W0 2008!082966
`
`PC Tl[7520077088028
`
`3/87
`
`
`
`
`
`1107 of 1754
`1107 of 1754
`
`
`
`PC Tl[7520077088028
`
`3/87
`
`
`
`
`
`1107 of 1754
`1107 of 1754
`
`
`
`4/87
`
`
`
`FIG. 1D
`
`1108 of 1754
`
`
`
`000000000000
`
`5/87
`
`
`
`1109 of 1754
`
`
`
`W0 2008!082966
`
`PC TlU52007i088028
`
`
`
`1110 of 1754
`1110 of 1754
`
`
`
`\V()2008fl082956
`
`PCT!U 5200731188028
`
`7/87
`
`
`
`
`
`
`1111 of 1754
`
`E103:
`
`w
`
`_.NoN
`
`um.wE
`
`
`
`.VON.....................
`
`..==_==_===._..
`
`NE
`
`EN
`
`.2:.NE02
`
`
`.OON.“'9..."...§Em¥3A.»...
`
`
`Mm.§.NNN
`
`
`
`._._...mNN
`
`.vom
`
`bow.mom
`
`
`
`
`
`W0 2088;!082966
`
`PCT! U 8200 7l0880 28
`
`8/87
`
`
`
`
`
`
`
`
`
`
`
`1112 of 1754
`1112 of 1754
`
`
`
`W0 20083082966
`
`PCTIUSZtIOWUSISUZS
`
`9/87
`
`
`
`1113 of 1754
`1113 of 1754
`
`
`
`“’0 200811182966
`
`PC Tl U 8200711188028
`
`10/87
`
`mom
`
`arm
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0mm
`
`
`
`
`
`
`
`NNN
`
`on?0mm
`
`gmflflfi
` .1..r...’4.
`
`
`
`n_m.9“—I
`
`Fm
`
`1114 of 1754
`1114 of 1754
`
`
`
`
`1115 of 1754
`
`fink—Lomr:
`
`W0 2008;082966
`
`PCT.Jr U 5200 770880 28
`
`11/87
`
`
`
`
`
`W0 2008I082966
`
`PCT/USZOO 71088028
`
`12/87
`
`1116 of 1754
`
`
`
`1116of1754
`
`562
`
`FIG.4B
`
`
`
`
`
`510
`
`511;
`
`
`
`W0 200811082966
`
`PCTIUSZtIOWUSISUZS
`
`13/87
`
`902
`
`
`1117 of 1754
`1117 of 1754
`
`
`
`W0 20081082966
`
`PCTIUSZOOWOSSOZS
`
`14/87
`
`
`
`1118 of 1754
`1118 of 1754
`
`
`
`
`
`
`
`1119 of 1754
`1119 of 1754
`
`
`
`1120 of 1754
`
`
`
`wmt.“—0cw:
`
`W0 2008;082966
`
`PCTIUSZUO7ft|8802S
`
`16/87
`
`
`
`
`
`W0 00000000000
`
`PCT)f
`
`U- 8200 7i[l88028
`
`17/87
`
`
`
`FIG.6D
`
`1121 of 1754
`1121 of 1754
`
`
`
`W0 20083082966
`
`PCT)f U- $2007fl188028
`
`18/87
`
`
`
`1122 of 1754
`1122 of 1754
`
`
`
`W0 2008;082966
`
`PCT! USZOGWOSSOZS
`
`19/87
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1123 of 1754
`1123 of 1754
`
`
`
`W0 20083082966
`
`PCTIUSZtIOWUSISUZS
`
`20/87
`
`
`
`
`
`
`
`1124 of 1754
`1124 of 1754
`
`
`
`WO 2008/082966
`
`PCTI'USZUUTKIJSSOZS
`
`21/87
`
`
`
`FIG. 61
`
`FIG. GJ
`
`1125 of 1754
`1125 of 1754
`
`
`
`1126 of 1754
`
`
`
`wmt.“—0mm:
`
`\VO 2008I082966
`
`PC T! U 82 007;“088028
`
`22/87
`
`000—
`
`USE:
`
`33:203.
`
`
`
`m_nm=m>¢
`
`
`
`W0 2008f082966
`
`PC Ti USZUU‘MISBUZB
`
`23/87
`
`vmop
`
`Nmo—
`
`Omow
`
`mflsw95mm
`
`3Q8
`
`wmo_
`
`
`
`
`
`1127 of 1754
`
`
`
`wmt.“—0hm:
`
`Nwo—
`
`m.wE
`
`
`
`2525.4Buck
`
`:595
`
`mE:_o>
`
`12::ovo—
`
`
`
`:onmEBEammmq
`
`535:2HS
`
`NEE33:3
`
`”9.59:20.;
`
`”Baa
`
`EEC.
`
`wwo—
`
`
`
`5:232;£33m
`
`
`
`wworE©¢o—
`
`953.8%.
`
`183@254
`
`33:3
`
`--”5::
`
`
`
`1128 of 1754
`
`
`
`wmt.“—0wNE.
`
`W0 2008I082966
`
`PC TlUSZ 00 ”9880 28
`
`24/87
`
`mmoF
`
`tumor
`
`mmor
`
`mmop
`
`=2535a:5:3N
`
`meowamo—
`
`
`
`.buuuuczoumfia.“3.“.th“m58%mm
`
`:23.630mn=m_
`
`
`
`
`
`
`
`53839:.565%
`
`
`
`
`
`
`
`W0 2008f082966
`
`PC Tl C5200 7108 8028
`
`25/87
`
`cook
`
`Empmxm
`
`1129 of 1754
`
`
`
`wmt.“—0mm:
`
`wwor
`
`.GE $20—.
`
`
`
`
`
`
`
`53282;
`
`mwnwmevoooo
`
`cofimEBEQua.“we”.
`
`LmnEzz#3
`
`
`
`W0 2008;082966
`
`PCT.Jr U 5200 770880 28
`
`26/87
`
`Wmofi
`
`Nmo_
`
`oooF
`
`
`
`E
`
`mvpo—
`
`mm_o_
`
` goon
`
`33:90.
`
`--“5;;
`
`:(mcm”ytfl
`
`”cucLH3t>su<
`
`Qom”:EVQE:B>
`
`1130 of 1754
`
`
`
`wmt.“—0an:
`
`NwoF
`
`_‘F.o_u_
`
`
`
`
`
`
`
`
`
`cosmgmamhaflcmymxm
`
`25%
`
`Com
`
`2:
`
`53:91WEE,
`
`com”SEW
`
`man>
`
`eméev
`
`
`
`ovo—
`
`mcszkmamz
`
`:ueogv>:>nu<
`
`3.3mevooootmnfizzyou.
`8823am”38
`
`c338323?.
`
`
`
`
`
`
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 7I088028
`
`27/87
`
`mmor
`
`Vmor
`
`Nmo—
`
`0mm:
`
`Nmo—
`
`coo—
`
`1131 of 1754
`
`
`
`wmt.“—0Fm:
`
`<2.oE
`
`
`
`
`
`
`
`5:882;EBmzw
`
`
`
`3384.33
`
`DE”8.5
`
`amen—208:;
`
`wE:_o>
`
`cm5.5ovoe
`
`
`
`3%mevoooorepeaz5..
`
`
`
`553.5%..384
`
`8833.on”Ban.
`
`:4mEBE;
`
`_:370.02”5.5£2fi<
`
`o.om”9.59:29;
`
`
`
`1132 of 1754
`
`
`
`wmt.“—0NM:
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`vmow
`
`Nmo_.
`
`82:5I
`
`28/87
`
`82—|8%.meana"9.5
`
`
`
`.92:N2:.
`
`CON.cUEV
`
`
`
`as'955.232;Emu—9m
`
`No_._.
`
`
`
`3%59x58$3523..
`
`meow22.ON“33
`
`:4mE.BE;
`
`0.0m”9,5wEEo>
`
`
`
`
`
`Door3%;odfiufiivbéfi<
`
`333%0
`
`
`
`mm—.OE
`
`
`
`
`
`1133 of 1754
`
`
`
`wmt.“—0mm:
`
`W0 2008I082966
`
`PC T! USZ 00 7I088028
`
`29/87
`
`£33m
`
`
`N:—
`
`wE:_o>
`
`8:832;
`
`00mE.
`
`_E82;magma
`
`:o_umE.£:_239‘.
`
`N35$2.54M“DEV9:39;m"mEfiN"3mm.0”LunEzz8..
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 7I088028
`
`30/87
`
`mmor
`
`vmop
`
`Nmo_.
`
`002
`
`mP“8::
`
`3333‘
`
`N“8,533:04
`
`mummwmmwcocorun—5:25..
`
`95.:ME:
`
`cormctohs>394
`
`882%8”BB
`
`0.3“cgmE:_o>Emin5E:
`
`odom”8.533:3
`
`1134 of 1754
`
`
`
`wmt.“—0fin:
`
`owoF
`
`N3:
`
`.3.0E
`
`0mgmm“.
`
`mmo_.8:3
`£33m
`
`ME
`
`
`
`2:254.38.
`
`m3”5E
`
`mE:_o>
`
`E5.5
`
`205282;
`
`
`
`W0 2008;082966
`
`PCT.Jr U 5200 770880 28
`
`31/87
`
`mmoe
`
`vmor
`
`Nmoe
`
`omofi
`
`ng
`
`000_.
`
`02:0nan—mmNN_.FR.
`
`meEsw
`
`éq«95¢
`
`«.23
`
`
`
`@®
`
`
`
`ET.5T232;(mm:
`
`
`
`
`
`umm‘rmumsoufizucfimcoufl—
`
`EmEpmzfid85D
`
`
`
`xumcuEzemxummD
`
`x850th_H_
`
`
`
`
`
`EoEmEmmmEbofimmfl—
`
`1135 of 1754
`
`
`
`wmt.“—0mm:
`
`
`
`
`m—.oE
`
`833m
`
`203988;
`
`
`
`8>28
`
`_.N_._.
`
`f
`
`
`om:
`
`
`
`LBEENEQ9:gas.533%o:m.“96$“we.“8%mm
`
`
`
`
`
`W0 2008;082966
`
`PCT.Jr U 5200 770880 28
`
`32/87
`
`000_
`
`
`
`om:
`
`Emuwxm
`
`1136 of 1754
`
`
`
`wmt.“—0an:
`
`<2.9“—
`
`mm»Hkm:
`0522mg33:329:m_
`tngwcucosmNEE
`
`2bmfimmU
`cocoPENU
`ocfimcouU3230mmU33gm.U
`
`
`
`
`
`umnEmfi.Eugen,2tmt...m£b..éuumo:m...Emfi5t8%mm
`
`
`
`8:982;
`
`
`
`W0 2008;082966
`
`PCT.Jr U 5200 770880 28
`
`33/87
`
`vmwF
`
`mm:
`
`mm.P_.
`
`
`
`coo?Ompfi
`
`
`
`Cowmhmamhaptmummm
`
`
`umafiwficommune2:"figb.3huma:Ma99...“RE.23mm.¥
`
`
`1137 of 1754
`
`
`
`wmt.“—0hm:
`
`
`
`amokhufizoofixscfimcooD
`
`
`
`E22938:bmflmmD
`
`
`
`xumfiuBEmeummD
`
`mm_..OE
`
`#58333.EmD
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`34/87
`
`mm:
`
`mmPF
`
`om,_
`
`
`
`uuafimfi3.33:2mfi$9.35.33%9:fl96:»:5Sawmm.
`
`
`
`53.8821Emymxm
`
`
`
`
`
`
`H5552?$5E:Fm—
`
`1138 of 1754
`
`
`
`wmt.“—0mm:
`
`2..GE
`
`
`
`l.58.3828328328E
`
`
`
`EwEoEmmoEbmfimmD
`
`xumcucczohmxumm_H_
`
`
`
`1139 of 1754
`
`
`
`wmt.“—0an:
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`35/87
`
`009.
`
`
`
`.EQEEUcosmNEQ58.58mama
`
`mam$88330..o.mm78888.
`.__m_S”NH
`
`88:3mm”38.
`
`24mE“2::.
`
`
`
`ES”8::533%.
`
`all
`
`@®$23:8:
`
`
`
`
`
`w_..wE
`
`
`
`VmopNF—
`
`‘
`
`.32E83288;
`
`EBfiw
`
`
`
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`36/87
`
` czohmxummSma?35S
`
`1140 of 1754
`
`
`
`wmt.“—0cw:
`
`mp.oE
`
`
`
`EME3938:EmfimmD
`
`3.:
`
`I
`
`can—Emzu:OENNEEED:Outflowgrasp—mm
`
`
`
`
`
`
`
`
`
`53832;5396
`
`
`
`1141 of 1754
`
`
`
`wmt.“—0Eu:
`
`W0 2008f082966
`
`PC Tl C5200 7108 8028
`
`37/87
`
`ooow
`
`vm:
`
`wN—_.
`
`mumSquzucfimcouax353:39.303m—
`58.
`
`
`
`EvEEzmmm:bmfimm_H_
`
`Ewe—.332mama
`
`NN——xuwzuBowa
`
`@
`
`om.wE
`
`
`
`
`
` ud23m.umaEEuenamwfiom.2tmEEbinaryonm.EmfiRE.83um
`
`om__.
`
`
`
`
`
`zen—ESE;Emumxw
`
`
`
`
`
`
`
`W0 2008f082966
`
`PC Ti USZUU‘MISBUZB
`
`38/87
`
`mmor
`
`wmoP
`
`Nmor
`
`omo—
`
`Nmo—
`
`000W
`
`1142 of 1754
`
`
`
`wmt.“—0Nw:
`
`
`
`3NA3985:5303:328
`
`meF
`
`”mm“om:£2mea
`
`
`
`E0.3
`
`_‘N.wE
`
`EBmzm
`09.3woow$20quvNumeEzm 5:232;
`
`8>28
`
`3:5953
`
`meEzm
`
`:4main.
`
`E"395.155,mamENS”9am230.3225in
`
`EmEHmagEm
`
`
`
`“webmofizoudiucflmcou
`
`
`
`asonӣ238.3%.:
`
`hmTwo“3302
`
`H
`
`E
`
`
`8%Eu952“.
`
` v_u9.6o...mNacomb)Ematoma35m53.55
`
`
`
` guano352303Ia5:3.
`
`mi“388.
`
`GE8”3236‘
`
`
`UEom"@2348:282.
`
`
`(aN60Ada3.0.3.8EESUEm
`
`
`
`
`
`.035“.m0EEC,8:233—«mm”38TB2233005938/1mFumemoon
`
`
`
`
`
`W0 20081082966
`
`PCT! USZ 00 71’088028
`
`39/87
`
`omo_.
`
`Nmor
`
`Omor3“am-:“53>$53.5:3.3NS“952.30.8“5:5358mm:3new»:
`Nmo_.535580335350_H_xumcu339303aEmEEsm
`
`Vmo—conmoNnwmm
`82E:.3:£5i
`E396
`£838“smegma?EmHx3523fl
`:4.wmtzn—GEom3:234
`
`
`<0m_.F
`
`
`
`EN3”5am_.o-mo.822.5$5
`
`539%a_.-u_6333
`
`5:882;
`
`
`
`:oEw)Emitom%atom“3:55“oob8.00”meE:
`
`1143 of 1754
`
`
`
`wmt.“—0aw:
`
`all
`
`EH
`
`Mn”mmmxg
`
`mm.9”.
`
`
`
`W0 20l}8f082966
`
`PC T! U520!) 710880 28
`
`40/ 87
`
`000_.
`
`
`
`
`
`_E
`
`3:202
`
` --A:33 95$ mEmzm>< 250125393
`32va
`
`
`
`
`00m
`
`1144 of 1754
`
`
`
`wmt.“—03.:
`
`moor
`
`
`
`
`\VO 20059082966
`
`PCTIUSZDOT’HISSUZS
`
`41/87
`
`COOP
`
`III
`
`3:30
`9&me
`
`WONF_uEmm-m33.34“macaw.
`
`Hal1E..98
`
`
`woo_.533%uefimnuEmEm
`
`
`
`ofimzmaq
`
`>Emcu_<
`
`1145 of 1754
`
`
`
`Int.“—0mw:
`
`moor
`
`woo—
`
`woo”
`
`
`
`
`W0 2008I082966
`
`PC T! U SE! 00 m 88028
`
`42/87
`
`mom—
`
`009
`
`33:3@2me mwm.oE
`
`QNON—
`
`£9253328.8
`
`GE
`
`
`
`>Eocu_<BEBE
`
`
`
`£902...E23“.L35.
`
`m_aa__a>4
`
`1146 of 1754
`
`
`
`wmt.“—0cw:
`
`
`
`2%;SE
`
`
`
`W0 2008;082966
`
`PC'U U 5200 770880 28
`
`43/87
`
`meow
`
`
`
`
`
`1147 of 1754
`
`
`
`wmt.“—0t»:
`
`uwm.wE
`
`p<_u:_r.o
`
`Emucfim
`
`£\_u:_m_.o
`
`DE5:.So
`
`05560;
`
`
`
`
`
`n:\GE_...0
`
`
`
`mm_.n=Ems?“5an
`
`@®@®
`
`
`
`man—1
`
`£9253323.8
`
`usam
`
`00m
`
`E..—
`
`
`
`@2548:30
`
`mssaé
`
`
`
`
`
`
`
`5202$8:
`
`2:5862mm
`
`
`
`
`
`
`
`
`
`
`
`1148 of 1754
`
`
`
`wmt.“—0aw:
`
`\VO 2008I082966
`
`PC T! U 82 0(l7f088028
`
`44/87
`
`000_.
`
`!“n:35
`
`
`
`£553.@332
` coinage;Emummmm3m=m>¢
`
`
`
`Ego;B33:28
`
`
`
`>38m_.Emymhw
`
`
`
`1149 of 1754
`
`
`
`wmt.“—0aw:
`
`W0 2008;082966
`
`PCT}r U 5200 770880 28
`
`45/87
`
`n:\GE_..0 A:$5
`
`
`$9ES52ONEmzwm.w_..._
`
`_E
`
`
`
`3.203.09va
`
`208..25393
`
`o_nm__m><
`
`05am
`
`08
`
`
`
`
`W0 2008;082966
`
`PCT}r U 5200 770880 28
`
`46/87
`
` 2%;
`
`1150 of 1754
`
`
`
`wmt.“—0cm:
`
`“zum.0:
`
`B “
`
`flan—mu
`
`@3263“
`
`
`
`25:24.BEBE
`
`#58m_Emumxm
`
`
`
`W0 2008(082966
`
`PCTIUSZOOWOSSOZS
`
`m
`
`NC
`
`)
`
`NN
`
`9
`
`EO
`
`ONO
`
`<9
`
`E
`
`@
`
`6)
`(9
`®
`®
`
`< L
`
`n N 9 L
`
`1.
`
`47/87
`
`1x.
`
`5
`
`
`_
`
`I. -
`
`
`
`
`
`
`
`C
`.3
`“5
`E
`2%
`E
`8
`to
`E
`'5
`‘=
`U
`a.)
`E
`
`g
`g
`‘5
`3
`._.
`5
`
`>1
`E
`g
`2
`<1
`E
`“C5
`
`E
`
`1151 of 1754
`1151 of 1754
`
`
`
`W0 2008I082966
`
`PCTIUSZUU‘MISBUZS
`
`1152 of 1754
`
`
`
`wmt.“—0Nm:
`
`mmor
`
`
`
`NNOF_.N0_.
`
`
`
`mmm.wE
`
`3%;Eng
`
`48/87
`
`
`
`mwfiw355000”9$8
`
`EESBEEma
`
`m
`
`29m2
`2:23
`
`n n3
`
`3:
`
`25mm
`
`com
`
`7...
`
`
`
`:2pr3th£393
`
`mfisfiau
`
`3584Egg
`
`
`
`
`
`
`
`
`
`W0 20l2|8f082966
`
`PC Tl USZOO 77088028
`
`49/87
`
`ONE
`
`wow—
`
`0FNF
`
`08_\
`
`
`
`1153 of 1754
`
`
`
`wmt.“—0mm:
`
`
`
`55232.“.£33m
`
`Q32EEGwzeaaq
`
`53335Ema
`
`
`mwmmEmwooooH:33
`
`
`
`
`5:230;“Erma
`
`n:\GE_..0
`
`@@@®q
`
`NOE.
`
`moor
`
`woo_.
`
`<©N.QE
`
`
`
`#2.._m5FE
`
`
`
`>Eo;u_<BEBE
`
`mEEE
`
`
`
`
`
`
`W0 2008;082966
`
`PCT.Jr U 5200 770880 28
`
`50/87
`
`nag—um:
`
`>520?
`
`Agem_8398.
`
`5EB
`
`mmmwFmmwo
`
`
`
`cobmhmnmhuEmu—mam
`
`
`
`
`
`3mm2£moam=uE9».30:0qu53:m__mmm:E
`
`3254Bing
`
`m3m=m><
`
`25%
`
`00m
`
`1154 of 1754
`
`
`
`wmt.“—0fin:
`
`N09.
`
`#00_.
`
`
`
`
`
`
`
`1155 of 1754
`
`
`
`wmt.“—0mm:
`
`W0 20l2|8f082966
`
`PC Tl USZUO 770880 28
`
`
`
`mAgigag<emF.......
`
`
`
`
`
`
`
`brace?swim—2
`
`51/87
`
`O_.N_.
`
`
`
`5:938;E253
`
`wow_.mmwmpmmwoooo”a.35
`
`2.33%2%
`
`n:\GE_..O
`
`ONO_.
`
`
`
`commiem23%35:2Emma2333..
`
`N00w
`
`wooa.
`
`
`
`000—.UNEN_.m.m_.a:£9955%;VOOF
`
`
`
`
`
`
`1156 of 1754
`
`
`
`wmt.“—0mm:
`
`W0 20l2|8f082966
`
`PC Tl USZUO 770880 28
`
`52/87
`
`
`
`c2532;Egan.
`
`@382559;
`
` mKN.wE
`
`3%82.88é38.5lGEcammnF3:3
`
`
`5533553%33:3.“.2meo_nm__m><
`
`Q_\_UEPd
`
`mm—.a:£925225
`
`
`
`>520?.088:
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`53/87
`
`1157 of 1754
`
`
`
`wmt.“—0hm:
`
`m.m_.a.5925Song
`
`mm:N87,.E:82<wm.UE
`
`
`
`
`
`€me3E033
`
`
`
`5:202.283:
`
`
`
`COURSE;Ewumzm
`
`53:2358msgaaq
`
`a:\GETo _E
`
`
`8%53008”9$8
`
`35333£91
`
`3:8
`
`8m
`
`
`
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`54/87
`
`(EN—
`
`0N9.
`
`o—N_.
`
`9_~_.
`
`
`
`539.82,...Emma;
`
`38we
`
`n:\GE_..o
`
`
`
`©©®®
`
`COO_.E29w;€ng
`
`
`
`mm;£398QasIGEcom
`5:938;EBmmm533$3:meo_nm__m>¢
`
`
`
`
`.353wa59._E
`
`
`
`xEmcuZnag—2
`
`
`
`amen.mctsmmmz
`
`25%
`
`1158 of 1754
`
`
`
`fin:“—0mm:
`
`woo“.
`
`woo—
`
`Lnoo—
`
`
`
`1159 of 1754
`
`
`
`wmt.“—0mm:
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`coo—
`
`
`
`mm_.n__39055.31
`
`
`
`82NNE@®@@
`
`55/87
`
`ONE
`
`momF
`
`o_m_.
`
`o—NF
`
`809on”.
`
`2:5E_.o
`
`
`
`53939.;E296
`
`mmnmamwoooo”2$8
`
`EBEBEEma
`
`
`
`:OEquEm«:2qu
`
`.mva_AEDGEEE
`EEEEEvoz:
`
`mdw
`
`£3m=m><
`Bironawn—92:3
`
`
`BEBE
`
`>830?
`
`How?2xummm
`
`
`
`
`
`
`
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`56/87
`
`335:3 sfiaé
`
`
`
`
`
`sausage;Eflmxm
`
`3358
`
`
`
`x805?3.622
`
`Um?SxUmmx
`
`
`
`
`
`1160 of 1754
`
`
`
`wmt.“—0cm:
`
`(Om.QE
`
`5:2QO
`
`Emm—
`
`3mm—
`
`£903Egg
`
`mmnm_~m¢oo.
`
`.358
`
`.womonnmuombxmas.9829
`
`
`
`1161 of 1754
`
`
`
`wmt.“—05:.
`
`W0 20l2|8f082966
`
`PC Tl USZUO 770880 28
`
`www—
`
`ONE.
`
`
`
`c3933;Emfihw
`
`332game@3953
`
`
`
`520238:
`
`@8585
`
`57/87
`
`@5333Ema
`
`mew_.3&5988Q38mInFGE
`
`Emu.
`
`SN“.
`
`
`
`£03832;Ewan;
`
`0:\CEfio
`
`$00an:
`
`
`
`mm_.n=EmEEEmzma
`
`com
`
`_E
`
`:3NOE
`
`——_woofl.
`_moow
`
`
`
`
`
`
`
`
`1162 of 1754
`
`
`
`wmt.“—0Na:
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`www—
`
`ONO,
`
`
`
`xEmcuZ.088:
`
`58/87
`
`Kan—33:439:
`
`pmm¢oooo“n:mmmuImom_m
`mwhm
`
`FGE
`
`2:3
`
`Gem
`
`E...
`
`moor
`
`
`
`55539;Eon—Rm
`
`
`
`5359‘nun—9&3“.
`
`magaé
`
`
`
`c3538“.Egan.
`
`OFNFmoo,
`
`wrmw
`
`ommw
`
`n:\GE_..0
`
`
`
` ©®®®
`E88man.WOO_.
`
`Fmdr—
`
`
`
`
`
`
`
`
`
`W0 2008I082966
`
`PCTIUSZUU‘MISBUZS
`
`59/87
`
`one.
`
`womw
`
`o—NF
`
`EN—
`
`
`
`1163 of 1754
`
`
`
`wmt.“—0mm:
`
`
`
`mommpmmmm—@®®®
`
`mmoowe“.
`
`3:GEfio
`
`
`
`mm—.9:Emma52$;
`
`<Nm.oE
`
`
`
`mwnmemmvooooun:$3
`
`_B_n:uouc<Ema
`
`
`
`case—ES“.Emzmm
`
`m.m_.
`
`33:333:8
`
`
`
`5:338“.E396uEm=m><
`
`
`
`
`
`
`
`5:05?38.82
`
`Beam
`
`2:3
`
`_E
`
`com
`
`
`
`
`
`
`
`
`
`
`W0 20l2|8f082966
`
`PC Tl USZUO 770880 28
`
`60/87
`
`
`
`munm$2.88
`
`.9Emma;
`
`“3,”#3we
`
`mmémmr
`
`Esagé2%
`
`“3a2
`
`>Em:u_<@9th
`
`1164 of 1754
`
`
`
`wmt.“—0#5:.
`
`mmm.OE
`
`
`
`
`
`BmEEOUsebum?
`
`23%:
`
`v.2GE
`
`
`
` 3326"“.9.2m:30...3_E
`
`699:8we
`
`Qmm
`
`25%
`
`PD.»
`
`_E
`
`
`
`1165 of 1754
`
`1165of1754
`
`W0 21108f082966
`
`PCT/[ESZUO7I088028
`
`1302
`
`1000
`
`PrintDays
`
`
`
`PrintSummary
`
`
`
`
`
`
`
`
`October2006
`
`
`
`
`
`InjectionHistory
`
`
`
`1166 of 1754
`
`
`
`wmt.“—0mm:
`
`W0 2008;082966
`
`PCTIUSZDU‘HIISBUZS
`
`62/87
`
`(NOMF
`
`
`
`
`
`
`
`
`SEE3a;“.82mm
`
`
`
`
`
`
`
`
`
`mmm.oE
`
`
`
`
`W0 2008;082966
`
`PCT}r U 5200 770880 28
`
`63/87
`
`nmom—
`
`
`
`
`
`
` l@61882885.:I
`P :EEi
`
`1167 of 1754
`
`
`
`wmt.“—0hm:
`
`
`
`0mm.oE
`
`mmmy
`
`_|
`
`.38:
`
`
`
`
`W0 2(1081’082966
`
`PC Tl C5200 7108 8028
`
`64/87
`
`88988888 8888898:
`
`
`
`
`Ed..855
`
`8888888
`
`.8859
`
`8808888
`
`888888
`
`8888888
`
`9&8
`
`honEsz“3
`ham“
`
`l N,
`
`_ m,
`
`_
`
`E:
`
`N‘—
`
`mr
`
`—
`
`ommF
`
`N‘—
`(“I")
`r-
`
`1168 of 1754
`
`
`
`wmt.“—0mm:
`
`
`
` ®
`
`ommF
`
`<¢m.oE
`
`E;880
`
`80888888
`
`E398
`
`8888888
`
`
`
`@8215:8?
`
`
`
`
`1169 of 1754
`
`
`
`wmt.“—0mm:
`
`W0 2008f082966
`
`PCT/[ESZUO7I088028
`
`65/87
`
`
`
`owmp
`
`mama—waoooo
`
`
`
`H:“6%.”.
`
`fl“3on“—
`
`wmlwmmp
`
`EEEBEEma
`
`"gawk:
`
` @821
`
`9m
`
`9mm5:.
`
`
`
`323:32::.38
`
`£38558?.
`
`fim_.55
`
`50.5289won.
`
`858.3.
`
`
`
`1170 of 1754
`
`
`
`wmt.“—0an:
`
`_wommmwww
`
`PC Tl C5200 7108 8028
`
`66/87
`
`meow?
`
`COOP
`
`
`
`mm.wE
`
`
`
`cofimhzmccou
`
`
`
`mmmsmcfiHum—mm
`
`
`
`W0 20l2|8f082966
`
`PC Tl USZUO 770880 28
`
`67/87
`
`meow—
`
`coop
`
`wFVF
`
`vF¢F
`
`E88“39¢E
`
`
`
`>3)spec:an
`
`
`
`
`
`"3E...Eutzu
`
`E400H:
`
`umELEmE_._.
`
`.50;m—
`
` Ig:
`
`
`1171 of 1754
`
`
`
`wmt.“—0E:
`
`mm.oE
`
`h
`
`
`
`8:235;.
`
`
`
`
`
`NF¢Fofivw
`
`conmLzmccou
`
`
`
`W0 2008f082966
`
`PCT/[ESZUO7I088028
`
`68/87
`
`30*.F
`
`000_.
`
`3%:3m:Eggs
`Qva—mwmv—35%
`
`corfizmccou
`
`mac—WEEK:
`
`1172 of 1754
`
`
`
`wmt.“—0NF:
`
`
`
`km.wE
`
`
`
`
`
`
`
`1173 of 1754
`
`
`
`wmt.“—0an:
`
`W0 2008;082966
`
`PCT} L’SZIKI‘HIISBUZS
`
`69/87
`
`mooi.
`
`002
`
`mm.oE
`
`cofifizmccou
`
`
`
`W0 2008;082966
`
`PCT} L’SZIKI‘HIISBUZS
`
`70/87
`
`noowp
`
`000—
`
`1174 of 1754
`
`
`
`wmt.“—0wk:
`
`<mm.oE
`
` oé
`
`
`
`
`omwr
`
`8393328
`
`
`
`va_.3:53.2:33
`
`Now—
`
`mgnEEu:3
`
`831
`
`firmEmoQuwmmm£995
`
`
`265mEEEEmEm:nmta
`la:
`
`3:38.33;
`
`
`
`W0 2008I082966
`
`PC T! USZ 00 ”088028
`
`71/87
`
`coop
`
`.
`
`www—
`
`Nn¢w
`
`h
`
`1175 of 1754
`
`
`
`wmt.“—0mp:
`
`mmm.oE
`
`
`
`Efigs%
`
`awnwr
`
`n__\_uEm_..o
`
`mEocsmz
`
`£\_QEo_..0
`
`253.56
`
`EzEEE
`
`330Eno.0
`
`0323.“—
`
`E:E_xm2
`
`mg
`
`23:22262
`
`nwnve
`
`mass“.302
`
`
`
`
`W0 2088I082966
`
`PC T! U S2 00 m 88028
`
`72/87
`
`Doo—
`
`ww¢F
`
`/||.|<lllll\
`
`_:.oooFt_nmmcmm
`
`Ell
`
`all
`
`
`mH—32?8&583Ill
`
`1176 of 1754
`
`
`
`wmt.“—0an:
`
`ow.wE
`
`
`
`
`
`confisgcou
`
`Now—
`
`wowfi
`
`wowfi
`
`
`
`
`W0 2008;082966
`
`PCTIUSZDU‘HIISBUZS
`
`73/87
`
`000—
`
`
`
`5:933:00
`
`Tn.oE
`
`1177 of 1754
`
`
`
`wmt.“—0kn:
`
`“.ch
`Ema
`
`
`
`
`
`W0 20l2|8f082966
`
`PC Tl USZUO 770880 28
`
`74/87
`
`ooow
`
`1178 of 1754
`
`
`
`wmt.“—0an:
`
`N?.wE
`
`
`
`”saw
`
`unv— cozmgzmccou
`
`”.5533
`
`Noww
`
`wowr
`
`woww
`
`
`
`W0 2008;082966
`
`PCT} L’SZIKI‘HIISBUZS
`
`75/87
`
`009.
`
`1179 of 1754
`
`
`
`wmt.“—0an:
`
`mw.QE
`
`82.
`
`gun—E22Ho."E3302
`
`:osfizmccou
`
`meow2&3anmw
`
`EdmE
`
`
`
`”mEFwucEfimm
`
`
`
`1180 of 1754
`
`
`
`wmt.“—0cw:
`
`W0 2008f082966
`
`PC Tl C5200 7108 8028
`
`76/87
`
`000_.
`
`
`
`
`
`EmEmsmma:252.39032:9:zmS
`
`as2:mIm:388238
`
`350m8:2sz
`
`
`
`32in:<¢¢.OE
`
`cozmgamccou
`
`
`
`
`1181 of 1754
`
`
`
`wmt.“—0rm:
`
`W0 20087082966
`
`PC T! USZ 00 77088028
`
`77/87
`
` mzuw.wE
`
`_mu:mu
`
`
`
`EwEmSmmoi3:854—
`
`
`
`EwEwSmmm:£QO
`
`333.
`
`33:3.
`
`
`
`1182 of 1754
`
`1182of1754
`
`W0 2008;082966
`
`PCT} L’SZIKI‘HIISBUZS
`
`78/87
`
`chamber?
`
`
`
`
`Configuration
`
`
`
`LinearityMeasurement
`
`Hasthesourcebeenloadedintotheionization
`
`
`
`
`
`
`
`
`
`
`
`W0 2008f082966
`
`PC Tl C5200 7108 8028
`
`79/87
`
`000—
`
`ufimsnmm— BE55=55.me828.
`
`1183 of 1754
`
`
`
`wmt.“—0mm:
`
`
`
`9V?.oE
`
`
`
`
`
`mEF
`
`monmtmm
`
`
`
`EmEmSmmmz3:82:
`
`
`
`corfizaccou
`
`
`
`NmmfiNwm—
`
`
`
`Stu“29:3033:9“.@2382
`
`.me—..U_<u:_u
`
`3.2....12.:
`
`
`
`W0 2008f082966
`
`PC Tl C5200 7108 8028
`
`80/87
`
`0
`
`anF
`
`w;—
`
`or:
`
`1184 of 1754
`
`
`
`wmt.“—0ww:
`
`
`
`XENR2(m?.QE
`
`82we:
`CO:No:
`
`
`
`3—:9592.catw—mi:95
`
`
`
`OPE
`
`8393350
`
`839:8595
`
`a”58w”58
`
`
`
`#0:.
`
`
`
`W0 2008;082966
`
`PCT}r U 5200 770880 28
`
`81/87
`
`wzl
`
`009“_.
`
`
`
`
`83.820:
`
`
`
`5395350
`
`voomm:
`
`Edoonw“mEF.2.3"Baa..
`
`
`
`mam5800“fin....
`
`
`
`3.8888...
`
`53SE333%.
`
`1185 of 1754
`
`
`
`wmt.“—0mm:
`
`No:
`
`mo:
`
`
`
`mmv.GE
`
`
`
`Eumhm'flmuium
`
`
`
`mm:awkw—EE
`
`
`
`
`
`1186 of 1754
`
`
`
`wmt.“—0cw:
`
`W0 20l2|8f082966
`
`PC Tl USZUO 770880 28
`
`82/87
`
`0003
`
`cooF
`
`wwwfi
`
`022mm22
`
`mum?9850m:3
`
`8.50mwuceflmm
`
`couezmccoo
`
`some.
`
`.0E\E39.03
`
`LmnEzz”.3
`
`53E
`
`3353‘
`
`
`
`hnoom9::m_EEC.moceflmm
`
`
`
`Ed.oouw
`
`No:
`
`vovF
`
`wows
`
`
`
`Umv.wE
`
`
`
`
`
`
`
`
`
`1187 of 1754
`
`
`
`wmt.“—0hm:
`
`W0 2008;082966
`
`PCT}r U 5200 770880 28
`
`83/87
`
`000F
`
`
`
`
`
`
`
`cozfizmccou
`
`
`
`1188 of 1754
`
`
`
`wmt.“—0mm:
`
`W0 2008;082966
`
`PCTIUSZDU‘HIISBUZS
`
`84/87
`
`ooow
`
`omm—
`
`:9320Bbmfimmc3&8than2.5%8E3Ema
`
`quEumEF!
`
`
`
`Emn.Engramm
`
`
`
`EoufifinmEéaa080-0868-—
`
`835w3882
`
`
`
`NOVF
`
`wow”
`
`wovr
`
`av.07.
`
`cormhsmccou
`
`
`
`
`1189 of 1754
`
`1189of1754
`
`W0 2008I082966
`
`PC TlUSZ 00 ”9880 28
`
`85/87
`
`
`
`
`
`W0 20083082966
`
`PCTIUSZtIOWUSISUZS
`
`86/87
`
`
`
`
`
`1190 of 1754
`1190 of 1754
`
`
`
`W0 2008(082966
`
`PCTIU52007K|88028
`
`87/87
`
`ovm
`
`w¢.OE
`
`
`
`1191 of 1754
`1191 of 1754
`
`
`
`Europilaches Patentamt
`
`*0
`
`9)
`
`European Patent Office
`
`(I) Publication number:
`
`O 160 303
`
`Office europeen des brevets
`
`A2
`
`69
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 85105293.5
`
`Omar: A 61 M 5(14
`
`Dateo‘lflling: 30.04.85
`
`(‘9 Date of publication of application:
`06.1 1.85 Bulletin 5145
`
`Designated Contracting States:
`BECI-lDEFflGBITLILUNLSE
`
`Lawrencevme-Prlncoton Road
`Princeton, NJ. WIUSI
`
`® Inventor: Bonner, Brian Clarence
`263 Glenn Avenue
`Lawrencevllle New Jersey oescclusi
`
` Priority: 01.05.34 us 005753
` ® Applicant: ER. Squibb 8! Sons; Inc.
`
`
`
`Hepreeeniativa: Vocal“: Vonlua Tauclmer Heunernann
`
`Hauh
`Siahat‘liltrana 4 PD. Box 86 07 57
`
`D6000 Minchen DEIDE}
`
` i
`
`® Stronflurn-rubkflum infusion system.
`® This novel strontium-rubidium infusion system includee
`means for generating a solution containing Fluhidium-Bz,
`measuring the radioactivity in the solution. and infusing it
`into a patient in order to perform various studies on the
`patient‘s heart. The new system includes a wash syringe
`which can be used by a physician to manually iniect a bolus
`containing a large amount of radioactivity directlyr into a
`patient
`in order to perform first pass ventriculogrephy
`studies.
`.0
`
`EP0160303A2
`
`1192 of 1754
`1192 of 1754
`
`ll.
`
`3?
`
`I
`
`:2“
`
`2:
`
`:e
`
`_.
`:-
`czrir'uign
`rllllllt
`
`3°
`
`35
`
`33
`
`as
`
`'
`
`at
`
`3‘
`
`Lo-.
`._°.. aw? .
`llll‘
`I
`3: a}!
`
`“ I!I
`
`_
`
`fa
`
`I 'fi“ LIE-I'l—‘i.
`
`
`901mm“
`w”
`common m“
`
`.- E1”
`to u 3
`' on a
`
`Owen-n Preairig WM Ltd.
`
`
`
`I
`_
`_
`2: 13—605, 758-5
`. Squibb & Sons, Inc.
`
`PATENT anLTe"
`marem.fi:ofin MfiNfiHE-‘IN m.-
`m-nva
`0160303
`
`-1-
`
`STRONTIUM-RUBIDIUM INFUSION SYSTEM
`
`The present invention relates to a
`
`strontiumrrubidium infusion system. More specif-
`
`ically, it relates to a strontium-rubidium infusion
`
`system which has an in—line, real time dosimetry
`system which can be used to infuse patients with
`
`Rubidium-Bz. particularly for first pass ventri-
`
`culography studies. More precisely. the present
`
`invention provides a strontim-rubidium infusion
`
`system comprising:
`(a) means for generating rubidium-B2 in a
`
`solution which can be infused into a patient;
`
`(b)
`
`means
`
`for collecting a predefined
`
`volume of solution containing rubidiumrsz;
`
`for measuring the radioactivity
`(c) means
`in said predefined volume before it is'
`
`‘
`
`present
`
`infused into said patient; and
`
`(d)
`
`means
`
`for
`
`quickly
`
`infusing
`
`said
`
`predefined volume of rubidium—82 into said patient
`
`5
`
`10
`
`15
`
`29
`
`as a single bolus.
`
`The present application is related to
`
`European Patent Application B4301269.1r entitled
`DOSIMETRY SYSTEM FOP. STRONTIUM-RUBIDIUM INFBSION
`
`PUMP, filed February 27, 1984 and published
`
`25
`
`September 5, 1984 under No. EP 0117752 A2.
`
`1193 of 1754
`1193 of 1754
`
`
`
`01 60303
`
`Current statistics show that approximately
`
`one-third of all deaths in the United States are
`relategi
`to coronary artery disease.
`See ,
`for
`
`example. ?ohost, 6., McKusick, 1L, and Strauss, w.,
`
`'Physiologic Basis
`
`and Utility of Myocardial
`
`Perfusion
`
`Imaging“, Proceedings of
`
`the
`
`Second
`
`International
`
`Symposium on Radiopharmaceuticals,
`
`Society of Nuclear: Medicine, New York 1979, pp.
`
`465-473. This fact has prompted extensive research
`
`to rare efficiently diagnose
`
`and manage
`
`this
`
`in radiophamaceutical
`Recent advances
`disease-
`developma-ent and instrument design have established
`
`nyocardi a1
`
`scintigraphy
`
`as
`
`an
`
`important
`
`new
`
`approach for evaluating coronary artery disease and
`
`myocardial perfusion.
`
`See,
`
`for example, Pierson,
`
`3., Friedman,
`
`IL, Tansley,
`
`1L, Castellana, F.,
`
`Enlander,
`
`1).,
`
`and Huang, P”
`
`“Cardiovascular
`
`Nuclear medicine:
`
`An Overview", Sen. Nucl. Med...
`
`. 10
`
`15
`
`1194 of 1754
`1194 of 1754
`
`
`
`0160303
`
`n.3—
`
`9, 224-240 (1979); Leppo, 3., Scheuer, J., Pohost,
`
`G., Freeman, L.,
`
`and Strauss, H.,
`
`"The Evaluation
`
`of
`
`Ischemic Heart Disease
`
`Thallium-ZDJ. with
`
`Cements on Radionuclide Angiography"; Sem. Nucl.
`
`5 Med., 10, 115-126 (1980): Vogel, R., "Quantitative
`
`Aspects of Myocardial Perfusion Imaging",
`
`Sem.
`
`NBC]. . Med. ,
`
`10,
`
`146-155
`
`(1980) r, Chervu,
`
`R. ,
`
`"Radiopharmaceuticals
`
`in Cardiovascular Nuclear
`
`Medicine", Sena. Nucl. Med., 9, 241-256 (1979); and
`10 Pitt, 13., and Strauss, H... "Cardiovascular Nuclear
`
`Medicine", Sem. Nucl. Med., 7,
`
`3—6 (1977).
`
`Myocardial
`
`scintigraphy studies have been
`
`performed with several
`
`isotopes of potassium,
`
`rubidium, cesium,
`
`and thallium (Tl-201), although
`
`15
`
`the usefulness of all of these nuclides is limited
`
`by their non—optimal physical properties.
`
`In spite
`
`of its long half-life and low-gamma energy, Tl-Zol
`
`is
`
`currently the most widely used agent
`
`for
`
`myocardial
`
`imaging.
`
`See,
`
`for example, Poe, N.,
`
`20
`
`"Rationale and Radiopharmaceuticals for Myocardial
`
`Imaging“, Sem. Nucl. Med., 7, 7—14 {1977); Strauss,
`
`H.
`
`and Pitt, 5.,
`
`"Thallium-zol as a Myocardial
`
`_
`
`Imaging Agent", Sem. Nucl. Med.,
`
`'1', 49—53 (1977);
`
`Botvinick, EL, Dunn, R., Hattner, R... and Massie,
`
`25
`
`B.,
`
`"A Consideration of Factors 'Affecting the
`
`Diagnostic Accuracy of TIL-20]. Myocardial Perfusion
`
`Scintigraphy in Detecting Coronary Artery Disease",
`Sem. N'uci. Med., 10, 157-167 (1980); and Wackers,
`F.,
`"Thallium—201 Myocardial Scintigraphy in Acute
`
`3O Myocardial
`
`Infarction and Ischemia",
`
`Sem. Nucl.
`
`Med., 10, 127—145 (1930}.
`
`In diagnostic procedures in which the heart
`
`is involved, it is desirable for a diagnostician to
`
`be able to View a patient's heart. Heretofore,
`various
`radioactive materials
`have
`been
`used
`
`35
`
`1195 of 1754
`1195 of 1754
`
`
`
`0160303
`
`-4...
`
`together with radiological procedure:
`
`for viewing
`
`internal
`
`organs
`
`of patients.
`
`It
`
`has
`
`been
`
`difficult, however,
`
`to view a heart, because the
`
`radioactive substances which could be used for
`
`5
`
`viewing the heart have had a very long half-life.
`
`Thus, using them with patients has
`
`involved an
`
`element of danger and each use reduces the number
`
`of times that a patient could be infused within
`
`It would,
`any given time period.
`desirable to have
`a diagnostic
`
`therefore,“ be
`apparatus
`and
`
`10
`
`procedure which could be used with relative safety
`
`for viewing .the heart.
`
`Rubiditm—Bz
`
`is a potassium analog.
`
`That
`
`means it acts in a manner similar to potassium when
`
`15
`
`it is infused into a patient. Thus it builds up at
`
`a very rapid rate,
`
`i.e-, within seconds,
`
`in the
`
`patient' 3
`
`heart.
`
`Ruhidiumvaz
`
`also
`
`has
`
`the
`
`advantage
`
`of
`
`having
`
`a very
`
`short halfulife,
`
`approximately 75
`
`seconds.
`
`Therefore,
`
`it decays
`
`20
`
`after a very short period of time following entry
`
`into the body,
`
`thereby allowing numerous procedures
`
`to be performed within a relatively short
`
`time
`
`period in a given patient.
`
`Rubidium—Bz also has
`
`the efivmtage of being observable using a modified
`
`-—“
`
`25
`
`such as a gamma camera of the type
`game “camera,
`manufactured by Searle Radiographics, Inc., called
`
`the BBQ Gama IV. A problem with using Rubidium—Bz
`
`in a patient
`
`involves measuring the amount of
`
`radiation _in£used into the patient.
`
`In viewr of the
`
`30
`
`very
`
`short half—life of Rubidium—az,
`
`it has
`
`heretofore
`
`been
`
`impractical
`
`to measure
`
`the
`
`radioactivity of
`
`a particular dose and to then
`
`infuse
`
`it into the patient using conventional
`
`means. An accurate method. for measuring the amount
`
`35
`
`of radiation being infused into the patient would
`
`1196 of 1754
`1196 of 1754
`
`
`
`-5-
`
`0160303
`
`be
`
`highly
`
`desirable
`
`for
`
`this
`
`particular
`
`application.
`
`The
`
`availability
`
`of
`
`improved
`
`instrumentation has stimulated interest in the use
`
`5
`
`of
`
`the
`
`positron
`
`emitter,
`
`Rubidium-Sz,
`
`for
`
`for example, Belle: 6.,
`See,
`imaging.
`myocardial
`and Smith. T.,
`"Radionuclide Techniques
`in the
`
`Assessment of myocardial Ischemia and Infarction",
`
`circulation,
`
`53
`
`(a,
`
`Supp.
`
`1)
`
`123—125
`
`(1975);
`
`10
`
`Budinger, T., Yano, Y., Derenzo, 5.. et al.,
`
`"Myocardial Uptake of Rubidium-BZ Using Positron
`Emission Tomography",
`J.,
`fiucl. Med.
`20,
`603
`
`(1979); Budinger, T., Yano, 2:, Derenzo, 5., et
`
`al.,
`
`"Infarction Sizing and myocardial Perfusion
`
`15 Measurements Using Rb-BZ
`
`and Positron Emission
`
`Tomography", Amer. J. Cardiol.Jr
`
`4-5,
`
`399
`
`(1980).
`
`Rubidium—az,
`
`an
`
`analog
`
`of
`
`the
`
`alkali metal
`
`potassium,
`
`is rapidly cleared from the blood and
`
`concentrated
`
`by
`
`the myocardium.
`
`The
`
`short
`
`20
`
`half-life of the Rubidium~82 (76 sec) offers the
`
`unique advantage of permitting repeat perfusion and
`
`blood flow studies
`
`in patients whose clinical
`
`status is rapidly changing.
`Rubidium-BZ is produced by the decay of its
`
`25
`
`parent,
`
`strontium—82.
`
`E. R. Squibb and Sons, Inc.
`
`has developed a Rubidium-BZ generator and infusion
`
`system which yields an isotonic saline solution of
`
`Rubidium-BZ
`
`at
`
`physiological
`
`pH
`
`for
`
`rapid
`
`administration.
`
`In animal experiments,
`
`the safety
`
`30
`
`and myocardial uptake of Rubidium—az has been
`
`demonstrated.
`
`Therefore,
`
`this
`
`agent has
`
`been
`
`selected as a candidate for clinical trials.
`
`In the EuroPean patent application identified
`
`above, a system for infusing Rubidiumraz into a
`patient while measuring the dose going into the patient
`
`35
`
`1197 of 1754
`1197 of 1754
`
`
`
`_o1eoaoa
`
`—6-
`
`C
`
`was described. That system is useful in myocardial
`
`scintig-raphy studies.
`
`In a modification to that
`
`system, described herein, a system which permits
`both myocardial scintigraphy studies, as well as
`
`5
`
`first pass ventriculography studies,
`
`is described.
`
`In accordance with the present invention, a
`
`strontium—rubidium infusion system is described.
`
`The
`
`system includes
`
`means
`
`for
`
`generating
`
`10
`
`rubiditm-Bz in a solution which can be infused into
`
`a patient-
`
`In particular,
`
`the strontimn—rubidium
`
`generator,
`
`described above,
`
`is typically used.
`
`Generated rubidium—82 is then collected in a piece
`of tubing seeing a predefined volume._ This tubing
`
`15
`
`is called the “dose volume" tubing, and it contains
`
`the dose volume of rubidium—32 solution which is to
`
`be inqued.
`
`'
`
`The system also includes means for measuring
`
`the radioactivity present in the dose volume before
`
`20
`
`the dose volume is infused into the patient and a
`
`wash syringe for quickly infusing the dose volume
`
`into the patient as a single bolus.
`
`' "
`
`In the Drawings:-
`
`25
`
`FIG.
`1
`is an overall schematic diagram of
`strontium—midium infusion system of
`the
`
`the
`
`present invention;
`
`FIG. 2 is a front View of the infusion pump
`
`control' used with the strontium—rubidium infusion
`
`30
`
`system:
`
`is a front View of the dosimetry
`3
`FIG.
`control used with the strontium-rubidium infusion
`
`system;
`
`FIG. 4 is a graph of radioactivity measured
`(on the y-aris) by the dosineter probe versus time
`
`35
`
`1198 of 1754
`1198 of 1754
`
`
`
`9160303
`
`(on the x—axis):
`
`5
`FIG.
`dosimetry probe;
`
`is
`
`a perspective View of
`
`the
`
`I
`
`FIG.
`
`6
`
`is
`
`a
`
`schematic
`
`diagram of
`
`the
`
`5
`
`interface between the dosimetry probe of FIG. 4 and
`
`the dosimetry control circuitry;
`
`FIG. 7 is a schematic diagram of the circuit
`
`for the Single Channel Analyzer used to convert and
`
`shape the raw pulses from the dosimetry probe of
`
`10
`
`FIG. 4;
`
`FIG. 8 is a schematic diagram of the circuit
`
`for the Multiply—Divide circuit used to carry out
`
`the formula which converts pulses from the Single
`
`Channel Analyzer
`
`into radioactivity present
`
`in
`
`15
`
`front of the dosimetry probe;
`
`FIG. 9 is a schematic diagram of one of the
`Display Controller circuits used to interface the
`
`switches and the displays to the other circuitry;
`
`FIG.
`
`10 is a schematic diagram of the Dose
`
`20
`
`Rate
`
`circuit used to provide a display of the
`
`amount of radiation present in the eluate;
`
`FIG.
`
`11
`
`is
`
`a
`
`schematic diagram of
`
`the
`
`Control Circuit which oversees the Operation of the
`
`remainder of. the circuitry; and
`
`25
`
`iFIG.
`
`12
`
`is a schematic diagram of a valve
`
`driver circuit.
`
`Referring now to FIG. 1, a saline bag 10 is
`connected,
`through a bullet nose fitting 12 and a
`
`30
`
`piece of tubing 14,
`
`to a T-shaped twoé-way check
`
`valve 16 having three arms.
`
`A first arm 20 is
`
`attached to a one—way valve 21 which permits saline
`
`to enter the check valve 16, but does not allow it
`
`—-
`
`to exit back into the tubing 14.
`
`A second arm 22
`
`35
`
`includes a check valve 23 which permits saline to
`
`1199 of 1754
`1199 of 1754
`
`
`
`-3-
`
`0169393
`
`exit
`
`from the check valve 16 into a filter 24
`
`through a
`
`tube 26, but does not
`
`allow it
`
`re-enter the check valve 16 from the tube 26.
`
`to
`
`An
`
`automatic syringe 18. connected to the check valve
`
`16 fills from the saline bag 10 and pumps out
`
`through the tubing 26 into the filter 24-.
`Saline
`pumped
`through
`the
`filter
`24 I enters
`a‘
`
`strontium-rubidium generator 28 which is of
`
`the
`
`type
`described more
`fully in- U.
`S. Patent
`4,405,716,
`issued September 27. 1983, entitled
`
`10
`
`32m; sesame ass-moo mm arm. The generator
`
`23 is preferably enclosed in a lead shield 29.
`
`Saline pumped through the strontim—rubidium
`
`15
`
`generator 28 exits the generator 28 through tubing
`
`30
`
`containing Rubidium-BZ.
`
`The
`
`tubing 30
`
`is
`
`connected to a diverter valve 33 having a first arm
`
`35 which connects
`
`to a manually operated wash
`
`syringe 37.. The remaining arm 39 is connected to a
`
`20:
`
`diveer valve 32 through a length of tubing 41
`
`which is called the ”dose volume“ tubing 41, which
`
`has a length,
`
`130'.
`
`The length. DV, of the dose
`
`volume
`
`tubing,
`
`times
`
`its cross-sectional
`
`area.
`
`gives its volume, hereinafter referred to as the
`
`25
`
`'dose volume”.
`
`Diverter‘ valve 32 has a first arm 34 which
`
`leads through tubing 38,
`
`an antibacterial filter
`
`through a tube 42, and ultimately to a waste
`40,
`collection container 43.
`The waste collection
`
`30
`
`container
`
`43
`
`is preferably enclosed in a lead
`
`shield 45.
`
`A second am 35 of the diver'ter valve
`
`32 is connected through tubing 44, an antibacterial
`
`filtez: 48,
`
`additional
`
`tubing 50,
`
`and into an
`
`infusion needle 52.
`
`The
`
`infusion needle 52
`
`is
`
`35
`
`typically-inserted into the arm 54 of a patient 56-
`
`1200 of 1754
`1200 of 1754
`
`
`
`-9-
`
`0160303
`
`In
`
`the
`
`preferred
`
`embodiment
`
`of
`
`the
`
`invention,
`
`the check valve 16 is a dual back check
`
`valve of the type made by Beckton Dickenson Inc.,
`
`and the antibacterial filters 24, 40, 48 are of the
`
`type made by Schleicher
`
`8: Schull as
`
`their type
`
`F?030/3.
`‘
`In the operation of the device to perform
`
`first pass ventriculography studies.
`
`the amount of
`
`radioactivity in the
`
`saline
`
`eluted from the
`
`strontium-rubidium generator 28 must be measured.
`
`Accordingly,
`
`a
`
`dosimetry probe
`
`58
`
`is
`
`placed
`
`adjacent
`
`to the tubing 30 where it measures
`
`the
`
`radioactivity of the rubidium-containing saline as
`it enters the the diverter valve 33. The diverter
`
`valve 33 is a three-part valve which permits flow
`
`from either the generator to the diverter valve 32
`
`or from the wash syringe 37 to the diverter valve
`32.
`
`The diver-tar valves 32, 33 are connected to
`
`a dosimetry controller 62 for automatic operation.
`
`The operation of the dosimetry controller 62 will
`
`be further explained hereinafter. Based upon the
`
`signal sent by the dosimetry controller 62 to the
`valves 32, 33,
`the elution from the generator 28 is
`
`directed through the valves 32,
`
`33 and the dose
`
`volume tubing 41 into the waste container 43 until
`
`such time as the minimum dose rate is met. Once
`
`the minimum dose rate for a first pass study has
`
`been reached,
`
`the dosimetry controller 62 starts
`
`integrating patient volume and dose to fill the
`
`dose volume
`
`tubing 41 with highly radioactive
`
`eluate. At that point,
`
`the valve 33 is switched to
`
`open the valve between the dose volume tubing 41
`
`and the wash syringe 37 and close the valve leading
`
`through tubing 30 to the generator 23. Similarly,
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`1201 of 1754
`1201 of 1754
`
`
`
`0160303
`
`_10_
`
`the diverts: valve 32 is switched from the waste
`
`position to the patient position, and the physician
`
`performing the study quickly injects saline from
`
`the wash syringe 37 directly into the patient 56.
`
`5
`
`That operation performs
`
`a number of different
`
`functions.
`
`In particular,
`
`it pushes
`
`the dose
`
`volume of radioactive eluate from the dose volmne
`
`tubing_4l
`radioactive
`
`into the patient as
`bolus.
`Thereafter.
`
`a single highly
`the
`remaining
`
`10
`
`saline in the wash syringe 37 clears the lines 41,
`
`44, 50, purging them of radioactivity.
`
`An advantage of the wash solution clearing
`
`the patient line of radioactivity is that the line
`
`does not "glow” in photos taken of the patient.
`
`15
`
`Such a glowing interferes with data
`
`from the
`
`p
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
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.
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.
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
