(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2016/0317656A1
`URANO et al.
`(43) Pub. Date:
`Nov. 3, 2016
`
`US 20160317656A1
`
`(54) COMBINATION OF ANTI-FGFR2 ANTIBODY
`AND OTHER AGENT
`
`(71) Applicant: DAIICHI SANKYO COMPANY.,
`LIMITED, Chuo-ku, Tokyo (JP)
`
`(30)
`
`Foreign Application Priority Data
`
`Oct. 8, 2013 (JP) ................................. 2013-211355
`O
`O
`Publication Classification
`
`(72) Inventors: y"RN),gly (JP): Yasuki
`s
`O O
`O
`(73) Assignee: Daiichi Sankyo Company, Limited,
`Chuo-ku, Tokyo (JP)
`
`(21) Appl. No.:
`(22) PCT Filed:
`
`15/027,489
`Oct. 7, 2014
`
`(86). PCT No.:
`S 371 (c)(1),
`(2) Date:
`
`PCT/UP2014/077276
`
`Apr. 6, 2016
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A 6LX 39/395
`A63/496
`A6II 3/47
`A6II 45/06
`(52) U.S. Cl.
`CPC ........... A61K 39/3955 (2013.01); A61K 45/06
`(2013.01); A61 K3I/496 (2013.01); A61 K
`31/47 (2013.01)
`
`ABSTRACT
`(57)
`The present invention provides a combination of an antibody
`binding to a fibroblast growth factor receptor, and another
`agent.
`
`1 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 1 of 86
`
`US 2016/031765.6 A1
`
`FIG. 1
`
`
`
`2
`
`;
`
`:
`
`O D.
`
`r
`wn
`c
`Y
`L
`t
`4.
`
`--
`
`
`
`
`
`o
`
`O
`O
`N
`
`--------
`O
`O
`O
`O
`O
`vil
`von
`l
`
`(AISueu huaose only ueeu e Allee)
`AAgoe fullpuig
`
`2 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 2 of 86
`
`US 2016/0317656A1
`
`FIG 2
`
`
`
`(AISueulueoseonly ueeu e Agee)
`AA3e fjupu
`
`3 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 3 of 86
`
`US 2016/0317656A1
`
`FIG. 3A
`
`
`
`(Iuu/6ni) uo??euque ouoo Apoq??uvy
`
`
`
`
`
`
`
`(IOI) uoo JO %)
`AApe e Seegon empele
`
`4 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 4 of 86
`
`US 2016/0317656A1
`
`FIG. 3B
`
`
`
`| 01 | | | y0 | 0
`
`Kidula | 0 || 0 | |
`
`0
`
`| 0 | |
`
`| | | “O | 0 | 0
`
`| 01 .
`
`OZI
`
`00||
`(IOI) uoo Jo 96)
`AAgoe eSelejon enee
`
`5 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 5 of 86
`
`US 2016/031765.6 A1
`
`FIG. 4
`
`ZH-H?H-d
`
`6 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 6 of 86
`
`US 2016/0317656A1
`
`F.G. 5
`
`
`
`fi
`
`oo
`O
`
`to
`O
`
`S.
`
`uu O67 epuedOSCe
`
`7 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 7 of 86
`
`US 2016/0317656A1
`
`FIG 6A
`
`
`
`(Iuu/6ni) uo?euque ouoo Apoq?uy
`
`
`
`
`
`----L. LU----—ET E---====-----0|
`
`
`--~~~~--~--~--~~~-----------------------------------— Oz
`
`(IOI)uo) JO %)
`AA3e eSeueylon enee
`
`
`
`-----------------------……..0?y
`
`—| 09
`
`8 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 8 of 86
`
`US 2016/031765.6 A1
`
`FIG. 6B
`
`
`
`
`
`(luu/firi) uo??euque ouoo Apoq?uy
`
`
`
`
`
`(Oluoo Jo 96)
`AA3e eSeleon empele
`
`9 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 9 of 86
`
`US 2016/0317656A1
`
`FIG. 7
`
`
`
`;
`
`:
`
`:
`
`:
`
`:
`:
`
`:
`
`:
`:
`
`:
`
`Cs
`O
`sm
`
`O
`va
`
`N
`
`wn SS S.
`
`| U
`
`: - 'b-
`
`ra
`
`3 S e o
`
`:
`i
`
`:
`:
`
`i
`:
`
`:
`
`:
`
`i-hi
`was
`
`:
`:
`
`:
`
`Cd
`o
`rem
`
`d
`vus
`
`: ---
`
`:
`
`:
`
`:
`-
`
`s 3 s s s s
`
`C.
`v
`
`Cd
`
`:
`:
`
`S
`
`:
`
`o
`O
`von
`
`------
`
`O
`
`v
`
`o
`
`e
`
`s
`
`rt-e
`
`s s
`
`
`
`i
`
`O O.
`ven
`
`s
`
`
`
`
`
`..
`
`d o Cs o
`c
`N
`was
`
`s go o go
`to
`r
`(eSeele olyoeds 9%)
`AA3e OOOW
`
`10 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 10 of 86
`
`US 2016/0317656A1
`
`FIG. 8
`
`
`
`O
`O
`w
`
`o
`o
`o
`
`o
`o
`n
`
`(Euu) aunow IQuun
`
`o
`O
`o
`co
`r
`(Euu) eunow JOLun paeuS
`
`o
`o
`l
`
`n
`o
`'s
`(Euu) aun|ON JOLLIn paeuS
`
`11 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 11 of 86 US 2016/0317656 A1
`
`Figure 9
`
`EVOLVESGGGLY
`(SEQID NO; 1 of Sequence Listing)
`
`Figure 10
`
`DQMTQSPSSLSA
`(SEQID NO. 2 of Sequence Listing)
`
`Figure 11
`
`QWKLL
`(SEQID NO; 3 of Sequence Listing)
`
`Figure 12
`
`DIQMTQSPASLSASLGE
`(SEQID NO. 4 of Sequence Listing)
`
`Figure 13
`
`QWKLL
`(SEQID NO. 5 of Sequence Listing)
`
`Figure 14
`
`DIQMTQSPASLSASLGE
`(SEQID NO; 6 of Sequence Listing)
`
`Figure 15
`
`GAGTTACTTTTGAGAGCAGTTCCAGGAG
`(SEQID NO; 7 of Sequence Listing)
`
`Figure 16
`
`GGTTCTCCCACTCAGTAATC
`(SEQID NO; 8 of Sequence Listing)
`
`Figure 17
`
`CATATGATCAGTGTCCTCTC
`(SEQID NO; 9 of Sequence Listing)
`
`12 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 12 of 86 US 2016/0317656A1
`
`Figure 18
`
`ATATGATCAGTGTCCTCTCC
`(SEQID NO; 10 of Sequence Listing)
`
`Figure 19
`gaggtgcagctggtggag totgggggaggcCtggtgcago Ctgga agg Ci Cigaaacta CC tigtig tagCC Ciggatt
`cagattcaatgact tttggatgacCtggat.ccgcCaggCiccagggaaggggctggag tiggg tigcatcCat tact tata
`ciggtgataacact tact atgcaggctCtgtga agg gCCga at Cactatic tccagagataatg.cgaagagcaccCtataC
`cgcaaatgaacagtic tigaggiCtgaggacacggcc act at tact giaca agagatgaCtacggagga tatagcCCC ta
`ctatatggatgcc tagggtoaaggaacticagt cactgtc. tcctica
`Variable region (1-366)
`(SEQID NO; 11 of Sequence Listing)
`
`Figure 20
`
`EWQLVESGGGLVQPGRSLKLSCWASGFRFNDFWMTWIRQAPGKGLEWYASITYTGDNTYYAGSYKGRITISRDNAKSTLY
`LQMNSLRSEDTATYYCTRDDYGGYSPYYMDAWGQGTSYTVSS
`Variable region (1-122)
`(SEQID NO. 12 of Sequence Listing)
`
`Figure 21
`Caggi taagctgctgcagtctggggct gagctgg taaaacCtggtgct tcagtgaagttgtcClgcaagact tctgg tit
`tacct tcagcactagot a tatgagttggitgaag Caggtgcct geaCCgag tatt gagiggattggatggatt tatgctg
`gagatggigg tactaagtataatcagaagttcaagggcaaggcCacactgacagtagacaaatct tctagoa cagcatac
`atggatcCagcagcCtga catctgaggacgct gCagtC tatt tttgttgcaa.cggatggittatggggattgg tittgct ta
`CtggggcCaaggCactCtgg toactgtCtct tca
`Variable region (I-354)
`(SEQID NO; 13 of Sequence Listing)
`Figure 22
`
`QWKLLQSGAELWKPGASWKLSCKTSGFTFSTSYMSWLKQVPGPSIEWIGWIYAGDGGTKYNQKFKGKATLTWDKSSSTAY
`MDLSSLTSEDAAWYFCATDGYGDWFAYWGQGTLYTYSS
`Variable region (1-118)
`(SEQID NO: 14 of Sequence Listing)
`
`Figure 23
`caggittaagctgctgcag totggggctgagctggtaaaacctggtgct tcagtgaagttgtcCtgcaagact tctggitt
`tacatl cageac tagtta tatgagttggttgaagCaggigCC tigga CCEagtact gag tiggattggatggatt tatgctg
`gagatggtgg tact aagtata at CagaagttcaagggcaaggCCaC actgacagagacaa at t t t c tag.ca cagoa taC
`a Eggat Ctcagcago CtgaCatctgaggacgct gCagic tatt Ctgtgcaa.cggatggi tatggggattgg it tact ta
`CtggggcCaaggCactCtgg Cactgtc. Ctt Ca
`Variable region (1-354)
`SEQID NO: 15 of Sequence Listing
`
`13 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 13 of 86 US 2016/0317656A1
`
`Figure 24
`
`QWKLQSGAELVKPGASYKLSCKTSGFTFSTSYMSWLKQVPGPSTEWIGWIYAGDGGTKYNQKFKGKATLTVDKFSSTAY
`MDLSSLTSEAAYYFCAT)GYGDWFTYWGQGTLYTYSS
`Variable region (l-l l8)
`(SEQID NO; 16 of Sequence Listing)
`
`Figure 25
`
`TTCATGAGGCACACGACTGAGGCACCTCC
`(SEQID NO:17 of Sequence Listing)
`Figure 26
`
`TCCAGTTGCTAACTGTTCCG
`(SEQID NO; 18 of Sequence Listing)
`
`Figure 27
`
`CAGTGGTATCAACGCAGAG
`(SEQID NO.19 of Sequence Listing)
`
`Figure 28
`gacatccagatgaccCagtCtcCatct tcCCtgtctgcatt Ctgggaga CagagiCaCt at tacttgCCgggCaagttca
`agacattggaaattatttaagatggttcCagcagaaacCggggaaatc. tcc taggct tatgatt tatggtgcaaccaact
`tggcaaatgggg.cccatcaaggttcagtggCagtagg to iggg teagattattic tict gaccatcaacaact tagag tict
`gaagacatggctatt tatt actgtctgaagcataatgagtat CCattcacgttcago CagggaCaaagttggaaataaa
`aCgggCt
`Variable region (1-327)
`(SEQID NO:20 of Sequence Listing)
`
`Figure 29
`
`DIQMTQSPSSLSAFLGDRVTITCRASQDIGNYLRWFQQKPGKSPRLMIYGATNLANGWPSRFSGSRSGSDYSLTINNLES
`EDMAIYYCLKHNEYPFTFGSGTKLEKRA
`Variable region (1-09)
`(SEQID NO: 21 of Sequence Listing)
`
`Figure 30
`
`TACGTCCTGTCTTTGCTGTCCTGATCAG
`(SEQID NO; 22 of Sequence Listing)
`
`14 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 14 of 86 US 2016/0317656A1
`
`Figure 31
`gaCatcCagatgaca Cagt CitcCagcticCCtgtctgcatc. tctgggaga a actgtcaccatcgaatgtcgagcaag tiga
`ggacatttacagtaatttagCgtggitaticagoagaaacCagggaactic ticcitcagcticct gatctatigatgcaaat atct
`tggCagatgggg.tcCCatCaCggttcagiggCagiggg to iggcacacag tatt Ctctaaaga taaa.cagoctgcaatct
`gaagatgtc.gcaagttatt Ctgtcaa.cagtataacaatta (CCiCCgttcacgt. Etggagttgggaccaagctggaact
`gaaacgggCf
`Variable region (1-330)
`(SEQID NO. 23 of Sequence Listing)
`
`Figure 32
`DIQMTQSPASLSASLGETVTIECRASEDIYSNLAYYQQKPGNSPQLLIYDANILADGVPSRFSGSGSGTQYSLKINSLQS
`EDWASYFCQQYNNYPPFTFGWGTKLELKRA
`Variable region (I-110)
`(SEQID NO. 24 of Sequence Listing)
`
`Figure 33
`gacatcCagatgacacaglict coagct tcCCtgtctgcatc. tctgggagaaactgtcacCatcgaatgtcgagcaagtga
`ggacatatacagtaatt tag.cgigg tatCagcagaaacCagggaactic ticCtcagotcCtgat Citat gatgcaaata toc
`tggcagatgggg toccatcacggttcagtggCagtggEtctggCacacagliatt Cic laaagataaa.cagcc tgcaatct
`gaagatgtc.gcaagttatt to tgtcaa Cagtataacaatt at CCCC9tt CacgtttggagCtgggaCCaagciggaact
`gaaacgggct
`Variable region (1-330)
`(SEQID NO. 25 of Sequence Listing)
`
`Figure 34
`
`DIQMTQSPASLSASLGETVTIECRASEDIYSNLAYYQQKPGNSPQLLIYDANILADGWPSRFSGSGSGTQYSLKINSLQS
`EDWASYFCQQYNNYPPFTFGAGTKLELKRA
`Variable region (1-10)
`(SEQID NO. 26 of Sequence Listing)
`
`Figure 35
`gcc ticcggactic tagagccaccATGGTGCTGCAGACCCAGGTGTTCATCTCCCTGCTGCTGTGGATCTCCGGCGCGTACG
`GCGATATCGTGATGATTAAACGTACGGTGGCCGCCCCCTCCGTGTTCATCTTCCCCCCCTCCGACGAGCAGCTGAAGTCC
`GGCACCGCCTCCGTGGTGTGCCTGCTGAATAACTTCTACCCCAGAGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCT
`GCAGTCCGGGAACTCCCAGGAGAGCGTGACCGAGCAGGACAGCAAGGACAGCACCTACAGCCTGAGCAGCACCCTGACCC
`TGAGCAAAGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGAGCTCCCCCGTCACCAAG
`AGCTTCAACAGGGGGGAGTGTTAGgggcc.cgtttaaacgggggaggcta
`(SEQID NO; 27 of Sequence Listing)
`Figure 36
`
`TATACCGTCGACCTCTAGCTAGAGCTTGGC
`(SEQID NO:28 of Sequence Listing)
`
`15 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`16 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 15 of 86
`
`US 2016/0317656 A1
`
`Figure 37
`
`GCTATGGCAGGGCCTGCCGCCCCGACGTTG
`(SEQ ID NO: 29 of SequenceListing)
`
`Figure 38
`
`gcctecggactctagagccaccATGAAACACCTGTGGTICTTCCTCCTGCIGGTGGCAGCTCCCAGATGGGTGCTGAGCC
`AGGTGCAATTGTGCAGGCGGTTAGCTCAGCCTCCACCAAGGGCCCAAGCGTCTTCOCCCTGGCACCCTCCTCCAAGAGCA
`CCTCTGGCGGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCOCCGAACCCGTGACCGTGAGCTGGAACTCAGGC
`GCCCTGACCAGCGGCGTGCACACCTTCCCCGCTGTCCTGCAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGT
`GCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCC CAGCAACACCAAGGTGGACAAGAGAG
`TIGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCCTGCCCAGCACCTGAACTCCTGGGGGCACCCTCAGTCTTC
`CTCTTCCCOCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGIGGACGTGAGCCA
`CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCCCGGGAGGAGC
`AGTACAACAGCACGTACCGGGTGETCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGL
`AAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGCCAGCCCCGGGAACCACAGGT
`GTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTICTATCCCA
`GCGACATCGCCGTGGAGTGGGAGAGCAATGGCCAGCCCGAGAACAACTACAAGACCACCCCTCCCGTGCTGGACTCCGAC
`GGCTCOTICTICCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTEGCAGCAGGGCAACGTCTICTCATECTCCGTGAT
`GCATGAGGCTCTGCACAACCACTACACCCAGAAGAGCCTCTCCCTGTCTCCCGGCAAATGAga tatcegecccett taaa
`cegesgagecta
`(SEQ ID NO: 30 of SequenceListing)
`
`Figure 39
`
`atgetectgcagacccagetgticatctcectgctyctgtegatctccegcecelacggcgacatccagatgacccagte
`tccatcttecctetctecattictesgagacagagtcactat tact tecceggcaagtcaagacallegaaattatitaa
`gatget lccagcagaaaccegggaaatcicctagecttateatttategtecaaccaacl tggcaaatggegtcccatca
`age ttcagtegcagtagetctgegtcagattatictctgaccatcaacaacttegagtctgaagacategctatttatta
`ctgtctgaagcataalgagtatccat tcacet tcegc tcagggaceaagt Lggaaataaaacgggctetgeccececcct
`cogtgttcatct tececccctccgacgagcage tgaagtccegcaccecctccetegtetgcctsctgaataacttctac
`eccagagageccaagetecagt ggaageteeacaaceccctecagtcceggaacicccaggagagcetgaccgagcagea
`cagcaaggacagcacc (acagcctgagcagcaccetgaccctgagcaaagcceactaceagaagcacaaggigtacecct
`gceagetgacccaccagegce tgagc teceecetcaccaagagct tcaacagggesgastal
`Signal sequence
`(1-60), Variable region (6 |-387), Constant region (389-702)
`(SEQ ID NO: 31 of SequenceListing)
`
`Figure 40
`
`MVLOTOQVE I SLLLWISGAYGDT QMTOSPSSLSAFLGDRVTI TCRASQD I GNYLRWEQQKPGKSPRLM YGATNLANGYPS
`RESGSRSGSDYSLTINNLESEDMATYYCLKANEYPETPGSGTKLEEKRAVAAPSVF I FPPSDEQLESGTASVVCLLUNNEY
`PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVIKSFNRGEC
`Signal sequence
`(1-20), Variable region (21-129), Constant region{ 130-234)
`(SEQ ID NO: 32 of SequenceListing)
`
`16 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`17 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 16 of 86
`
`US 2016/0317656 A1
`
`Figure 41
`
`ATCTCCGGCECGTACGGCGACATCCAGATGACCCAGTCTCCATCTTICC
`(SEQ ID NO: 33 of SequenceListing)
`
`Figure 42
`
`GGAGGGGGCEGCCACAGCECGTTTTATTITCCAACTICGTCCCTG
`(SEQ ID NO: 34 of SequenceListing)
`
`Figure 43
`
`atgaaacaccteteeticttcctccigctggtgecagctcccagategetectgagceagetecagctegtgsagictes
`gegaseccteelecagcctegaaggtctctgaaactatcctetgtagcctctegat tcagattcaateacttttgeatga
`cclggatcegccagectccagggaagesectggagtegetlecatccattactlatactggtgataacacttactateca
`eectctetgaageecceaatcactatctccagagataatecgaagaecaccc tatacclgcaaatgaacagtctgaggtec
`tgaggacacgeccacttattacletacaagagatgaclacggaggatatagcccclaclatalggatecctegggtcaag
`gaacttcagtcactgtcagctcagcctccaccaagggcccaagcgtel teccectgecaccctcctccaagagcacctct
`gecegcacagccecccteegctecctggtcaaggactact tceccgaacccetgaccelgagctgeaactcagececccl
`saccagcegcetgcacacct tececectatcctecagtcctcaggactctactccctcagcagcetgetgaccetsccct
`ecagcagc lteggcacccagacctacatctgcaacet gaatcacaagcccagcaacaccaagg tegacaagagagt tgag
`eccaaatcttetgacaaaactcacacatgecccaccclgcccageacctyaactcclegeggeaccctcagtcttectett
`coececaaaacccagggacaccctcatgatcicccggaccccteagetcacatgcetgeteyelgeaceteagcecacgaag
`accctgagetcaagttcaactegtacgtggacescet ggagetgcataateccaagacaaagccccegeaggagcagtac
`aacagcacetaccegetgetcagcgtcctcaccetccigcaccaggactgectgaatgecaaggagtacaagtgecaaget
`ctccaacanageccteccagecceca tcgagaaaacca tc tccaaagccaaapeccagcccceggaaccacagetetaca
`cectececccatccceggaggagatgaccaagaaccagetcagccteacctacctggicaaagect tclatcccagcgac
`atceccetgeagteegagagcaalegccagcccgagaacaactacaagaccacccctcecetectggactccgacegctc
`cticttectctacagcaagctcaccetggacaagagcagel egcagcagggcaacetcttctcatectccetgatgcate
`agectctgcacaaccaclacacccageagagcctctecctgtcicccegcaaa
`Signal sequence
`(1-57), Variable region (58-423) , Constant region(424~ 1418)
`(SEQ ID NO: 35 of SequenceListing)
`
`Figure 44
`
`MKHLWEFLLLVAAPRWVLSEVOLVESGGGLYVQPGRSLKLSCVASGFRFNDFWMTWIRQAPGKGLEWVAS ITYTGDNTYYA
`GSVKGRITISRDNAKSTLYLQNNSLRSEDTATYYCTRDDYGGYSPYYNDAWGOGTSVTVSSASTKGPSVFPLAPSSKSTS
`GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTOTYI CNYNHKPSNTKYDKRVE
`PKSCDKTHTCPPCPAPELLGGESVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEYVKENWYVDGVEVHNAKTRKPREEQY
`NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKT [SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD
`LAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNEYTQKSLSLSPGK
`Signal sequence
`(1~19), Variable region (20-141) , Constant region(142~-47 f)
`(SEQ ID NO: 36 of SequenceListing)
`
`Figure 45
`
`CCAGATGGGTGCTGAGCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGC
`(SEQ ID NO: 37 of SequenceListing)
`
`17 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 17 of 86 US 2016/0317656A1
`
`Figure 46
`
`CTTGGTGGAGGCTGAGCTGACAGTGACTGAAGTTCCTTGACCCCAGGC
`(SEQID NO:38 of Sequence Listing)
`
`Figure 47
`
`atggtgctgcagaccCaggtgttcatcticCCtgctgctgtggat Ctc.cgg.cgcgtacggcga-catccagatgacacagtC
`to cagott coctgtctgcatcCtgggagaaacgiCaccatcgaatgtcgagCaag gaggacatt tacagtaatt tag
`cgtgg tat cagcagaaaccagggaactC toc (CagCtcCtgat C tatgatgcaaat at CttggCagatgggg ccCatCa
`cggttcag tiggcagtggg fictggCacacag tattic tictaaagataa acagoctgcaatctgaagatgtc.gcaagttattt
`ctgtcaa.cagtataacaattat CCiCCSt Cacgt EtggagttgggaCCaag Ctggaactgaaacgggctgtggcc.gcCC
`cCtcc.gtgttcatct tcCCCCCC toCgaCgagCagctgaag tecggCaccgcCtcCgtgg fgtgcCtgctgaataact tc
`taccc.cagagaggccaaggtgcagtggaaggtggacaacgcCC tigcagtCCggga accCCaggagagcgtgaccgagca
`ggacagcaaggacagcacciacagcCtgagcagcaCCCtgaCCC tigagcaaagCC&actacgagaag Cacaaggtgtacg
`Cctg.cgaggtgacccaccagggCCtgagCtCCCCCgtCaCCaaga gCttcaaCaggggggagtgt
`Signal sequence (1-60), Variable region (6-390), Constant region (391-705)
`(SEQID NO:39 of Sequence Listing)
`
`Figure 48
`MYLQTQVFISLLIWISGAYGDIQMTQSPASLSASLGETVTIECRASEDIYSNLAWYQQKPGNSPQLLIYDANILADGYPS
`RFSGSGSGTQYSLKINSLQSEDYASYFCQQYNNYPPFTFGWGTKLELKRAWAAPSVFIFPPSDEQLKSGTASYYCLLNNF
`YPREAKYQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKWYACEYTHQGLSSPWTKSFNRGEC
`Signal sequence (1-20), Variable region (21-130), Constant region (131-235)
`(SEQID NO. 40 of Sequence Listing)
`Figure 49
`
`ATCTCCGGCGCGTACGGCGACATCCAGATGACACAGTCTCCAGCTTCC
`(SEQID NO:41 of Sequence Listing)
`Figure 50
`
`GGAGGGGGCGGCCACAGCCCGTTTCAGTTCCAGCTTGGTCCCAAC
`(SEQID NO: 42 of Sequence Listing)
`
`18 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`19 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 18 of 86
`
`US 2016/0317656 A1
`
`Figure 51
`
`atganacaccteteetteticctcctectegtggcagctcccagaleeetgclgagccagel taagcleclecagtcleg
`gectgagctegtanaacctggtecttcagtgaagttgtcclecaagacttctgettttaccttcagcactagclatalga
`et teettgaagcagetecctggacceagtatlgagtgeattegatgeatttatectsgagatggtggtactaagtataal
`cagaag! tcaaggecaageccacactgacagtagacaaatcttctagcacagcatacategatctcagcaegcctgacatec
`teageacectgcagictlattttigtycaacegategttategegattgetttecttactegegsccaaggcactctestca
`clgtcagctcagcctccaccaagggcccaagcetcttceccctgecacccicctccaagagcaccicteecegcacagce
`ecectegectgcctggtcaageactact tccccgaacccetgaccetgage tggaactcagececcclgaccagcegcet
`gcacaccttcocecactgtcetgcagtcctcaggactctacicectcagcagcetegigaccgtecectccagcagcl tge
`gcacccagacctacatctecaaceteaatcacaagcccagcaacaccaagel egacaagagagt leagcccaaatcttet
`pacaaaactcacacatecccacectgcccageacc tgaactcetegegesaccctcagtcttccteticececcaaaacc
`caageacaccc tcatgatcteceggacecctgaggtcacatecetegtegtgeacgtgagccacgaagaccc teageltca
`agttcaacteelacelggacgecetegagelecataaleccaagacaaagcccceggaggagcaglacaacagcacstac
`cepetegtcagcetcctcaccetcctgcaccaggactgectgaal gecaaggagtacaagtecaage ic iccaacaaage
`ectcccagececcatcgagaaaacca tc tccaaagccaaageccagccccggeaaccacagelgtacaccclgcceccat
`coceggaggagaleaccaagaaccagetcagcctgacctecctggtcaaagectictatcccagcgacatceccgelggag
`teggagagcaateeccagccceagaacaactacaagaccaccccleecelectggactcceacgectccttctticctcta
`cagcaagc tcaccetggacaagagcaggtgecagcagsecaacgtctictcatgciccgtgalgcatgagectctgcaca
`accactacacccagaagagccicteectgtctcccggcaaa
`Signal sequence
`(1-57), Variable region (58-411), Constant region (412-1401)
`(SEQ ID NO: 43 of SequenceListing)
`
`Figure 52
`
`MKBLWEFLLLVAAPRWVLSQVKLLOS GAELVKPGASVKLSCKTSGETESTSYMSWLKQVPGPS LEWLGW] YAGDGGTEYN
`QKEKGKATLTVDKSSSTAYMDLSSLTSEDAAVYECATOGYGDWEAYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTA
`ALGCLVKDYFPEPYTYSUNSGALTSGVATFPAVLOSSGLYSLSSVVTVPSSSLGTQTYI CNYNHKPSNTKVDKRVEPKSC
`DKTHTCPPCPAPELLGGPSVFLEPPKPKDTLMISRTPEVTCVVYDVSHEDPEVKENWYVDGVEVANAKTKPREEQYNSTY
`RVVSVLTVLHQDULNGKEYECKVSNKALPAP LEKT I SKAKGQPREPQVYILPPSREEMTENQVSLTCLVKGFYP SDIAVE
`WESNGQPENNYKTTPPYLDSDGSFFLYSKLTVDKSRVQOQGNVESCSVMHEALHNHYTQKSLSLSPGK
`Signal sequence
`(1-19), Variableregion (20-137), Constant region( 138-467)
`(SEQ ID NO: 44 of SequenceListing)
`
`Figure 53
`
`CCAGATGGGTGCTGAGCCAGGTTAAGCTGCTGCAGTCTGGGGCTGAG
`(SEQ ID NO: 45 of SequenceListing)
`
`Figure 54
`
`CTTGGTEGAGGCTGAGCTGACAGTGACCAGAGTGCCTTGGCCCCAG
`(SEQ ID NO: 46 of SequenceListing)
`
`19 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`20 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov.3,2016 Sheet 19 of 86
`
`US 2016/0317656 A1
`
`Figure 55
`atggtectgcagacccagetgt tcatctccctecteclgtggalctcceececetacgscgaca lccagatgacacagic
`tecagcttecctgtctecatctctgggagaaactgtcaccatcgaatgetcgagcaagtgaggacatatacagtaatltag
`catggtatcagcagaaaccagggaactctcctcagclectgatctatgatgcaaatalcctigecagatggggtcccatca
`ceet tcagtgecagtegetcteecacacagtat tctctaaagataaacagcctgecaatctgaagalgatcgcaagitalll
`clgtcaacagtataacaaltatcctccal tcacetltggagctesgaccaagc tggaactgaaacegec tetegccecce
`cctccgtgttcatcttccececetecgacgagcagc tgaagtccgecaccecctecgtagtgtacctactgaataacttc
`taccccagagageccaaggtecagtegaagst ggacaaceccctecagtccgggaactcccaggagagcg tgaccgagca
`geacagcaaggacagcacctacagcc tgagcagcacccigacce Lgagcaaagccgactacgagaagcacaaggtgtacg
`cctgcgagetgacccaccaggeccigagcicceccgtcaccaagagc lt tcaacageggesagist
`Signal sequence
`(1-60), Variable region (6 1-390) , Constant region (39 1-705)
`(SEQ ID NO: 47 of SequenceListing)
`
`Figure 56
`
`MVLQTOVEISLLLWI SGAYGD [QMTQSPASLSASLGETVT I ECRASED1 YSNLAWYQQKPGNSPQLLIJ YDANILADGYPS
`RESGSGSGTQYSLKINSLQSEDVASYF CQQYNNYPPFTFGAGTKLELKRAVAAPSYFI FPPSDEQLESGTASVVCLLNNE
`YPREAKVQHKYDNALQSGNSQESVIEQDSKDS TYSLSSTL TLSKADYEKHKVYACEVIHQGLSSPVTKSFNRGEC
`Signal sequence—({-9()) . Variable region (9 j -1 39), Constant region (1 3 1-235)
`(SEQ ID NO:48 of SequenceListing)
`
`Figure 57
`
`GGAGGGGGCGGCCACAGCCCGTTTCAGTTCCAGCTTGGTCCCAGC
`(SEQ ID NO: 49 of SequenceListing)
`
`20 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`21 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 20 of 86
`
`US 2016/0317656 A1
`
`Figure 58
`atgaaacacctgtgeticttcctcctgctegtescasctcccaga tegetectgagccaget Laagetgctecagtctgs
`gectgagclggtaaaacclegtecttcagtgaagttetectecaagacttctegtttiacattcagcactasttatatga
`gitegttgaagcagetecctegacceagtacteagtegattegateeatttatectggagatestegtactaagtataat
`cagaagt tcaageecaageccacactgacaglagacaaatt ttctagcacagcatacatgegatctcagcagcctgacatec
`tgaggacectgcagtctatttctgtgcaacggatggt tategegattegtt tact tacteggeccaaggcactctegtca
`ctgtcagctcagcciccaccaagggcccaagcetct tecccctggcaccctcctccaagagcacctc Legcescacagec
`gcectggectgcctggtcaaggactact tecccgaacccetgaccetgagc legaactcaggceccc tgaccagcggcelt
`gcacaceliccccgctetcctgcagtcctcaggactctactccctcagcagcelegtgaccetgccc tccagcage tisg
`gcacccagacclacatctgcaacglgaatcacaagcccagcaacaccaaget ggacaagagagl tgagcccaaatcttet
`gacaaaactcacacatgcccaccc tececagcacctgaactccigegeggaccc tcagtcttcctet tccecccaaaacc
`caaggacaccctcatgatctcccegaccectgagetcacatecetegtegtegacglgagccacgaagaccctegaggica
`agt tcaactggtacgtgeaceecet ggagetecataatgccaagacaaagcceceggaggagcagtacaacagcacg tac
`cegetegtcagcetcctcaccetcetgcaccageac legctgaategcaaggastacaagtgcaaggtctccaacaaagc
`cctcccageccccatcgagaaaaccatc tccaaagccaaageccagcccceggaaccacagetgtacaccctecccccal
`cccgggaggagatgaccaagaaccagetcagcc lgacctgcctegtcaaagect tclalcccagcgacatceccetegag
`tegeagagcaatgeccagcccgagaacaactacaagaccacceciccceieciggactccgacggctccticttcctcta
`cagcaagctcaccelegacaagagcagetgecagcagegcaacetcltctcatectccgtgatecatgagecictecaca
`accaclacacccagaagagcctctccctetcteccegcaaa
`Signal sequence
`(1-57),Variable region (58-41 1), Constant region (412-1401)
`(SEQ ID NO: 50 of SequenceListing)
`
`Figure 59
`
`MKHLWEELULVAAPRWVLSOVKLLQSGAELVEPGASVKLSCKTSGFTFSTSYMSWLKQVPGPSTEW] GW YAGDGGTKYN
`QKEKGKATLTVDKFSSTAYMDLSSLTSEDAAYYPCATDGYGDWFTYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTA
`ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKYDERVEPKSC
`DKTHICPPCPAPELLGGPSVFLEPPKPKDTLNI SRTPEVICVVVDVSHEDPEVKENWYVDGVEVHNAKTKPREEQYNSTY
`RVVSVLTVLEQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGOQPREPQVYTLPPSREEMTENQVSLTCLYKGFYPSDIAVE
`WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVNHEALHNHYTQKSLSLSPGK
`Signal sequence
`(1-19), Variable region (20-37), Constant region( 138-467)
`(SEQ ID NO: 51 of SequenceListing)
`
`Figure 60
`
`DFWMT
`(SEQ ID NO: 52 of SequenceListing)
`
`Figure 61
`
`SITYTGDNTYYAGSVKG
`(SEQ ID NO: 53 of SequenceListing)
`
`Figure 62
`
`DDBYGGYSPYYMDA
`(SEQ ID NO:54 of SequenceListing)
`
`21 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`Patent Application Publication
`
`Nov. 3, 2016 Sheet 21 of 86 US 2016/0317656 A1
`
`Figure 63
`
`TSYMS
`(SEQID NO. 55 of Sequence Listing)
`
`Figure 64
`
`WIYAGDGGTKYNQKFKG
`(SEQID NO. 56 of Sequence Listing)
`
`Figure 65
`
`DGYGDWFAY
`(SEQID NO. 57 of Sequence Listing)
`
`Figure 66
`
`TSYMS
`(SEQID NO. 58 of Sequence Listing)
`
`Figure 67
`
`WYAGDGGTKYNQKFKG
`(SEQID NO. 59 of Sequence Listing)
`
`Figure 68
`
`DGYGDWFTY
`(SEQID NO: 60 of Sequence Listing)
`
`Figure 69
`
`RASQDIGNYLR
`(SEQID NO: 61 of Sequence Listing)
`
`Figure 70
`
`GATNLAN
`(SEQID NO: 62 of Sequence Listing)
`
`Figure 71
`
`KHNEYPFT
`(SEQID NO: 63 of Sequence Listing)
`
`22 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`23 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 22 of 86
`
`US 2016/0317656 A1
`
`Figure 72
`
`RASEDIYSNLA
`(SEQ ID NO: 64 of SequenceListing)
`
`Figure 73
`
`DANILAD
`(SEQ ID NO: 65 of SequenceListing)
`
`Figure 74
`
`QQYNNYPPFT
`(SEQ ID NO:66 of SequenceListing)
`
`Figure 75
`
`RASEDLYSNLA
`(SEQ ID NO: 67 of SequenceListing)
`
`Figure 76
`
`DANILAD
`(SEQ ID NO: 68 of SequenceListing)
`
`Figure 77
`
`QQYNNYPPFT
`(SEQ ID NO: 69 of SequenceListing)
`
`Figure 78
`
`NVSWGRFICLYVVIMATLSLARPSESLVEDTTLEPEEPPTKYQI SQPEVYVAAPGESLEVRCLLKDAAYI SHIKDGVHLG
`PNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAI SSGDDEDDTDGAEDFVSENSNNKRAPYWINTE
`KMEKRLHAVPAANTVKERCPAGGNPMP TMRWLENGKEFKQEHRI GGYKVRNQHWSLIMESVVP SDKGNYTCVVENEYGSI
`NATYHLDVVERSPHRP ILQAGLPANASTYVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSS
`NAEVLALFNVTEADAGEYI CKVSNYI GQANQSAWLTVLPKQQAPGREKEI TASPDYLETATYC] GVFL TACMVVTVILCR
`MKNTTEKPDFSSQPAVAKLTERI PLRROVTYSAESSSSMNSNTPLYRITTRLSSTADTPMLAGYSEYELPEDPKWEFPRD
`KLTLGKPLGEGCFGQVVMAEAVGIDKDKPKEAVTVAVENLKDDATEKDLSDLVSENEMMKMI GRHKNT INLLGACTQDGP
`LYVIVEYASKGNLREYLRARRPPGMEYSYD I NRVPEEOMTFADLYSCTYQLARGMEYLASQKCIHRDLAARNVLYTENNY
`NE TLADEGLARD INNIDYYKKTINGRLPVKWMAPEALFDRVYTHOSDVWSFGVLNWEI FTLGGSPYPGT PVEELPELLKEG
`HRMDKPANCTNELYMNMRDCWHAVP SORPTFKQLVEDLDRILTLTTINEEYLDLSQPLEQYSPSYPDTRSSCSSGDDSVES
`PDPMPYEPCLPQYPHINGSVET
`(SEQ ID NO: 70 of SequenceListing)
`
`23 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`24 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 23 of 86
`
`US 2016/0317656 Al
`
`Figure 79
`
`MVSWGRF I CLVVYTMATLSLARPSESLVEDTTLEP EEPPTKYQISQPEVYVAAPGESLEYRCLLKDAAY I SWTKDGYHLG
`PNNRTVLIGEYLGIKGATPRDSGLYACTASRTVDSETHYEMYNVTDAI SSGDDEDDTDGABDFVSENSNNKRAPYWINTE
`KMEKRLEAYPAANTVKFRCPAGGNPNPTNRWLENGKEFKQEHRIGGYKVRNQHWSL IMES VVPSDKGNYTCVVENEYGS J
`NHTYHLDYVERSPHRP ILQAGLPANASTVYVGGDVEFYCKVYSDAQPH! QW I KHVEKNGSKYGPDGLPYLKVLKAAGYNTT
`DAEIEVLY I RNVTFEDAGEYTCLAGNS IGI SFHSAVLTVLPAPGREKE] TASPDYLEIAI YCIGVFLIACMVYTVILCRM
`KNTTKKPDFSSQPAVHKLTKRIPLRRQVIVSAESS SSMNSNTPLVRITERLSSTADTPMLAGVSEYELPEDPKWEEPRDK
`LTLGKPLGEGCFGQYVMAEAVG1 DKDKPKEAVTYAVEMLKDDATEKDLSDLVSEMEMMKM I GRHENT INLLGACTQDGPL
`YVIVEYASKGNLREYLRARRP PGMEYSYD INRVPEEQNTFEDLVSC TYQLARGMEYLASGKCIRRDLAARNVLVTENNYM
`KIADFGLARDINN [DYYKKTINGRLPVKWMAPEALFORVYTHOSDVWSFGYLMVE J FTLGGSPYPG] PVEELFELLKEGH
`RMDKPANCTNELYNMMRDCWIAVPSORPTFKOLVEDLDRILTLTTNEEYLDLSOPLEQYSPSYPDTRSSCSSGDDSVFSP
`DPMPYEPCLPQYPHINGSVKT
`(SEQ ID NO: 71 of Sequence Listing)
`
`Figure 80
`
`atggtectecagacccagelgttcatcicectgctectglegatclccegcecgtacegcgacatccagalgacccagag
`ccoccagcagec tgagceccagcel gegegacagaglgaccalcaccletcgegccagceageacatclacagcaaccl gg
`cctegtatcagcagaagcccegcaagagcccccagctgctgatctacgacgccaacatcctggccgacescetgcccage
`agat [cagcegcagcegctcogecacceactacaccctgaccatctccagccetgcagceccgaggact tcgceacctacta
`cteccagcaglacaacaactaccecccaltcacct tcesccagescaccaaget geaaalcaagcetacest geccgcce
`ectecgtgttcatcttcceccectccgacgagcage tgaagtccegcaccecc tccelgetgtecctectgaataactic
`taccccagagageccaaget ecagt geaagetegacaaceccctgcegteceggaac icccaggagagce lt gaccgagca
`peacagcaagpacagcacclacagccigagcagcacccteaccc t gagcaaagcegac tacgagaagcacaaggtgtacg
`ectecgageigacccaccaggscctgagctccecccgtcaccaagagcltcaacaggesgeagtet
`Signal sequence 1-80), Variable region (61~390), Constant ragion (391-705)
`(SEQ ID NO: 72 of SequenceListing)
`
`Figure 81
`
`MVLOTOVFISLLEWI SGAYGD [ QUTQSPSSLSASVGDRVT [TCRASED I YSNUAWYQQKPGKSPOLL LYDANILADGYPS
`RESGSGSGIDYTLTISSLOPEDFATYYCQQYNNYPPFTFGQGTKVE I KRTVAAPSVF I FPPSDEQLESGTASVVCLLNNE
`YPREAKVQHKVDNALOSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
`Signal sequence
`(1-20), Variable region (21-130), Constant region (131-235)
`(SEQ ID NO:73 of SequenceListing)
`
`24 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`25 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 24 of 86
`
`US 2016/0317656 Al
`
`Figure 82
`
`atgaaacacctetegttcticctcctgctggtegcagctcccagatgggtectgagccagetecagctggtecagtctge
`ceccgaagtgaagaaacctegeectagcelgaugetetcclecaaggccagcescl tcaccticagcaccagclatatga
`gctggetcceccagectccageccaggeactegaatggategectsgatclatgccesceacegcegcaccaagtacaac
`cagaaat [caagegcagagtgacec tgaccelggacaagagcaccagcaccecctacaigeaac lt sagcagcclecegag
`Ceageacacceccetgtactactgceccacceacggctacgecesactest tcacatactegeeccagegcaccctesiga
`ccgtegagetcagcc tccaccaagggcccaagcetcticceccteecaccctcc tccaagagcacctcteecescacagcc
`eccctegectgectgetcaaggactact tccccgaacccetgaccelgagctggaactcaggceccclgaccagcegcet
`gcacacct teccceclgtcclecagtcctcaggactctactccctcagcagcgtegtgacceteccctccagcagctleg
`gcacccagacclacatctgcaacgteaatcacaageccagcaacaccaage lt geacaagagagt tgagcccaaatctigt
`gacaaaactcacacatgcccaccctecccagcacctgaactcctgegegeaccctcagicttectettccecccaaaacc
`caageacaccctcatgatctcecegaccccteagetcacatece(egteetgeacet gagccacgaagaccctgagetca
`agttcaactggtacelegacegcetgeagelecataateccaagacaaagcccceggaggagcaglacaacagcacgelac
`ceggtegtcagcetcctcaccgtcctgcaccaggactescteaategcaaggagtacaagtgcaagetc tccaacaaagc
`ccicccageccccatcgagaaaaccatci{ccaaagccaaageccagcccceggaaccacaggtetacacccigcccccal
`cccgggaggagat gaccaagaaccageltcagcctgacctecctggtcaaaggct tctalcccagcgacalceccetggag
`Leggagagcaatggeccagcccgagaacaact acaagaccaccccicccelectggactcceacegctccttcttcctcta
`cagcaagctcaccelggacaagagcaget ggcagcagescaacelcttetcatgctccatgalecatgageciclecaca
`accactacacccagaagagcctctccctetctcceggcaaa
`Signal sequence (1-57), Variableregion (58-411), Constant region (412-1401)
`(SEQ ID NO: 74 of SequenceListing)
`
`Figure 83
`
`MKHLWEFLLLVAAPRYYLSQVQLVOSGAEVEKPGASVRVSCKASGETESTSYMSWVRQAPGQGLEWMGW1 YAGDGGTKYN
`QKFKGRVTLTYDKSTSTAYMELSSLRSEDTAVYYCATDGYGDWETYWGQGTLYTVSSASTKGPSVFPLAPSSKSTSGGTA
`ALGCLYKDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVYTVPSSSLGTOTYI CNVNEKPSNTKVDKRVEPKSC
`DKTHTCPPCPAPELLGGPSVELFPPKPKDTLMI SRIPEVICYVVDVSHEDPEVKENWYVDGVEVHNAKTKPREEQYNSTY
`RVVSVLTVLHQDWLNGKEYKCKVSNKALPAP I ERT 1 SKAKGQPREPQVYTLPPSREENTKNQVSLTCLVKGFYPSDIAVE
`WESNGQP ENNYKTTPPYLDSDGSFFLYSKLTVDKSRWQQGNYES CSYMHEALHNHYTQKSLSLSPGK
`Signal sequence
`({~[9), Variable region (20-137), Constant region( 138-467)
`(SEQ ID NO: 75 of SequenceListing)
`
`25 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`26 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 25 of 86
`
`US 2016/0317656 Al
`
`Figure 84
`
`atgaaacacctgtggticlicctcclgctggtgecagc icccagatgggtectgagccagg lecagclegtgcagicleg
`ceccgaag (gaagaaacctgggectagcelgaagelgtcctecaageccagcgact icacctlcagcaccagctatatga
`ectgegtcceccagectccageccagegactggaategategectegatclateccegcgacgeceecaccaagtacaac
`cagaaat lcaagggcagagt gaccclgaccecceacaagagcaccagcaccecc lacalggaactgagcagcclecegag
`cgageacacceccetgtactactgceccacceacesclacgsceactget tcacalactegeeccageecaccctesiga
`ccetgagctcagce tccaccaaggecccaagcelcltccecctggcaccctec tecaagagcacctclegcegcacagcc
`gccctgegectecctggtcaaggactacticcccgaacccetgaccetgagctegaaclcagececcetgaccagcgscet
`gcacaccttecccectstcctgcagtcctcaggactctactccctcagcagcg i getsaccelecce tccagcagcl leg
`ecacccagacctacatclecaacgtgaalcacaagcccagcaacaccaagetggacaagagagt tgagcccaaatctigt
`gacaaaacicacacalacccaccclacccagcacctgaacteclggegegaccctcagtctticctcttccccecaaaacc
`caaggacaccctcatgatcteccegacccct gaggtcacatscetegtestegaceteagccacgaagaccclgagetca
`agttcaactgetacetegacescglegagel gcalaaleccaagacaaagcccceggaggagcagtacaacagcacelac
`cgegtegtcagcgtcctcaccetcclecaccageactegctgaal gecaaggagtacaagtecaagetctccaacaaagc
`cctcecageccecatcgagaaaaccatctccaaagccaaageccagcccceggaaccacagetetacaccclecccccal
`ccegsgaggagat gaccaagaaccaggetcagccleacclecctegtcaaagact tctatcccagcgacatceccgtggag
`tgegagagcaategccagcccgagaacaact lacaagaccaccccteccetectggactccgacgectcclticttectcta
`cagcaagclcaccetggacasgagcagstggcagcaggecaacetcltictcatgcetccgtgalgcatgaggcetctgcaca
`accactacacccagaagagccltctcccletctceceggcaaa
`Signal sequence
`(1-57), Variable region (58-41 1) , Constant region(4 12-1401)
`(SEQ ID NO: 76 of SequenceListing)
`
`Figure 85
`
`MKHLYFFLLLVAAPRYVLSQVQLVQSGAEVKKPGASVKVSCKASGFTESTSYMSWVRQAPGOGLEWMGWI YAGDGGTEYN
`QKFKGRVTLTADKSTSTAYMELSSLRSEDTAVYYCATDGYGDWFTYWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTA
`ALGCLYKDYFPEPVTVSWNSGALTSGVHTEPAVLOSSGLYSLSSVVTVPSSSLGTOQTY] CNYNHKPSNTKVDKRVEPKSC
`DKTHTCPPCPAPELLGGPSVELFPPKPKDTLMI SRTPEVICVVVDVSHEDPEVKENWYVDGVEVHNAKTKPREEQYNSTY
`RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKT I SKAKGQPREPQVYTLPPSREENTKNQVSLTCLVKGFYPSDIAVE
`WESNGQPENNYKTTPPYLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
`Signal sequence
`(1-19), Variable region (20-187), Constant region (138~467)
`(SEQ ID NO:77 of SequenceListing)
`
`26 of 243
`
`OnCusp
`Ex. 1006
`
`

`

`27 of 243
`
`OnCusp
`Ex. 1006
`
`Patent Application Publication
`
`Nov. 3,2016 Sheet 26 of 86
`
`US 2016/0317656 A1
`
`Figure 86
`
`algaaacacctetggttcttectectgctggtegcagc tcccagatgestectgagccagetecagctggtacagictgs
`cgccgaagtgaagaaacc tggeectagcetgaagetetce tgcaaggccagcegct tcacet icagcaccagctatatga
`gc tgeetececcagectccaggccccagcaccgaalegatepectegatctalgeccegceacegcegcaccaagtacaac
`cagaaat tcaagegcagagtgaccct gaccgtggacaagagcaccascaccecctacalegaaclgagcagcclgcegag
`crageacacceccetgtactactececcacceacgsc lacggcgactest tcacatactsggeccagegcaccctgetea
`ccetgagctcagectccaccaageecccaagcetcttccecctggcaccctcetccaagagcaccictggcgecacagec
`eccctegectecctgetcaaggactact tccccgaacccetgaccetgage tegaac tcaggceccc teaccagcgsgcst
`gcacaccttceccectetccigcagicctcaggactclaciccctcagcagcetggtgaccetaccctceagcagciteg
`gcacccagacc lacatctecaacetgaalcacaagcccagcaac