1111111111111111 IIIIII IIIII 1111111111 11111 lllll 111111111111111 lllll 111111111111111 11111111
`US 20110229479Al
`
`c19) United States
`c12) Patent Application Publication
`Vogelstein et al.
`
`c10) Pub. No.: US 2011/0229479 Al
`Sep. 22, 2011
`(43) Pub. Date:
`
`(54) GENETIC ALTERATIONS IN ISOCITRATE
`DEHYDROGENASE AND OTHER GENES IN
`MALIGNANT GLIOMA
`
`(75)
`
`Inventors:
`
`(73) Assignees:
`
`Bert Vogelstein, Baltimore, MD
`(US); Kenneth W. Kinzler,
`Baltimore, MD (US); D. Williams
`Parsons, Ellicott City, MD (US);
`Xiaosong Zhang, Baltimore, MD
`(US); Jimmy Cheng-Ho Lin,
`Baltimore, MD (US); Rebecca J.
`Leary, Baltimore, MD (US);
`Philipp Angenendt, Baltimore, MD
`(US); Nickolas Papadopoulos,
`Towson, MD (US); Victor
`Velculescu, Dayton, MD (US);
`Giovanni Parmigiani, Baltimore,
`MD (US); Rachel Karchin,
`Towson, MD (US); Sian Jones,
`Baltimore, MD (US); Hai Yan,
`Chapel Hill, NC (US); Darell
`Bigner, Mebane, NC (US);
`Chien-Tsun Kuan, Cary, NC (US)
`
`THE JOHNS HOPKINS
`UNIVERSITY, Baltimore, MD
`(US); DUKE UNIVERSITY,
`Durham, SC (US)
`
`(21) Appl. No.:
`
`13/060,191
`
`(22) PCT Filed:
`
`Sep.3,2009
`
`(86) PCT No.:
`
`PCT /US09/55803
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jun. 7, 2011
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/093,739, filed on Sep.
`3, 2008, provisional application No. 61/110,397, filed
`on Oct. 31, 2008, provisional application No. 61/162,
`737, filed on Mar. 24, 2009.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61K 39/395
`C12Q 1168
`GOIN 331574
`C07K 16132
`A61K 39/00
`C12N 9/04
`C07H 21104
`C12Q 1132
`A61P37/04
`A61P35/00
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl. .................. 424/138.1; 435/6.18; 424/174.1;
`435/7.1; 435/6.11; 530/387.7; 424/185.1;
`435/190; 536/23.2; 435/26
`
`(57)
`
`ABSTRACT
`
`We found mutations of the R132 residue of isocitrate dehy(cid:173)
`drogenase 1 (IDHl) in the majority of grade II and III astro(cid:173)
`cytomas and oligodendrogliomas as well as in glioblastomas
`that develop from these lower grade lesions. Those tumors
`without mutations in IDHl often had mutations at the analo(cid:173)
`gous Rl 72 residue of the closely related IDH2 gene. These
`findings have important implications for the pathogenesis and
`diagnosis of malignant gliomas.
`
`Rigel Exhibit 1008
`Page 1 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 1 of 131
`
`US 2011/0229479 Al
`
`Normal
`
`C394A(R132S)
`'1t
`
`Br104X )J[/{;!j;/~j{}Ji
`Br129X ;\/4\~/v~~~;JA
`
`G395A (R 132H)
`~
`
`Fig. 1.
`
`Rigel Exhibit 1008
`Page 2 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 2 of 131
`
`US 2011/0229479 Al
`
`Fig. 2.
`
`Rigel Exhibit 1008
`Page 3 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 3 of 131
`
`US 2011/0229479 Al
`
`-~ 80
`g -ca >
`-~
`
`100
`
`60
`
`:,
`Cl)
`
`(0
`"-
`(I,)
`>
`0
`
`Fig. 3.
`
`40
`
`20
`
`a
`0
`
`p<0.001
`
`2
`
`4
`
`6
`
`Years
`
`Rigel Exhibit 1008
`Page 4 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 4 of 131
`
`US 2011/0229479 Al
`
`R172G GGG
`R172M ATG
`R172K AAG
`
`t
`ATT!GGC AGG
`1,10 I G,1, R,12
`
`n=2
`n=3
`n=3
`
`CACl GCC
`H113! A174
`
`Fig. 4A
`A
`
`IDH2
`
`IDH1
`
`1,3oj G131 R132
`
`H133i A134
`
`CAT!GCT
`
`ATAjGGT CGT •
`
`R132H CAT
`R132C
`TGT
`R132L CTT
`
`R132S AGT
`R132G GGT
`
`n = 148
`n=B
`n=B
`n=2
`n = 1
`
`Fig. 48
`
`B
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`313
`
`717
`
`■ IDH2 mutated
`
`• IDH1 mutated
`
`1/7
`
`0/21
`
`0/30···'···
`
`0115
`
`0/55
`
`0/494
`
`71150 •
`
`Rigel Exhibit 1008
`Page 5 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 5 of 131
`
`US 2011/0229479 Al
`
`Fig. SA
`
`0
`
`~
`
`r:::==::J
`
`a:,
`ci
`
`£
`ii <!)
`ci
`"'
`.0 e a.
`ro
`> "
`·1:
`=>
`U)
`
`ci
`
`(\J
`
`ci
`
`a
`ci
`
`Fig. SB
`
`"
`
`a:,
`ci
`
`£
`ii (0
`ci
`"'
`.0 e o._
`'"
`> "
`
`ci
`
`-~
`=>
`Cf)
`
`"' ci
`
`0
`ci
`
`~
`
`~ . IDH wild type
`
`IDH mutated
`
`I
`
`L.._____,
`
`' i
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Survival Time (Months)
`
`IDH mutated
`I DH wild type
`
`\~~
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Survival Time (MontnsJ
`
`Rigel Exhibit 1008
`Page 6 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 6 of 131
`
`US 2011/0229479 Al
`
`Fig. 6
`
`♦
`
`Pilocyticastrocytoma
`WHO Gradel
`
`IDH1,1
`mutation
`
`;
`
`WHO Grade II
`
`WHOGradelll
`
`WHO Grade IV
`
`0
`
`Oligodendroglioma
`
`Anapfasticoligodendroglioma
`
`1 p 1 9 q (cid:173)
`t
`CDKN2A
`
`lp l9q (cid:173)
`CDkNill)!I
`
`~~o-
`
`'V pathway
`
`GBM
`WHOGtddeJV
`
`IDHl,2
`
`;
`
`-a-----+--'---mu-tatfon )- • - - - - - - • - - •
`
`Diffuse astroc,torna
`
`IDH , -
`TP 5 3 -
`1p19q(cid:173)
`CDkNU,,
`
`Anaplastic astrocvtoma
`IDH . (cid:173)m,_
`
`Jp19q .•
`CDK~?A
`Ill
`
`GBM
`1 0 , _
`
`TP53 ~
`lpl':lq ND
`COKN2A-
`
`Glialstemcell
`
`Astrocyteand
`oligodE!ndrocyte
`prewrsorcell
`
`0
`
`Ependymal
`precurwrcell
`
`1DH1,2
`mutation
`
`;
`
`Epem:tm,oma
`WHOGradell
`
`lpl'Jq
`CDKNZA•
`
`Ana plastic @y
`
`Ependvmoma
`WHO Grade Ill
`
`•··•· • •.
`
`Oligoastroc,ttoma
`
`Ana plastic oligoastrocytoma
`
`TP53W!t,,'1W,;
`
`lpl9q •
`CDKN2A
`
`lpl9q •
`
`!DH-independent pathway
`
`!DH-dependent pathway
`
`Rigel Exhibit 1008
`Page 7 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 7 of 131
`
`US 2011/0229479 Al
`
`Fig. 7
`
`IDH1
`
`C
`
`. : .
`
`. $. : .... T.
`
`.
`
`.
`
`.C.
`
`. ·
`
`.J... .
`
`. T.
`
`. ,
`
`.
`i f .
`H
`
`•
`
`f
`
`'"··. ·.
`.
`~:
`, .. 1 ...
`, Normal
`
`/ ' •
`
`.
`
`640
`
`1088
`
`Normal
`
`IDH2
`
`: .... 1 .... : .... o .... : .... Q ..•• : .... c ....... , ..... : o .... : .... o .... ; .... <; ......... i .... : ... -~---·: .... 6 ... .
`
`if'iJI\>SA,,:r~·;;,QNAu~~~;AA H476
`
`Rigel Exhibit 1008
`Page 8 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 8 of 131
`
`US 2011/0229479 Al
`
`Fig. 8
`
`Normal
`
`J easel
`
`j Case II
`
`Case Ill
`
`.
`
`G395A(R13?H).
`
`/AJ::fJ/\Dl&/\J.:T~~&i :,~~
`
`•
`
`.
`
`. .•
`•
`G395GA(R 132H)
`•
`f \ ·;·• ~··· . [/\ •l, "'f\: . /\: 1688
`/. \/'v. :: yl\y.. --VY ~· ;/\/ \ Ana plastic Astrocytoma
`A~.Tf\1\ iv\ · /\/\ :,~3
`
`G395A(R132H)
`
`~
`
`Rigel Exhibit 1008
`Page 9 of 180
`
`

`

`Patent Application Publication
`
`Sep. 22, 2011 Sheet 9 of 131
`
`US 2011/0229479 Al
`
`11!11 0 and AO
`!11!1 DAand AA
`illlGBM
`
`0-19
`
`20-29 30-39 40-49 50-59
`
`>60
`
`Age
`
`7
`
`Fig. 9A
`
`-
`
`V,
`(1) :I:
`~ 0
`V
`-
`0 a.
`Q)
`... >
`J;: +;-
`E~
`:::, ::
`z
`
`70,
`
`60
`
`50 -
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Fig. 9B
`
`35 1
`30 j
`
`I.I)
`QI
`Ill
`
`0
`
`QI
`.C!
`
`....
`
`(IJ
`
`:::C: Go
`.... -
`... C
`.... 15
`::J E E
`::J
`z
`
`1
`20 i
`1
`0 L,aL-----
`
`Iii Oand AO
`ill DA and AA
`ti GBM
`
`25
`
`10
`
`5
`
`0-19
`
`20-29 30-39 40-49 50-59
`
`>60
`
`Age
`
`,-
`
`Rigel Exhibit 1008
`Page 10 of 180
`
`

`

`('D
`('D
`
`rJJ
`
`0
`N
`N
`N
`'?
`('D
`rJJ
`
`~
`
`=
`..... ....
`O" -
`....
`=
`=
`.... 0
`~ .....
`"e -
`....
`~
`('D = .....
`~ .....
`""O
`
`0
`
`~
`(')
`
`""O
`
`(')
`
`> ....
`
`1,0
`-....J
`.i;...
`1,0
`N
`N
`0
`
`~
`
`---
`....
`....
`0
`N
`rJJ
`c
`....
`....
`....
`0
`0
`....
`.....
`=-
`....
`....
`
`0
`<0'
`-n
`
`Synonymous
`
`Missense
`
`Synonymous
`Synonymous
`
`Missense
`
`Synonymous
`Synonymous
`
`N~nsense
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`Nonsense
`
`Synonymous
`Synonymous
`Splice Site
`Nonsense
`Missense
`Missense
`
`Synonymous
`Splice Site
`Missense
`
`Synonymous
`
`Missense
`Nonsense
`Missense
`Missense
`
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`
`Missense
`Missense
`Nonsense
`
`Synonymous
`
`Missense
`Missense
`Missense
`
`Synonymous
`Synonymous
`
`Missense
`Missense
`Type
`
`Mutation
`
`p.K54K
`p.T3971
`p.K355K
`p.K26K
`p.S145L
`p.T249T
`p.S466S
`p.\'l/34X
`p.G43S
`p.S525A
`p.E326K
`p.P277S
`p.P414S
`p.G161S
`p.L348X
`p.S155S
`p.L400L
`Splice Site
`p.C753X
`p.P487L
`p.S275N
`p.Y287Y
`Splice Site
`p.E190K
`p.V569V
`p.L580M
`p.Q432X
`p.D1505Y
`p.A601V
`p.L 1422L
`p.R638C
`p.A250T
`p.T253T
`p.R286C
`p.L916F
`p.G1559X
`p.R811R
`p.S1558F
`p.E620K
`p.Q532H
`p.S282S
`p.A104A
`p.V316M
`p.T306N
`
`(protein)'*
`Amino acid
`
`Nucleotide (cDNA)t
`
`Nucleotide (genomic)*
`
`Tumor
`
`table 53. Somatic mutations identified in GBM Discovery Screen
`
`c.162G>A
`c.1190C>T
`c.1065G>A
`c.78G>A
`c.434C>T
`c.747C>T
`c.1398C>T
`c.102G>A
`c.127G>A
`c.1573T>G
`c.976G>A
`c.829C>T
`c.1240C>T
`c.481G>A
`c.1043T>G
`c.465C>T
`c.1200G>A
`IVS13-1G>A
`c.2259C>A
`c.1460C>T
`c.824G>A
`c.861C>T
`IVS4-4C>T
`c.568G>A
`c.1707C>T
`c.1738C>A
`c.1294C>T
`c.4513G>T
`c.1802C>T
`c.4264C>T
`c.1912C>T
`c.748G>A
`c.759G>A
`c.856C>T
`c.2746C>T
`c.4675G>T
`c.2433C>T
`c.4673C>T
`c.1858G>A
`c.1596G>C
`c.846C>T
`c.312T>G
`c.946G>A
`c.917C>A
`
`g.chr10:124800607T>G (homozygous)
`
`g.chrX:126911559G>A (homozygous)
`
`g.chr3:53881563C>T
`g .ch r10: 1 04230676G>A
`g.chr14:57739326G>A
`g .chr14:68446506C> T
`g.chr17:77092864C> T
`g.chr12:6619514C>T
`g.chr19:11549031 G>A
`g.chr4:8536193G>A
`g.chr17:3730284DT>G
`g.chr10:52245937G>A
`g.chr7:150185508C>T
`g .chr17:28375101 C> T
`g .chr6: 160160062G>A
`
`g.chr12:119637983C>T
`g.chr12:119639932G>A
`g.chr3:130110513G>A
`g.chr11 :34132451 C>A
`g.chr1 :175815771C>T
`g.chr1 :92230203G>A
`g.chr14:22148578C> T
`g.chr18:17498193C>T
`g.chr4:89400087G>A
`g.chr7: 150349640C> T
`g.chr12:38266275C>A
`g.chr3:185178995C> T
`g.chr17:46123489G> T
`g.chr16:46796828C> T
`g.chr6:43525676C>T
`g.chr2:219902670C>T
`g.chr7:86835309G>A
`g.chr17:64551266G>A
`
`g.chr19:994398C>T
`g.chr17:64781713C> T
`g.chr1 :94199521G>T
`g.chr1 :94232842C> T
`g.chr7:48091360C> T
`g.chr2:215691839G>A
`g .chr17:64701274G>C
`g.chr12:124116625C>T
`g.chr3:139332485T>G
`g.chr22:41413510G>A
`g.chr12:9150431C>A
`
`Br03x
`Br27P
`Br27P
`Br27P
`Br27P
`Br15X
`Br14X
`Br27P
`Br27P
`Br29P
`Br27P
`Br27P
`Br27P
`Br27P
`Br14X
`Br11P
`Br15X
`Br27P
`Br26X
`Br15X
`Br27P
`Br10P
`Br27P
`Br27P
`Br27P
`Br25X
`Br04X
`Br14X
`Br27P
`Br27P
`Br25X
`Br27P
`Br05X
`Br25X
`Br27P
`Br14X
`Br27P
`Br27P
`Br27P
`Br11P
`Br27P
`Br13X
`Br08X
`Br9PT
`
`CCDS14611.1
`CCDS2875.1
`CCDS7536.1
`NM_018477
`CCDS9792.1
`CCDS11782.1
`CCDS8554.1
`CCDS12265.1
`CCDS3401.1
`CCDS11412.1
`CCDS7241.1
`CCDS5914.1
`CCDS11276.1
`CCDS5268.1
`CCDS7634.1
`CCDS9207.1
`CCDS9207.1
`CCDS3053.1
`CCDS7890.1
`NM_007314
`CCDS736.1
`CCDS9572.1
`NM_ 138340
`CCDS3628.1
`CCDS5922.1
`CCDS8734.1
`NM_005688
`NM_003786
`CCDS10732.1
`CCDS4896.1
`CCDS2436.1
`CCDS5608.1
`CCDS11681.1
`CCDS12055.1
`CCDS11685.1
`CCDS747.1
`CCDS747.1
`NM_152701
`NM_015657
`CCDS11684.1
`CCDS9263.1
`CCDS3097.1
`CCDS14041.1
`NM_000014
`Accession
`Transcript
`
`ACTRT1
`ACTR8
`ACTR1A
`ACTR10
`ACTN1
`ACTG1
`ACRBP
`ACP5
`ACOX3
`ACLY
`ACF
`
`ACCN3
`ACCN1
`ACAT2
`ACADSB
`ACADS
`ACADS
`ACAD9
`ABTB2
`ABL2
`ABHD7
`ABHD4
`ABHD3
`ABCG2
`ABCF2
`ABCD2
`ABCCS
`ABCC3
`ABCC11
`ABCC10
`ABCB6
`ABCB1
`ABCA9
`ABCA7
`ABCA5
`ABCA4
`ABCA4
`ABCA13
`ABCA12
`ABCA1C
`AACS
`A4GNT
`A4GALT
`
`A2M
`
`Gene
`
`Rigel Exhibit 1008
`Page 11 of 180
`
`

`

`> ....
`
`1,0
`-....J
`.i;.,.
`1,0
`N
`N
`0
`
`---
`....
`....
`0
`N
`rJJ
`c
`....
`....
`....
`....
`..... ....
`=- ('D
`....
`....
`
`(,H
`
`0
`
`('D
`
`rJJ
`
`0
`N
`N
`N
`'?
`('D
`rJJ
`
`~
`
`=
`.... 0
`~ .....
`...
`= O"
`=
`..... ....
`"e -
`....
`"e
`>
`= .....
`~ .....
`""O
`
`0
`
`~
`(')
`
`('D
`
`-.
`
`""O
`
`(')
`
`;::;
`<ei'
`"Tl
`
`Synonymous
`
`Missense
`
`INDEL
`
`Missense
`
`Synonymous
`Splice Site
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`Splice Site
`Missense
`Splice Site
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`
`Missense
`Missense
`Nonsense
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`Synonymous
`
`M1ssense
`
`Synonymous
`
`Missense
`Missense
`
`3'UTR
`
`p.T100T
`p.A350V
`
`fs
`
`p.A88V
`p.03550
`Splice Site
`p.N304N
`p.D107N
`p.L763L
`p.T2921
`p.E930K
`p.S537S
`p.R1730K
`p.C155C
`p.T5571
`p.K2644K
`p.S1837F
`p.A876A
`p.R1631K
`p.P313P
`p.S228L
`p.P508S
`p.P278P
`Splice Site
`p.R1604P
`Splice Site
`
`p.P23P
`p.D489N
`p.G952G
`p.G337D
`p.L649L
`p.P720S
`p.R322H
`p.L 1000L
`p.T6521
`p.R795H
`p.G597G
`p.1576T
`p.D434G
`p.W1076X
`p.R670H
`p.Y840Y
`p.T746M
`p.D373D
`p.G321G
`p.T5831
`p.T487T
`p.G405E
`p.A19DT
`3'UTR
`
`c.300G>A
`c.1049C>T
`c.2035delC
`c.263C>T
`c.1065C>T
`IVS10-1G>A
`
`c.912C>T
`c.319G>A
`c.2287C>T
`c.875C>T
`c.2788G>A
`c.1611G>A
`c.5189G>A
`c.465C>T
`c.1670C>T
`c.7932G>A
`c.5510C>T
`c.2628C>T
`c.4892G>A
`c.939G>A
`c.683C>T
`c.1522C>T
`c.834C>T
`IVS35-3C>T
`c.4811G>C
`IVS14+1G>A
`
`c.69C>T
`
`c.1465G>A
`c.2856G>A
`c.1010G>A
`c.1945C>T
`c.2158C>T
`c.965G>A
`c.3000C>T
`c.1955C>T
`c.2384G>A
`c.1791C>T
`c.1727T>C
`c.1301A>G
`c.3227G>A
`c.2009G>A
`c.2520C>T
`c.2237C>T
`c.1119T>C
`c.963C>T
`c.1748C>T
`c.1461T>C
`c.1214G>A
`c.568G>A
`UTR+1A>T
`
`g.chr18:54397977G>A
`g.chr2:233148489C> T
`g.chr17:7940771delC
`g.chr17:6840996C>T
`g.chr2:3243411 C>T
`
`g.chr12:110700429G>A
`g.chr3: 12735201 SC>T
`g.chr15:56093392G>A
`g.chr10:9735661 OC> T
`g.chr1 :19377861C>T
`g.chr9:114198755G>A
`g.chr9:114209494G>A
`g.chr7 91318999G>A
`g .chrX:49661935C>T
`g .chrX:49660730C> T
`g .chr15:84085604G>A
`g .ch r15: 84052299C> T
`g.chr15:83924931 C> T
`g.chr13:41775774G>A
`g.chr1 :26356352G>A
`g.chr1 :26356608C>T
`g.chr6:135811225C>T
`g.chr1 :27561935C> T
`g.chr1:1030124C>T
`g.chr1: 1025272G>C
`g.chr2:178189966G>A
`g.chr6 32247183C>T
`g .ch r1: 1 00055259G>A
`g.chr15:87199676G>A
`g.chr22:24410762G>A
`g.chr8:131966156C>T
`g.chr7:45498/l85C> T
`
`g.chr1 o: 1395335G>A (homozygous)
`
`g.chr1 :151373693C>T
`g,chr11:129783713C>T
`g.chr1 :157974131G>A
`g chr12:42132735C> T
`g.chr12:4213401 OT>C
`g.chr15:98512929A>G
`g chr9:133349273G>A
`g.cMl:133337114G>A
`g.chr21 :27132153C>T
`
`g.chr4: 176273643C> T (homozygous)
`
`g.chr4:176272525T>C
`g.chr8:24240084C>T
`g.chr8:39656829C> T
`g.chr8:39644808T>C
`g,chr1 :151842802G>A
`g.chr10:127796641G>A
`
`g.chrX 126910589A>T (homozygous)
`
`Br16X
`Br15X
`Br27P
`Br27P
`Br07X
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br05X
`Br27P
`Br27P
`Br27P
`Br17X
`Br07X
`Br27P
`Br27P
`Br23X
`Br17X
`Br27P
`Br27P
`Br27P
`Br15X
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br15X
`Br27P
`Br27P
`Br17X
`Br27P
`Br27P
`Br20P
`Br27P
`Br27P
`Br27P
`Br07x
`Br07X
`Br26X
`Br03X
`Br13X
`Br27P
`Br27P
`Br15X
`
`CCDS11966.1
`CCDS2492.1
`CCDS11130.1
`CCDS11084.1
`NM_018436
`CCDS9155.1
`CCDS3034.1
`CCDS10163.1
`CCDS7443.1
`CCDS194.1
`CCDS6805.1
`CCDS6805.1
`CCDS5622.1
`CCDS14329.1
`CCDS14329.1
`NM_007200
`NM_007200
`NM_0072DO
`CCDS9383.1
`NM_017977
`NM_017977
`NM_017651
`
`NM_001029882
`
`NM_198576
`NM_ 198576
`CCDS2275.1
`CC□S4744.1
`CCDS759.1
`NM_001135
`CCDS13832.1
`CCDS6363.1
`Nl\1_021116
`CCDS7C58.1
`CCDS1071.1
`NM_007037
`CCDS1223.1
`NM_175851
`NM_175851
`CCDS10383.1
`CCDS6970.1
`CCDS6970.1
`NM_006988
`CCDS3823.1
`CCDS3823.1
`NM_D14265
`CCDS6113.1
`CCDS6113.1
`CCDS1084.1
`CCDS7653.1
`CCDS14611.1
`
`ALPK2
`ALPI
`
`ALOXE3
`ALOX12
`
`ALLC
`ALDH2
`ALDH1L1
`ALDH1A2
`ALDH18A1
`AKR?A2
`AKNA
`AKNA
`AKAP9
`AKAP4
`AKAP4
`AKAP13
`AKAP13
`AKAP13
`AKAP11
`AJM1L
`AJM1L
`AHl1
`AHDC1
`AGRN
`AGRN
`AGPS
`AGPAT1
`
`AGL
`AGC1
`
`ADRBK2
`ADCYB
`ADCY1
`ADARB2
`
`ADAR
`
`ADAMTS8
`ADAMTS4
`ADAMTS20
`ADAMTS20
`ADAMTS17
`ADAMTS13
`ADAMTS13
`ADAMTS1
`ADAM29
`ADAM29
`ADAM28
`ADAM18
`ADAM18
`ADAM15
`ADAM12
`ACTRT1
`
`Rigel Exhibit 1008
`Page 12 of 180
`
`

`

`> ....
`
`1,0
`-....J
`.i;...
`1,0
`N
`N
`0
`
`(,H
`
`---
`....
`....
`0
`N
`rJJ
`c
`....
`....
`....
`0
`N
`....
`.....
`=-
`....
`....
`
`('D
`('D
`
`rJJ
`
`0
`N
`N
`N
`'?
`('D
`rJJ
`
`~
`
`=
`.... 0
`.....
`...
`=
`=
`0
`....
`.....
`....
`"e
`"e
`>
`('D = .....
`~ .....
`""O
`
`~
`(')
`
`-
`
`~
`(')
`
`-.
`
`O"
`""O
`
`~
`cp·
`.,,
`
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`INDEL
`
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`Splice Site
`Missense
`Missense
`Missense
`
`Synonymous
`Synonymous
`Synonymous
`
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`Splice Site
`Splice Site
`Synonymous
`Synonymous
`
`M1ssense
`
`Synonymous
`
`M1ssense
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`
`Missense
`Splice s,te
`Missense
`Mis sense
`Nonsense
`
`Synonymous
`Synonymous
`Synonymous
`
`Missense
`
`Synonymous
`
`p.I201V
`p.R184H
`p.D109N
`p.G1043R
`p.D282N
`
`p.S9F
`
`p.R84W
`p.A215V
`Unknown
`p.P84L
`p.I105V
`p.P582Q
`p.T161 I
`p.P16S
`p.G414E
`Splice Site
`p.E142K
`p.R199H
`p.S1124L
`p.C34C
`p.G187G
`p.A749A
`p.A79T
`p.A29T
`p.E170K
`p.E2802K
`p.E1674G
`p.F592S
`Splice Site
`Splice Site
`p.03500
`p.sns
`p.H146P
`p.E197E
`p.S1085N
`p.P2097L
`p.N190S
`p.G658S
`p.P1035S
`p.A199A
`p.T1851I
`Splice Site
`p.R466H
`p.G271 R
`p.Q135X
`p.E660E
`p.Y117Y
`p.L471 L
`p.V1541I
`p.T1873T
`
`c.601A>G
`c.551G>A
`c.325G>A
`c.3127G>C
`c.844G>A
`c.26C>T
`c.250C>T
`c.644C>T
`
`UTR-2_ 1 delACA
`
`c.251C>T
`c.313A>G
`c.1745C>A
`c.482C>T
`c.46C>T
`
`c.1241G>A
`IVS9+3A>C
`c.424G>A
`c.596G>A
`c.3371C>T
`c.102C>T
`c.561G>A
`c.2247C>T
`c.235G>A
`c.85G>A
`c.508G>A
`c.8404G>A
`c.5021A>G
`c.1775T>C
`IVS8+1G>A
`IVS5+1G>A
`c.1050G>A
`c.216C>T
`c.437A>C
`c.591G>A
`c.3254G>A
`c.6290C>T
`c.569A>G
`c.1972G>A
`c.3103C>T
`c.597C>T
`c.5552C>T
`IVS6-3C>T
`c.1397G>A
`c.811G>A
`c.403C>T
`c.1980G>A
`c.351C>T
`c.1411C>T
`c.4621G>A
`c.5619C>T
`
`g.chr1: 173733513A>G
`g.chr1 :173733563G>A
`g.chr20:32320560G>A
`g.chr1 :152262607G>C
`g.chr17:7017734G>A
`g.chr1:197816276C>T
`g.chr12:106671712C>T
`
`g.chr7:94801932C> T
`
`g.chrX:2871804_2871802delACA
`
`g.chr22:37821842C> T
`g.chr15:78549732A>G
`g.chr15:78659938C>A
`g.chr12:1 OD292678C> T
`g.chr1 :26707082C>T
`g.chr1 :26740387G>A
`g .chrX:62646878A>C
`g.chr16272477G>A
`g.chr22:L3451484G>A
`g.chr14:31632997C> T
`g.chrX:152708075C> T
`g.chr4:83603788G>A
`g.chrX:66720414C> T
`g.chr1:151108533G>A
`g.chr3:37433846G>A
`g.chr22:37802017G>A
`g.chr2:21142988G>A
`g.chr2:21146371A>G
`g.chr2:21162905T>C
`g.chr11 :43306005G>A
`g.chr3:11329895G>A
`g.chr5:77507409G>A
`g.chr12:47152930C> T
`g.chr3:15753569A>C
`g.chr9:701831 G>A
`g.chr18:924651 SG>A
`g.chr16:87874161C> T
`g.chr13:110343498A>G
`g.chr2:241171315G>A
`
`g.chr10:61538664C>T (homozygous)
`
`g.chr4:114515860C>T
`g.chr4:114632930C> T
`g.chr1 O: 71544885C> T
`
`g.ch r1 O: 116036087G>A (homozygous)
`
`g.chr2:201997816G>A
`g.chr3:46703608C> T
`g.chr3:46693184G>A
`g.chr1 :21634962C> T
`g.chr1 :21649283C> T
`g.chr15:83204060G>A
`g.chr18:54300218C> T
`
`Br04X
`Br9PT
`Br07X
`Br15X
`Br27P
`Br27P
`Br27P
`Br27P
`Br9PT
`Br03x
`Br11P
`Br15X
`Br14X
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br04X
`Br12P
`Br27P
`BrOSX
`Br27P
`Br07X
`Br08X
`Br27P
`Br27P
`Br27P
`13r27P
`Br27P
`Br9PT
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br17X
`Br27P
`Br27P
`Br27P
`Br15X
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br26X
`Br27P
`
`CCDS1319.1
`CCDS1319.1
`CCDS 13232.1
`CCDS1113.1
`CCDS11089.1
`
`E NST00000344317
`
`NM_203436
`CCDS5641.1
`CCDS14122.1
`CCDS13985.1
`NM_014862
`NM_014862
`NM_001177
`CCDS285.1
`CCDS285.1
`NM_015185
`CCDS10404.1
`CCDS14058.1
`NM_001173
`CCDS14736.1
`
`ENST00000286794
`
`CCDS14387.1
`CCDS1065.1
`NM_178339
`CCDS13984.1
`CCDS1703.1
`CCDS1703.1
`CCDS1703 1
`NM_006595
`CCDS2605.1
`CCDS4041.1
`NM_012404
`NM_015199
`CCDS6441.1
`CCDS11843.1
`NM_013275
`CCDS9520.1
`CCDS2536.1
`CCDS7258.1
`CCDS3702.1
`CCDS3702.1
`CCDS7297.1
`CCDS7589.1
`CCDS2346.1
`CCDS2743.1
`CCDS2743.1
`CCDS217.1
`CCDS217.1
`CCDS10333.1
`CCDS11966.1
`
`ASTN
`ASTN
`ASIP
`ASH1L
`ASGR1
`ASCL5
`ASCL4
`ASB4
`ARSE
`ARP10
`ARNT2
`ARNTZ
`ARL1
`ARID1A
`ARID1A
`ARHGEF9
`ARHGDIG
`ARHGAP8
`ARHGAP5
`ARHGAP4
`
`ARD1B
`
`AR
`
`AQP10
`APRG1
`
`APOBEC3G
`
`APOB
`APOB
`APOB
`APl5
`APG7L
`AP3B1
`ANP32D
`ANKRD28
`ANKRD15
`ANKRD12
`ANKRD11
`ANKRD10
`ANKMY1
`
`ANK3
`ANK2
`ANK2
`AMID
`AMACO
`
`ALS2CR12
`
`ALS2CL
`ALS2CL
`
`ALPL
`ALPL
`ALPK3
`ALPK2
`
`Rigel Exhibit 1008
`Page 13 of 180
`
`

`

`0
`N
`N
`N
`'?
`('D
`rJJ
`
`~
`
`=
`0
`....
`.....
`O" -
`....
`=
`=
`0
`....
`.....
`"e -
`....
`~
`('D =
`.....
`~ .....
`""O
`
`~
`(')
`
`""O
`
`~
`(')
`
`---
`....
`....
`0
`N
`rJJ
`c
`....
`....
`0 ....
`....
`.....
`rJJ =-
`....
`....
`
`> ....
`
`1,0
`--.J
`.i;...
`1,0
`N
`N
`0
`
`~
`
`~
`
`('D
`('D
`
`0
`c1'i"
`77
`
`Synonymous
`Synonymous
`Synonymous
`Synonymous
`
`Missense
`Splice Site
`Missense
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`
`Nonsense
`Missense
`Missense
`Mlssense
`Missense
`Missense
`
`Synonymous
`Synonymous
`
`INDEL
`
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`Synonymous
`
`Missense
`Missense
`Missense
`Missense
`Splice Site
`Missense
`Missense
`
`Synonymous
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`
`Missense
`Missense
`Missense
`
`Synonymous
`
`p.G1744G
`p.R315R
`p.A3140A
`p.H779H
`p.A107T
`Splice Site
`
`p.T310I
`p.R312H
`p.P322S
`p.A65T
`p.P640L
`p.A248A
`p.F961K
`p.Y138Y
`p R203H
`p.L402V
`p.Q529Q
`p.R1513X
`p.G159S
`p.E131G
`p.T296I
`p.A137T
`p.P404S
`p.E447E
`p,R1002R
`
`fs
`
`p.P1413L
`p.S124F
`p.P277S
`p.G245E
`p.A734V
`p.P1048S
`p,P89P
`
`p,Q1273Q
`p,T317N
`p.A482V
`p.G341 E
`p.A1358T
`Splice Si:e
`p.G356D
`p.L 1681
`p.N706N
`p.G704G
`pV759M
`p.A898V
`p.G418G
`p.Q712E
`p.L519F
`p.F1136I
`
`p.N3N
`
`c.5232G>A
`c.943A>C
`c.9420C>T
`c.2337C>T
`c.319G>A
`
`IVS14+1G>A
`
`c.929C>T
`c.935G>A
`c.964C>T
`c.193G>A
`c.1919C>T
`c.744C>G
`c,2881G>A
`c.414C>T
`c.608G>A
`c.1204C>G
`c.1587G>A
`c.4537C>T
`c.475G>A
`c.392A>G
`c.887C>T
`c.409G>A
`c.1210C>T
`c.1341G>A
`c.3006G>A
`c.614dupA
`c.4238C>T
`c.371C>T
`c.829C>T
`c.734G>A
`c.2201C>T
`c.3142C>T
`c.267G>A
`c.3819G>A
`c.950C>A
`c,1445C>T
`c.1022G>A
`c.4072G>A
`IVS1-3A>T
`c.1067G>A
`c.502T>A
`c.2118C>T
`c.2112C>T
`c.2275G>A
`c.2693C>T
`c.1254G>A
`c.2134C>G
`c.1555C>T
`c.3406T>A
`
`c.9C>T
`
`g.chr10:93776485G>A
`g.chr4:15409723A>C
`g.chr3:49673702C> T
`g.chr3:9760305C>T
`
`g.chr6: 166749339G>A
`g.chr14:104756379G>A
`g.chr7:139953397C>T
`g.chr19: 17698128G>A
`g.chr3:114474608C>T
`g.chr9:16572987G>A
`g.chr7:33965986C>T
`g.chr4:82324498C>G
`g.chr2:32565957G>A
`g.chr5:70344085C> T
`g.chr2: 127537450G>A
`g.chr2: 127524280C>G
`g.chr20:17423130G>A
`g.chrX:39670947C> T
`g.chr3: 188930420G>A
`g.chr14:22847208A>G
`g. ch r19: 54865490C> T
`g.chr20:29717517G>A
`g.chr1 ·93760355C> T
`g.chr14:34333728G>A
`g.chr1:168241275G>A
`g.chr10:29011167dupA
`g.chr1 :31865600C>T
`g,chr11.63795668C>T
`g,chr11 :76429072C>T
`g.chr17:76790689G>A
`g,chr17:60962242C>T
`g.chr7:69699995C>T
`g.chr6:16436254G>A
`g.chr10:117476771G>A
`g.chr18:53512891C>A
`g.chr18:53503330C>T
`g.chr4:42421311 G>A
`g.chr13:51407782G>A
`g.chr1 :195237514A>T
`g.chr3:10392328G>A
`g.chr12:88531401T>A
`g.chr17:3787662C>T
`g.chr16:28820696C>T
`g.chr1 :156918456G>A
`g.ch r1: 17060192C> T
`g.chr19:19626975G>A
`g.chr13:24178566C>G
`g.chr13:24170838C> T
`g.chr5:159958513T>A
`g.chr2:24061283C>T
`
`Br27P
`Br04X
`Br27P
`Br27P
`Br27P
`Br20P
`Br27P
`Br08X
`Br27P
`Br27P
`Br17X
`Br08X
`Br27P
`Br26X
`Br27P
`Br07X
`Br27P
`Br08X
`Br27P
`Br9PT
`Br27P
`Br27P
`Br17X
`Br27P
`Br27P
`Br06X
`Br25X
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br16X
`Br27P
`Br27P
`Br27P
`Br26X
`Br27P
`Br12P
`Br9PT
`Br27P
`Br27P
`Br27P
`Br27P
`Br13X
`Br27P
`Br03X
`Br27P
`
`CCDS7419.1
`CCDS3416.1
`CCDS2800.1
`CCDS2575.1
`CCDS5293.1
`CCDS10001.1
`CCDS5863.1
`NM_D18174
`CCDS2971.1
`CCDS6482.1
`CCDS5442.1
`CCDS3588.1
`NM_016252
`CCDS4009.1
`CCDS2137,1
`CCDS2137.1
`CCDS13126.1
`CCDS14250.1
`CCDS3289.1
`CCDS9591.1
`CCDS12776.1
`CCDS13188.1
`CCDS745.1
`CCDS9651.1
`CCDS1296.1
`CCDS7162.1
`CCDS346.1
`CCDS8065.1
`NM_138706
`
`NM_001009811
`CCDS 11662.1
`CCDS5539.1
`NM_000332
`CCDS7592.1
`CCDS11965.1
`CCDS11965.1
`CCDS3466.1
`NM_000053
`CCDS1396.1
`CC□S2601.1
`CCDS9035.1
`CCDS11041.1
`CCDS10643.1
`CCDS1196.1
`CCDS175.1
`NM_020410
`NM_001676
`NM_001676
`
`ENST00000327245
`ENST00000295142
`
`BTAF1
`BST1
`BSN
`BRPF1
`BRP44L
`
`BRF1
`BRAF
`
`BPY2IP1
`
`BOC
`BNC2
`BMPER
`BMP3
`BIRC6
`BIRC1
`BIN1
`BIN1
`BFSP1
`BCOR
`BCL6
`BCL2L2
`BCL2L12
`BCL2L 1
`BCAR3
`BAZ1A
`BAT2O1
`BAMBI
`BAl2
`BAD
`
`B3Gn-T6
`
`AZl1
`AXIN2
`AUTS2
`ATXN1
`ATRNL1
`ATP8B1
`ATP8B1
`ATP8A1
`ATP7B
`
`ATP6V1G3
`
`ATP282
`ATP281
`ATP2A3
`ATP2A1
`ATP1A2
`ATP13A2
`ATP13A1
`ATP12A
`ATP12A
`ATP10B
`ATAD2B
`
`Rigel Exhibit 1008
`Page 14 of 180
`
`

`

`> ....
`
`1,0
`-....J
`.i;...
`1,0
`N
`N
`0
`
`~
`
`0
`.i;...
`
`('D
`('D
`
`rJJ
`
`---
`....
`....
`0
`N
`rJJ
`c
`....
`....
`....
`....
`.....
`=-
`....
`....
`
`0
`N
`N
`N
`"e
`('D
`rJJ
`
`~
`
`.
`
`=
`.... 0
`.....
`...
`=
`=
`0
`....
`.....
`....
`"e
`~
`('D = .....
`~ .....
`""O
`
`~
`(')
`
`-
`
`~
`(')
`
`-.
`
`O"
`""O
`
`;::;
`co·
`"T7
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Nonsense
`
`Synonymous
`Splice Site
`Synonymous
`
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`
`Missense
`Mis sense
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`Synonymous
`Synonymous
`Synonymous
`
`Missense
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`Synonymous
`Synonymous
`Synonymous
`
`Missense
`Missense
`Nonsense
`Missense
`Missense
`Missense
`Nonsense
`
`Synonymous
`
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`
`p.I402I
`p.A382V
`p.S38S
`p.W283X
`p.K1003K
`Splice Site
`p.Y2222Y
`p.A1038T
`p.C345Y
`p.S47F
`p.S10F
`p.R310P
`p.S701R
`p.A255V
`p.G272G
`p.P913S
`p.R2360Q
`p.A492T
`p.K195K
`p.L 192S
`p.P166P
`p.G300R
`p.L32L
`p.C579C
`p.D461D
`p.D376D
`p.R30H
`p.R241C
`p.K400N
`pS384F
`p.V291 I
`p.S28S
`p.P624L
`p.R247R
`p.E639E
`
`p.I48I
`p.L307L
`p.S72N
`p.R2S7W
`p.E119X
`p.G561V
`p.P164S
`p.E1262K
`p.W40X
`p.P98P
`p.G310E
`p.H491Y
`p.V127I
`p.A303T
`p.R326R
`
`c.1206C>T
`c.1145C>T
`c.114C>T
`c.849G>A
`c.3009G>A
`IVS39-3T>A
`c.6666C>T
`c.3112G>A
`c.1034G>A
`c.140C>T
`c.29C>T
`c.929G>C
`c.2103C>G
`c.764C>T
`c.816C>T
`c.2737C>T
`c.7079G>A
`c.1474G>A
`c.585G>A
`c.575T>C
`c:498G>A
`c.898G>A
`c.94C>T
`c.1737C>T
`c.1383C>T
`c.1128C>T
`c.89G>A
`c.721C>T
`c.1200G>C
`c.1151C>T
`c.871G>A
`c.84C>T
`c.1871C>T
`c.741G>A
`c.1917G>A
`c.144C>T
`c.921G>A
`c.215G>A
`c.889C>T
`c.355G>T
`c.1682G>T
`c.490C>T
`c.3784G>A
`c.119G>A
`c.294G>A
`c.929G>A
`c.1471C>T
`c.379G>A
`c.907G>A
`c.978G>A
`
`g.chr20:31355490C>T
`g.chr20:31355429C>T
`g.chr20:35965280C>T
`g.chr20:43435985G>A
`g.chr12·30754328G>A
`g.chr1 :43577029T>A
`g.chr1 :43582385C>T
`g.chr1 :74750303G>A
`g.chr1 :180234495G>A
`g.chr1:19695301C>T
`g.chr1 :203059417C>T
`g.chr19:3569902G>C
`g.chr18:63330753C>G
`g.chr18:42087709C>T
`g.chr17:2149981C>T
`g.chr17:2086668C>T
`g.chr17:75961478G>A
`g.chr16:254837G>A
`g.chr15:87920406G>A
`g.chr15:87920396T>C
`g.chr15:22472605G>A
`g.chr14:94991706G>A
`g.chr14:73276371 C>T
`g.chr14:51264389C>T
`g.chr14:90735956C>T
`g.chr14:90725215C>T
`g.chr14:44045852G>A
`g.chr14:80398895C>T
`g.chr14:76965843G>C
`g.chr14:101878133C> T
`g.chr14:73894110G>A
`g.chr12:102297915C> T
`g .chr12:26955452C> T
`g.chr11 :63812220G>A
`g.chr11:61264574G>A
`g.chr10:115516387C>T
`g.chr10:106118299G>A
`g.chr10:50203424G>A
`
`g.chr10:49710728C>T (homozygous)
`
`g.chr10:11948752G>T
`g.chr10:100133609G> T
`g.chr10:104562539C>T
`g.chr10:5843371 G>A
`g.chr16:20609893G>A
`
`g.chr5:180407717G>A (homozygous)
`
`g.chr6:32471943G>A
`g.chrX:100417280C>T
`g.chr4:76033011 G>A
`g.chr20: 11851652G>A
`g.chr15:81489969G>A
`
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br15X
`Br27P
`Br27P
`Br04X
`Br25X
`Br07X
`Br27P
`Br27P
`Br27P
`Br17P
`Br27P
`Br17X
`Br23X
`Br27P
`Br05X
`Br02X
`Br27P
`Br27P
`Br17X
`Br26X
`Br26X
`Br27P
`Br9PT
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br14X
`Br04X
`Br27P
`Br27P
`Br05X
`Br27P
`Br07X
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`
`CCDS13218.1
`CCDS13218.1
`CCDS13299.1
`CCDS13352.1
`CCDS8720.1
`NM_015284
`NM_015284
`
`NM_001002912
`
`CCDS1355.1
`NM_001032363
`NM_001025592
`
`ENST00000221899
`
`CCDS11995.1
`NM_001008239
`CCDS11016.1
`CCDS11016.1
`NM_020914
`CCDS 10402.1
`
`ENST00000268138
`ENST00000268138
`
`CCDS10015.1
`CCDS9935.1
`CCDS9819.1
`CCDS9704.1
`NM_024952
`NM_024952
`CCDS9679.1
`NM_152-!46
`CCDS9862.1
`NM_018335
`CCDS9833.1
`NM_198521
`CCDS87081
`CCDS8066.1
`NM_006133
`CCDS7583.1
`
`NM_001008723
`
`ENSTD0000323868
`ENST00000265453
`
`CCDS7085.1
`CCDS7474.1
`CCDS7540.1
`
`ENST00000263123
`
`CCDS10587.1
`CCDS4460.1
`CCDS4749.1
`CCDS14482.1
`CCDS3566.1
`CCDS13113.1
`CCDS10322.1
`
`C20orf114
`C20orf114
`C20orf102
`C20orf10
`C1QDC1
`C1orf84
`C1orf84
`C1orf173
`C1orf16
`C1orf151
`C1orf147
`C19orf29
`C18orf4
`C18orf25
`C17orf31
`C17orf3I
`C17orf27
`C16orf9
`C15orf42
`C15orf42
`C15orf2
`C14orf49
`C14orf43
`C14orf31
`C14orf159
`C14orf159
`C14orf155
`C14orf145
`C14orf133
`C14orf131
`C14orf115
`C12orf42
`C12orf11
`C110RF4
`C11orf11
`C10orf81
`C10orf80
`C1 Oorf71
`C10orf64
`C10orf47
`C10orf33
`C10orf26
`C10orf18
`BUCS1
`BTNL9
`BTNL2
`BTK
`BTC
`
`BTBD3
`BTBD1
`
`Rigel Exhibit 1008
`Page 15 of 180
`
`

`

`=
`.... 0
`~ .....
`....
`= O"
`=
`..... ....
`...
`"e
`~
`= .....
`~ .....
`""O
`
`-
`
`""O
`
`> ....
`
`1,0
`-....J
`.i;...
`1,0
`N
`N
`0
`
`(,H
`
`---
`....
`....
`0
`N
`rJ'1
`c
`....
`....
`....
`0
`Ul
`....
`.....
`rJ'1 =-
`....
`....
`
`('D
`('D
`
`0
`N
`N
`N
`'?
`('D
`rJ'1
`
`~
`
`(')
`
`0
`
`~
`(')
`
`-.
`
`('D
`
`0
`,] cp·
`
`Synonymous
`Synonymous
`
`M·,ssense
`Nonsense
`
`Synonymous
`Synonymous
`
`Missense
`Missense
`Missense
`
`Synonymous
`Synonymous
`Synonymous
`
`Missense
`Missense
`Missense
`
`3'UTR
`
`Missense
`Missense
`
`INDEL
`
`Synonymous
`
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`Missense
`Missense
`Missense
`
`Synonymous
`
`Missense
`
`Synonymous
`Synonymous
`
`Missense
`
`Synonymous
`
`Missense
`Missense
`
`Synonymous
`
`Missense
`Missense
`Missense
`
`Synonymous
`
`Missense
`Missense
`Missense
`
`Synonymous
`
`INDEL
`
`Synonymous
`
`p.D1507D
`p.R152R
`p.V1499M
`p.Q1159X
`p.117351
`p.112241
`p.G1047E
`
`p.A49D
`p.P1994S
`p.G152G
`p.L635L
`p.G6G
`p.K18T
`p.R117K
`p T7691
`3'UTR
`
`p.R581Q
`p.K70
`
`fs
`
`p,T59T
`p.P543L
`p.R484H
`p.V50I
`p.G53D
`p.R551R
`p.G611D
`p.N166N
`p.G290D
`p.S157F
`p.R152C
`p.R215W
`p.R69R
`p.P190S
`p.E481 E
`p.S568S
`p,A739S
`p.V712V
`p.V190M
`
`p.K3N
`p.H73H
`p.E108K
`p.D217N
`p.L453F
`p.A17A
`p.E375V
`p.T270M
`p.S605T
`p,13801
`
`fs
`
`p.R1014R
`
`c.4521C>T
`c.456C>T
`c.4495G>A
`c.3475C>T
`c.5205C>T
`c.3672C>T
`c.3140G>A
`c.146C>A
`c.5980C>T
`c.456G>A
`c.1903C>T
`c.18G>A
`c.53A>C
`c.350G>A
`c.2306C>T
`UTR+1C>T
`c.1742G>A
`
`c.19A>C
`
`c. 109_ 112delGAAG
`
`c.177C>T
`c.1628C>T
`c.1451G>A
`c.148G>A
`c.158G>A
`c.1653G>A
`c.1832G>A
`c.498C>T
`c.869G>A
`c.470C>T
`c.454C>T
`c.643C>T
`c.207G>A
`c.568C>T
`c.1443G>A
`c.1704T>C
`c.2215G>T
`c.2136C>T
`c.568G>A
`
`c.9A>T
`c.219C>T
`c.322G>A
`c.649G>A
`c.1357C>T
`c.51C>T
`c.1124A>T
`c.809C>T
`c.1813T>A
`c.1140C>T
`c.111delA
`c.3042G>A
`
`g.chr1 :197748332C>T
`g.chr22:38321132C>T
`g.chr16.1201735G>A
`g,chr16:1199144C>T
`g.chr1: 178476959C> T
`g.chr1 :178439999C> T
`g.chr12:2585197G>A
`g.chr12:2094747C>A
`g.chr19:1318451 SC>T
`g.chr12:119561719G>A
`g.chr22:22785070C> T
`g.chr2:231450239G>A
`g.chr8:86564771A>C
`g,chr9:129462058G>A
`g.chr9: 108878134C>T
`g.chr9:36152520C>T
`
`g.chr9: 124813204G>A (homozygous)
`
`g.chr8: 125037438A>C
`
`g.chr8: 146199285_ 146199288delGAAG
`
`g.chr1 :57137786C>T
`g.chr1:57107246C> T
`g.chr1 :57090167G>A
`g.chr7:31508388G>A
`g.chr6:118103684G>A
`g.chr6:111987373G>A
`g.chr6:31940771G>A
`g.chr6:123373937C>T
`g.chr6:31786174G>A
`
`g.chr6:121680365C> T (homozygous)
`g.chr6:121680381C>T (homozygous)
`
`g.chr6:99878221 C> T
`g.chr6:88180261 G>A
`g.chr6:88131789C>T
`g.chr6:74191797G>A
`g.chr6:14 7063896T>C
`g,chr5:41189744G>T
`g.chr5:41189823C> T
`g .chr19:52515442G>A
`g.ch r4:71277680A>T
`g.chr3:62292081 C>T
`g.chr2:75845376G>A
`g.chr2:101332905G>A
`g.chr2:219872581C>T
`g.chr21 :45178476C>T
`g.chr21 :36508719A>T
`g.chr21 :44772876C> T
`g.chr21:44749134T>A
`g.chr21:44771612C> T
`g.chr20:18753915delA
`g.chr20 16307605G>A
`
`Br27P
`Br27P
`Br05X
`Br15X
`Br27P
`Br27.P
`Br27P
`Br17X
`Br15X
`Br27P
`Br27P
`Br27P
`Br15X
`Br27P
`Br04X
`Br27P
`Br07x
`Br9PT
`Br29P
`Br27P
`Br27P
`Br03X
`Br20P
`Br27P
`Br27P
`Br27P
`Br27P
`Br27P
`Br04X
`Br04X
`Br27P
`Br27P
`Br27P
`Br27P
`Br9PT
`Br13X
`Br27P
`Br9PT
`Br03X
`Br27P
`Br27P
`Br27P
`Br02X
`Br27P
`Br29P
`Br05X
`Br9PT
`Br17X
`Br08X
`Br27P
`
`CCDS1407.1
`NM_G01003406
`
`NM_021098
`NM_021098
`NM_000721
`NM_000721
`NM_000719
`NM_000719
`NM_000068
`CCDS9204.1
`CCDS 13823.1
`CCDS2478.1
`CCDS6239.1
`NM_199350
`NM_032012
`CCDS6598.1
`NM_173690
`
`NM_001039112
`NM_001039382
`
`NM_000066
`NM_OOOD66
`CCDS606.1
`CCDS5436.1
`CCDS5118.1
`CCDS5092.1
`CCDS4724.1
`NM 001010852
`NM_001003693
`
`NM_152730
`NM_152730
`NM_032511
`CCDS5009 1
`NM_001010868
`
`CCDS49781
`
`ENST00000326929
`
`CCDS3936.1
`CCDS3936.1
`NM_001736
`CCDS3537.1
`CCDS2896.1
`CCDS1961.1
`CCDS2050.1
`CCDS2434.1
`NM_058189
`CCDS13643.1
`CCDS13712.1
`CCDS13712.1
`CCDS13712.1
`
`ENST00000278779
`
`CCDS13122.1
`
`CACNA1S
`CACNA11
`CACNA1H
`CACNA1H
`CACNA1E
`CACNA1E
`CACNA1C
`CACNA1C
`CACNA·IA
`
`CABP1
`CABIN1
`CAB39
`
`CA2
`
`C9orf50
`C9orf5
`C9orf19
`C9crf126
`C80RFK23
`
`CBor/77
`
`C8B
`C8B
`CSA
`
`C7~rf16
`C6orf68
`C6orf4
`C6orf29
`C6orf213
`C6orf21
`C6orf170
`C6orf170
`C6orf168
`C6orf'65
`C6orf163
`C6orf150
`C6orf103
`
`C6
`C6
`
`C5AR1
`C4orf7
`C3orf14
`C2orf3
`C2orf29
`C2orf17
`C21 or/69
`C21orf5
`C21 orf29
`C21orf29
`C21 orf29
`C2Dorf78
`C20orf23
`
`Rigel Exhibit 1008
`Page 16 of 180
`
`

`

`('D
`
`rJ'1
`
`0
`N
`N
`N
`'?
`('D
`rJ'1
`
`~
`
`=
`0
`....
`.....
`O" -
`....
`=
`=
`0
`....
`~ .....
`....
`"e
`~
`('D = .....
`~ .....
`""O
`
`~
`(')
`
`""O
`
`-
`
`