ~!m~p ~#}
`~~Ol}O .Wni/1<$
`.
`
`¢'
`
`1Z
`
`~ --g
`·~ :,
`....
`,E-
`'t§
`Q a
`@ i::,.,
`l'J'
`Q
`
`Miltenyi Ex. 1001 Page 12
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 8 of 26
`
`US 9,464,140 B2
`
`)
`I I I
`
`u
`M
`C1J g
`I,..
`:J
`tl.O
`u,_
`
`,,..
`
`..
`
`0
`'<'"'
`
`""'
`~
`(~11asaq tl/b-4. ~u~ ~ PIO!}
`aui~o,llo blru~s
`
`Miltenyi Ex. 1001 Page 13
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 9 of 26
`
`US 9,464,140 B2
`
`~
`0 u
`
`.... --~·...,:~~~tt:\:•,,. '."··'
`r ~,
`I
`
`(()
`Q
`0
`
`Miltenyi Ex. 1001 Page 14
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 10 of 26
`
`US 9,464,140 B2
`
`co
`"-t'
`Q)
`I...
`::J
`tl.O
`LL.
`
`~~
`c:.J » ·
`I.,.) °\'$
`0
`
`?:
`
`~
`
`l,
`
`,,
`
`~
`
`'
`'
`.,
`<
`
`Miltenyi Ex. 1001 Page 15
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 11 of 26
`
`US 9,464,140 B2
`
`~ ...
`. B·
`
`~
`.8
`
`,..
`.. ~
`
`r-, a (J
`
`>l>l
`~ ·o .
`l'
`
`~
`Cl ~'
`
`B;J ~
`
`.,.
`~
`Q
`(;
`
`.
`
`.
`
`..
`
`r~
`N
`Q
`I)
`
`~
`0
`~
`
`.
`
`~
`
`ttO:tii
`
`j :~
`
`st-Q:>
`
`$fUD
`
`f,.,
`
`~
`
`',.\
`
`~
`Q
`~
`
`~-♦~d
`
`kQd
`
`:l.1;1:iJ
`
`rs-.
`~
`~ !J
`
`~ -
`
`~-
`
`..
`
`W'©
`
`-~u-::,
`
`·tt()o
`
`••'CM-
`
`at©
`
`~:
`0
`~
`
`P....
`
`t:1
`~
`
`ro.
`>('l,
`8
`
`"'
`It',
`Q
`t.;)
`
`l!i.
`r',I ·
`0
`u
`
`~
`
`a·
`
`.tta~
`
`JZ(l!J
`
`~
`. N ·
`0
`~
`
`t~OP
`
`lt&O
`
`m·
`
`. Q ·
`•U
`
`PJ·Q~
`
`a:-ao
`
`P:®'·
`
`t~tl~
`
`\\
`
`lj
`
`e~J =l
`
`0
`
`•'?.- ~ • ' c-
`
`!
`
`Miltenyi Ex. 1001 Page 16
`
`

`

`U.S. Patent
`
`Oct. 11, 2016
`
`Sheet 12 of 26
`
`US 9,464,140 B2
`
`Figure 4D
`
`NOTARGE,T
`
`U.PNO$
`t);6;Y' 5S
`
`:u.i
`
`n:1
`
`,~,-4,.
`
`lJFN ·Oi
`OAY.16$
`
`,.
`
`S:M
`
`J:}:s?.,:
`
`<l'U'
`
`?l.~4: ·
`
`7:Mt·
`
`8...1~
`
`».~
`
`,,.,
`
`a
`
`$ .1'6'
`
`~Z>
`
`'l>.1•
`
`·$Ml·
`
`K5&2
`
`KSS2. ~
`
`C!P19 < u
`
`NALM~
`
`?MA+
`tONOMY'CI~
`
`~-·~,•
`
`O.'t8:
`
`~n
`
`.(;~1
`
`ll
`
`CDlO?A
`
`Miltenyi Ex. 1001 Page 17
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 13 of 26
`
`US 9,464,140 B2
`
`<!
`l.f')
`,._
`QJ
`:J
`tlO
`LL
`
`·------------""-+ .ra
`I i i· A . ' I I~·
`\t:W'WJ~A} l,$}· @.tj;1J
`
`Miltenyi Ex. 1001 Page 18
`
`

`

`U.S. Patent
`
`Oct. 11, 2016
`
`Sheet 14 of 26
`
`US 9,464J40 B2
`
`....
`i;;li
`:it
`0.
`~
`
`co
`LI)
`a,
`::l
`0.0
`u..
`
`!,,_
`
`... e
`z
`a. ::,
`
`u
`I.fl
`a,
`::l
`
`!,,_
`
`tl.O ·-
`
`LL.
`
`Miltenyi Ex. 1001 Page 19
`
`

`

`U.S. Patent
`
`Oct 11, 2016
`
`Sheet 15 of 26
`
`US 9,464,140 B2
`
`LL
`
`<(
`\0
`Q)
`~
`:J
`0.01
`LL
`
`u..
`
`Miltenyi Ex. 1001 Page 20
`
`

`

`U.S. Patent
`
`Oct. 11, 2016
`
`Sheet 16 of 26
`
`US 9,464,140 B2
`
`,..
`,.. .
`
`•.
`
`I
`
`..,._.,._..;.,o«.,,..«"-,glt,(.;:.,.•;,:·-1
`
`~L .. __ i:,J
`
`ffl
`
`-11
`
`l :
`
`I i
`
`0
`r-,..
`Q)
`I....
`::l
`b.O
`LL
`
`u r-,..
`
`Q)
`I

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket