                         SEQUENCE LISTING

<110>  THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE 
       SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
 
<120>  METHODS FOR TREATING BILE DUCT CANCERS WITH TIVOZANIB

<130>  4239-107547-02

<160>  2     

<170>  PatentIn version 3.5

<210>  1
<211>  1096
<212>  PRT
<213>  Homo sapiens

<400>  1

Met Ala Asp His Val Gln Ser Leu Ala Gln Leu Glu Asn Leu Cys Lys 
1               5                   10                  15      


Gln Leu Tyr Glu Thr Thr Asp Thr Thr Thr Arg Leu Gln Ala Glu Lys 
            20                  25                  30          


Ala Leu Val Glu Phe Thr Asn Ser Pro Asp Cys Leu Ser Lys Cys Gln 
        35                  40                  45              


Leu Leu Leu Glu Arg Gly Ser Ser Ser Tyr Ser Gln Leu Leu Ala Ala 
    50                  55                  60                  


Thr Cys Leu Thr Lys Leu Val Ser Arg Thr Asn Asn Pro Leu Pro Leu 
65                  70                  75                  80  


Glu Gln Arg Ile Asp Ile Arg Asn Tyr Val Leu Asn Tyr Leu Ala Thr 
                85                  90                  95      


Arg Pro Lys Leu Ala Thr Phe Val Thr Gln Ala Leu Ile Gln Leu Tyr 
            100                 105                 110         


Ala Arg Ile Thr Lys Leu Gly Trp Phe Asp Cys Gln Lys Asp Asp Tyr 
        115                 120                 125             


Val Phe Arg Asn Ala Ile Thr Asp Val Thr Arg Phe Leu Gln Asp Ser 
    130                 135                 140                 


Val Glu Tyr Cys Ile Ile Gly Val Thr Ile Leu Ser Gln Leu Thr Asn 
145                 150                 155                 160 


Glu Ile Asn Gln Val Ser Ala Thr Ala Phe Leu Ile Glu Ala Asp Thr 
                165                 170                 175     


Thr His Pro Leu Thr Lys His Arg Lys Ile Ala Ser Ser Phe Arg Asp 
            180                 185                 190         


Ser Ser Leu Phe Asp Ile Phe Thr Leu Ser Cys Asn Leu Leu Lys Gln 
        195                 200                 205             


Ala Ser Gly Lys Asn Leu Asn Leu Asn Asp Glu Ser Gln His Gly Leu 
    210                 215                 220                 


Leu Met Gln Leu Leu Lys Leu Thr His Asn Cys Leu Asn Phe Asp Phe 
225                 230                 235                 240 


Ile Gly Thr Ser Thr Asp Glu Ser Ser Asp Asp Leu Cys Thr Val Gln 
                245                 250                 255     


Ile Pro Thr Ser Trp Arg Ser Ala Phe Leu Asp Ser Ser Thr Leu Gln 
            260                 265                 270         


Leu Phe Phe Asp Leu Tyr His Ser Ile Pro Pro Ser Phe Ser Pro Leu 
        275                 280                 285             


Val Leu Ser Cys Leu Val Gln Ile Ala Ser Val Arg Arg Ser Leu Phe 
    290                 295                 300                 


Asn Asn Ala Glu Arg Ala Lys Phe Leu Ser His Leu Val Asp Gly Val 
305                 310                 315                 320 


Lys Arg Ile Leu Glu Asn Pro Gln Ser Leu Ser Asp Pro Asn Asn Tyr 
                325                 330                 335     


His Glu Phe Cys Arg Leu Leu Ala Arg Leu Lys Ser Asn Tyr Gln Leu 
            340                 345                 350         


Gly Glu Leu Val Lys Val Glu Asn Tyr Pro Glu Val Ile Arg Leu Ile 
        355                 360                 365             


Ala Asn Phe Thr Val Thr Ser Leu Gln His Trp Glu Phe Ala Pro Asn 
    370                 375                 380                 


Ser Val His Tyr Leu Leu Ser Leu Trp Gln Arg Leu Ala Ala Ser Val 
385                 390                 395                 400 


Pro Tyr Val Lys Ala Thr Glu Pro His Met Leu Glu Thr Tyr Thr Pro 
                405                 410                 415     


Glu Val Thr Lys Ala Tyr Ile Thr Ser Arg Leu Glu Ser Val His Ile 
            420                 425                 430         


Ile Leu Arg Asp Gly Leu Glu Asp Pro Leu Glu Asp Thr Gly Leu Val 
        435                 440                 445             


Gln Gln Gln Leu Asp Gln Leu Ser Thr Ile Gly Arg Cys Glu Tyr Glu 
    450                 455                 460                 


Lys Thr Cys Ala Leu Leu Val Gln Leu Phe Asp Gln Ser Ala Gln Ser 
465                 470                 475                 480 


Tyr Gln Glu Leu Leu Gln Ser Ala Ser Ala Ser Pro Met Asp Ile Ala 
                485                 490                 495     


Val Gln Glu Gly Arg Leu Thr Trp Leu Val Tyr Ile Ile Gly Ala Val 
            500                 505                 510         


Ile Gly Gly Arg Val Ser Phe Ala Ser Thr Asp Glu Gln Asp Ala Met 
        515                 520                 525             


Asp Gly Glu Leu Val Cys Arg Val Leu Gln Leu Met Asn Leu Thr Asp 
    530                 535                 540                 


Ser Arg Leu Ala Gln Ala Gly Asn Glu Lys Leu Glu Leu Ala Met Leu 
545                 550                 555                 560 


Ser Phe Phe Glu Gln Phe Arg Lys Ile Tyr Ile Gly Asp Gln Val Gln 
                565                 570                 575     


Lys Ser Ser Lys Leu Tyr Arg Arg Leu Ser Glu Val Leu Gly Leu Asn 
            580                 585                 590         


Asp Glu Thr Met Val Leu Ser Val Phe Ile Gly Lys Ile Ile Thr Asn 
        595                 600                 605             


Leu Lys Tyr Trp Gly Arg Cys Glu Pro Ile Thr Ser Lys Thr Leu Gln 
    610                 615                 620                 


Leu Leu Asn Asp Leu Ser Ile Gly Tyr Ser Ser Val Arg Lys Leu Val 
625                 630                 635                 640 


Lys Leu Ser Ala Val Gln Phe Met Leu Asn Asn His Thr Ser Glu His 
                645                 650                 655     


Phe Ser Phe Leu Gly Ile Asn Asn Gln Ser Asn Leu Thr Asp Met Arg 
            660                 665                 670         


Cys Arg Thr Thr Phe Tyr Thr Ala Leu Gly Arg Leu Leu Met Val Asp 
        675                 680                 685             


Leu Gly Glu Asp Glu Asp Gln Tyr Glu Gln Phe Met Leu Pro Leu Thr 
    690                 695                 700                 


Ala Ala Phe Glu Ala Val Ala Gln Met Phe Ser Thr Asn Ser Phe Asn 
705                 710                 715                 720 


Glu Gln Glu Ala Lys Arg Thr Leu Val Gly Leu Val Arg Asp Leu Arg 
                725                 730                 735     


Gly Ile Ala Phe Ala Phe Asn Ala Lys Thr Ser Phe Met Met Leu Phe 
            740                 745                 750         


Glu Trp Ile Tyr Pro Ser Tyr Met Pro Ile Leu Gln Arg Ala Ile Glu 
        755                 760                 765             


Leu Trp Tyr His Asp Pro Ala Cys Thr Thr Pro Val Leu Lys Leu Met 
    770                 775                 780                 


Ala Glu Leu Val His Asn Arg Ser Gln Arg Leu Gln Phe Asp Val Ser 
785                 790                 795                 800 


Ser Pro Asn Gly Ile Leu Leu Phe Arg Glu Thr Ser Lys Met Ile Thr 
                805                 810                 815     


Met Tyr Gly Asn Arg Ile Leu Thr Leu Gly Glu Val Pro Lys Asp Gln 
            820                 825                 830         


Val Tyr Ala Leu Lys Leu Lys Gly Ile Ser Ile Cys Phe Ser Met Leu 
        835                 840                 845             


Lys Ala Ala Leu Ser Gly Ser Tyr Val Asn Phe Gly Val Phe Arg Leu 
    850                 855                 860                 


Tyr Gly Asp Asp Ala Leu Asp Asn Ala Leu Gln Thr Phe Ile Lys Leu 
865                 870                 875                 880 


Leu Leu Ser Ile Pro His Ser Asp Leu Leu Asp Tyr Pro Lys Leu Ser 
                885                 890                 895     


Gln Ser Tyr Tyr Ser Leu Leu Glu Val Leu Thr Gln Asp His Met Asn 
            900                 905                 910         


Phe Ile Ala Ser Leu Glu Pro His Val Ile Met Tyr Ile Leu Ser Ser 
        915                 920                 925             


Ile Ser Glu Gly Leu Thr Ala Leu Asp Thr Met Val Cys Thr Gly Cys 
    930                 935                 940                 


Cys Ser Cys Leu Asp His Ile Val Thr Tyr Leu Phe Lys Gln Leu Ser 
945                 950                 955                 960 


Arg Ser Thr Lys Lys Arg Thr Thr Pro Leu Asn Gln Glu Ser Asp Arg 
                965                 970                 975     


Phe Leu His Ile Met Gln Gln His Pro Glu Met Ile Gln Gln Met Leu 
            980                 985                 990         


Ser Thr Val Leu Asn Ile Ile Ile  Phe Glu Asp Cys Arg  Asn Gln Trp 
        995                 1000                 1005             


Ser Met  Ser Arg Pro Leu Leu  Gly Leu Ile Leu Leu  Asn Glu Lys 
    1010                 1015                 1020             


Tyr Phe  Ser Asp Leu Arg Asn  Ser Ile Val Asn Ser  Gln Pro Pro 
    1025                 1030                 1035             


Glu Lys  Gln Gln Ala Met His  Leu Cys Phe Glu Asn  Leu Met Glu 
    1040                 1045                 1050             


Gly Ile  Glu Arg Asn Leu Leu  Thr Lys Asn Arg Asp  Arg Phe Thr 
    1055                 1060                 1065             


Gln Asn  Leu Ser Ala Phe Arg  Arg Glu Val Asn Asp  Ser Met Lys 
    1070                 1075                 1080             


Asn Ser  Thr Tyr Gly Val Asn  Ser Asn Asp Met Met  Ser 
    1085                 1090                 1095     


<210>  2
<211>  1235
<212>  PRT
<213>  Homo sapiens

<400>  2

Met Ser Phe Phe Asn Phe Arg Lys Ile Phe Lys Leu Gly Ser Glu Lys 
1               5                   10                  15      


Lys Lys Lys Gln Tyr Glu His Val Lys Arg Asp Leu Asn Pro Glu Asp 
            20                  25                  30          


Phe Trp Glu Ile Ile Gly Glu Leu Gly Asp Gly Ala Phe Gly Lys Val 
        35                  40                  45              


Tyr Lys Ala Gln Asn Lys Glu Thr Ser Val Leu Ala Ala Ala Lys Val 
    50                  55                  60                  


Ile Asp Thr Lys Ser Glu Glu Glu Leu Glu Asp Tyr Met Val Glu Ile 
65                  70                  75                  80  


Asp Ile Leu Ala Ser Cys Asp His Pro Asn Ile Val Lys Leu Leu Asp 
                85                  90                  95      


Ala Phe Tyr Tyr Glu Asn Asn Leu Trp Ile Leu Ile Glu Phe Cys Ala 
            100                 105                 110         


Gly Gly Ala Val Asp Ala Val Met Leu Glu Leu Glu Arg Pro Leu Thr 
        115                 120                 125             


Glu Ser Gln Ile Gln Val Val Cys Lys Gln Thr Leu Asp Ala Leu Asn 
    130                 135                 140                 


Tyr Leu His Asp Asn Lys Ile Ile His Arg Asp Leu Lys Ala Gly Asn 
145                 150                 155                 160 


Ile Leu Phe Thr Leu Asp Gly Asp Ile Lys Leu Ala Asp Phe Gly Val 
                165                 170                 175     


Ser Ala Lys Asn Thr Arg Thr Ile Gln Arg Arg Asp Ser Phe Ile Gly 
            180                 185                 190         


Thr Pro Tyr Trp Met Ala Pro Glu Val Val Met Cys Glu Thr Ser Lys 
        195                 200                 205             


Asp Arg Pro Tyr Asp Tyr Lys Ala Asp Val Trp Ser Leu Gly Ile Thr 
    210                 215                 220                 


Leu Ile Glu Met Ala Glu Ile Glu Pro Pro His His Glu Leu Asn Pro 
225                 230                 235                 240 


Met Arg Val Leu Leu Lys Ile Ala Lys Ser Glu Pro Pro Thr Leu Ala 
                245                 250                 255     


Gln Pro Ser Arg Trp Ser Ser Asn Phe Lys Asp Phe Leu Lys Lys Cys 
            260                 265                 270         


Leu Glu Lys Asn Val Asp Ala Arg Trp Thr Thr Ser Gln Leu Leu Gln 
        275                 280                 285             


His Pro Phe Val Thr Val Asp Ser Asn Lys Pro Ile Arg Glu Leu Ile 
    290                 295                 300                 


Ala Glu Ala Lys Ala Glu Val Thr Glu Glu Val Glu Asp Gly Lys Glu 
305                 310                 315                 320 


Glu Asp Glu Glu Glu Glu Thr Glu Asn Ser Leu Pro Ile Pro Ala Ser 
                325                 330                 335     


Lys Arg Ala Ser Ser Asp Leu Ser Ile Ala Ser Ser Glu Glu Asp Lys 
            340                 345                 350         


Leu Ser Gln Asn Ala Cys Ile Leu Glu Ser Val Ser Glu Lys Thr Glu 
        355                 360                 365             


Arg Ser Asn Ser Glu Asp Lys Leu Asn Ser Lys Ile Leu Asn Glu Lys 
    370                 375                 380                 


Pro Thr Thr Asp Glu Pro Glu Lys Ala Val Glu Asp Ile Asn Glu His 
385                 390                 395                 400 


Ile Thr Asp Ala Gln Leu Glu Ala Met Thr Glu Leu His Asp Arg Thr 
                405                 410                 415     


Ala Val Ile Lys Glu Asn Glu Arg Glu Lys Arg Pro Lys Leu Glu Asn 
            420                 425                 430         


Leu Pro Asp Thr Glu Asp Gln Glu Thr Val Asp Ile Asn Ser Val Ser 
        435                 440                 445             


Glu Gly Lys Glu Asn Asn Ile Met Ile Thr Leu Glu Thr Asn Ile Glu 
    450                 455                 460                 


His Asn Leu Lys Ser Glu Glu Glu Lys Asp Gln Glu Lys Gln Gln Met 
465                 470                 475                 480 


Phe Glu Asn Lys Leu Ile Lys Ser Glu Glu Ile Lys Asp Thr Ile Leu 
                485                 490                 495     


Gln Thr Val Asp Leu Val Ser Gln Glu Thr Gly Glu Lys Glu Ala Asn 
            500                 505                 510         


Ile Gln Ala Val Asp Ser Glu Val Gly Leu Thr Lys Glu Asp Thr Gln 
        515                 520                 525             


Glu Lys Leu Gly Glu Asp Asp Lys Thr Gln Lys Asp Val Ile Ser Asn 
    530                 535                 540                 


Thr Ser Asp Val Ile Gly Thr Cys Glu Ala Ala Asp Val Ala Gln Lys 
545                 550                 555                 560 


Val Asp Glu Asp Ser Ala Glu Asp Thr Gln Ser Asn Asp Gly Lys Glu 
                565                 570                 575     


Val Val Glu Val Gly Gln Lys Leu Ile Asn Lys Pro Met Val Gly Pro 
            580                 585                 590         


Glu Ala Gly Gly Thr Lys Glu Val Pro Ile Lys Glu Ile Val Glu Met 
        595                 600                 605             


Asn Glu Ile Glu Glu Gly Lys Asn Lys Glu Gln Ala Ile Asn Ser Ser 
    610                 615                 620                 


Glu Asn Ile Met Asp Ile Asn Glu Glu Pro Gly Thr Thr Glu Gly Glu 
625                 630                 635                 640 


Glu Ile Thr Glu Ser Ser Ser Thr Glu Glu Met Glu Val Arg Ser Val 
                645                 650                 655     


Val Ala Asp Thr Asp Gln Lys Ala Leu Gly Ser Glu Val Gln Asp Ala 
            660                 665                 670         


Ser Lys Val Thr Thr Gln Ile Asp Lys Glu Lys Lys Glu Ile Pro Val 
        675                 680                 685             


Ser Ile Lys Lys Glu Pro Glu Val Thr Val Val Ser Gln Pro Thr Glu 
    690                 695                 700                 


Pro Gln Pro Val Leu Ile Pro Ser Ile Asn Ile Asn Ser Asp Ser Gly 
705                 710                 715                 720 


Glu Asn Lys Glu Glu Ile Gly Ser Leu Ser Lys Thr Glu Thr Ile Leu 
                725                 730                 735     


Pro Pro Glu Ser Glu Asn Pro Lys Glu Asn Asp Asn Asp Ser Gly Thr 
            740                 745                 750         


Gly Ser Thr Ala Asp Thr Ser Ser Ile Asp Leu Asn Leu Ser Ile Ser 
        755                 760                 765             


Ser Phe Leu Ser Lys Thr Lys Asp Ser Gly Ser Ile Ser Leu Gln Glu 
    770                 775                 780                 


Thr Arg Arg Gln Lys Lys Thr Leu Lys Lys Thr Arg Lys Phe Ile Val 
785                 790                 795                 800 


Asp Gly Val Glu Val Ser Val Thr Thr Ser Lys Ile Val Thr Asp Ser 
                805                 810                 815     


Asp Ser Lys Thr Glu Glu Leu Arg Phe Leu Arg Arg Gln Glu Leu Arg 
            820                 825                 830         


Glu Leu Arg Phe Leu Gln Lys Glu Glu Gln Arg Ala Gln Gln Gln Leu 
        835                 840                 845             


Asn Ser Lys Leu Gln Gln Gln Arg Glu Gln Ile Phe Arg Arg Phe Glu 
    850                 855                 860                 


Gln Glu Met Met Ser Lys Lys Arg Gln Tyr Asp Gln Glu Ile Glu Asn 
865                 870                 875                 880 


Leu Glu Lys Gln Gln Lys Gln Thr Ile Glu Arg Leu Glu Gln Glu His 
                885                 890                 895     


Thr Asn Arg Leu Arg Asp Glu Ala Lys Arg Ile Lys Gly Glu Gln Glu 
            900                 905                 910         


Lys Glu Leu Ser Lys Phe Gln Asn Met Leu Lys Asn Arg Lys Lys Glu 
        915                 920                 925             


Val Ile Asn Glu Val Glu Lys Ala Pro Lys Glu Leu Arg Lys Glu Leu 
    930                 935                 940                 


Met Lys Arg Arg Lys Glu Glu Leu Ala Gln Ser Gln His Ala Gln Glu 
945                 950                 955                 960 


Gln Glu Phe Val Gln Lys Gln Gln Gln Glu Leu Asp Gly Ser Leu Lys 
                965                 970                 975     


Lys Ile Ile Gln Gln Gln Lys Ala Glu Leu Ala Asn Ile Glu Arg Glu 
            980                 985                 990         


Cys Leu Asn Asn Lys Gln Gln Leu  Met Arg Ala Arg Glu  Ala Ala Ile 
        995                 1000                 1005             


Trp Glu  Leu Glu Glu Arg His  Leu Gln Glu Lys His  Gln Leu Leu 
    1010                 1015                 1020             


Lys Gln  Gln Leu Lys Asp Gln  Tyr Phe Met Gln Arg  His Gln Leu 
    1025                 1030                 1035             


Leu Lys  Arg His Glu Lys Glu  Thr Glu Gln Met Gln  Arg Tyr Asn 
    1040                 1045                 1050             


Gln Arg  Leu Ile Glu Glu Leu  Lys Asn Arg Gln Thr  Gln Glu Arg 
    1055                 1060                 1065             


Ala Arg  Leu Pro Lys Ile Gln  Arg Ser Glu Ala Lys  Thr Arg Met 
    1070                 1075                 1080             


Ala Met  Phe Lys Lys Ser Leu  Arg Ile Asn Ser Thr  Ala Thr Pro 
    1085                 1090                 1095             


Asp Gln  Asp Arg Asp Lys Ile  Lys Gln Phe Ala Ala  Gln Glu Glu 
    1100                 1105                 1110             


Lys Arg  Gln Lys Asn Glu Arg  Met Ala Gln His Gln  Lys His Glu 
    1115                 1120                 1125             


Asn Gln  Met Arg Asp Leu Gln  Leu Gln Cys Glu Ala  Asn Val Arg 
    1130                 1135                 1140             


Glu Leu  His Gln Leu Gln Asn  Glu Lys Cys His Leu  Leu Val Glu 
    1145                 1150                 1155             


His Glu  Thr Gln Lys Leu Lys  Glu Leu Asp Glu Glu  His Ser Gln 
    1160                 1165                 1170             


Glu Leu  Lys Glu Trp Arg Glu  Lys Leu Arg Pro Arg  Lys Lys Thr 
    1175                 1180                 1185             


Leu Glu  Glu Glu Phe Ala Arg  Lys Leu Gln Glu Gln  Glu Val Phe 
    1190                 1195                 1200             


Phe Lys  Met Thr Gly Glu Ser  Glu Cys Leu Asn Pro  Ser Thr Gln 
    1205                 1210                 1215             


Ser Arg  Ile Ser Lys Phe Tyr  Pro Ile Pro Ser Leu  His Ser Thr 
    1220                 1225                 1230             


Gly Ser  
    1235 


