                         SEQUENCE LISTING

<110>  The Johns Hopkins University
       Duke University
       BioSpecifics Technologies Corp.
       Segars, James H.
       Leppert, Phyllis C
       Wegman, Thomas L.
       Soma, Jean-Marie
 
<120>  Treatment of Uterine Fibroids using Purified Collagenese

<130>  3762A-143PCT

<140>  PCT/US2020/055570
<141>  2020-10-14

<150>  US 62/915,360
<151>  2019-10-15

<160>  2     

<170>  PatentIn version 3.5

<210>  1
<211>  1118
<212>  PRT
<213>  Clostridium histolyticum

<400>  1

Met Lys Lys Asn Ile Leu Lys Ile Leu Met Asp Ser Tyr Ser Lys Glu 
1               5                   10                  15      


Ser Lys Ile Gln Thr Val Arg Arg Val Thr Ser Val Ser Leu Leu Ala 
            20                  25                  30          


Val Tyr Leu Thr Met Asn Thr Ser Ser Leu Val Leu Ala Lys Pro Ile 
        35                  40                  45              


Glu Asn Thr Asn Asp Thr Ser Ile Lys Asn Val Glu Lys Leu Arg Asn 
    50                  55                  60                  


Ala Pro Asn Glu Glu Asn Ser Lys Lys Val Glu Asp Ser Lys Asn Asp 
65                  70                  75                  80  


Lys Val Glu His Val Lys Asn Ile Glu Glu Ala Lys Val Glu Gln Val 
                85                  90                  95      


Ala Pro Glu Val Lys Ser Lys Ser Thr Leu Arg Ser Ala Ser Ile Ala 
            100                 105                 110         


Asn Thr Asn Ser Glu Lys Tyr Asp Phe Glu Tyr Leu Asn Gly Leu Ser 
        115                 120                 125             


Tyr Thr Glu Leu Thr Asn Leu Ile Lys Asn Ile Lys Trp Asn Gln Ile 
    130                 135                 140                 


Asn Gly Leu Phe Asn Tyr Ser Thr Gly Ser Gln Lys Phe Phe Gly Asp 
145                 150                 155                 160 


Lys Asn Arg Val Gln Ala Ile Ile Asn Ala Leu Gln Glu Ser Gly Arg 
                165                 170                 175     


Thr Tyr Thr Ala Asn Asp Met Lys Gly Ile Glu Thr Phe Thr Glu Val 
            180                 185                 190         


Leu Arg Ala Gly Phe Tyr Leu Gly Tyr Tyr Asn Asp Gly Leu Ser Tyr 
        195                 200                 205             


Leu Asn Asp Arg Asn Phe Gln Asp Lys Cys Ile Pro Ala Met Ile Ala 
    210                 215                 220                 


Ile Gln Lys Asn Pro Asn Phe Lys Leu Gly Thr Ala Val Gln Asp Glu 
225                 230                 235                 240 


Val Ile Thr Ser Leu Gly Lys Leu Ile Gly Asn Ala Ser Ala Asn Ala 
                245                 250                 255     


Glu Val Val Asn Asn Cys Val Pro Val Leu Lys Gln Phe Arg Glu Asn 
            260                 265                 270         


Leu Asn Gln Tyr Ala Pro Asp Tyr Val Lys Gly Thr Ala Val Asn Glu 
        275                 280                 285             


Leu Ile Lys Gly Ile Glu Phe Asp Phe Ser Gly Ala Ala Tyr Glu Lys 
    290                 295                 300                 


Asp Val Lys Thr Met Pro Trp Tyr Gly Lys Ile Asp Pro Phe Ile Asn 
305                 310                 315                 320 


Glu Leu Lys Ala Leu Gly Leu Tyr Gly Asn Ile Thr Ser Ala Thr Glu 
                325                 330                 335     


Trp Ala Ser Asp Val Gly Ile Tyr Tyr Leu Ser Lys Phe Gly Leu Tyr 
            340                 345                 350         


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


Met Tyr Lys Tyr Gly Lys Ile Ala Phe Val Ala Met Glu Arg Ile Thr 
    370                 375                 380                 


Trp Asp Tyr Asp Gly Ile Gly Ser Asn Gly Lys Lys Val Asp His Asp 
385                 390                 395                 400 


Lys Phe Leu Asp Asp Ala Glu Lys His Tyr Leu Pro Lys Thr Tyr Thr 
                405                 410                 415     


Phe Asp Asn Gly Thr Phe Ile Ile Arg Ala Gly Asp Lys Val Ser Glu 
            420                 425                 430         


Glu Lys Ile Lys Arg Leu Tyr Trp Ala Ser Arg Glu Val Lys Ser Gln 
        435                 440                 445             


Phe His Arg Val Val Gly Asn Asp Lys Ala Leu Glu Val Gly Asn Ala 
    450                 455                 460                 


Asp Asp Val Leu Thr Met Lys Ile Phe Asn Ser Pro Glu Glu Tyr Lys 
465                 470                 475                 480 


Phe Asn Thr Asn Ile Asn Gly Val Ser Thr Asp Asn Gly Gly Leu Tyr 
                485                 490                 495     


Ile Glu Pro Arg Gly Thr Phe Tyr Thr Tyr Glu Arg Thr Pro Gln Gln 
            500                 505                 510         


Ser Ile Phe Ser Leu Glu Glu Leu Phe Arg His Glu Tyr Thr His Tyr 
        515                 520                 525             


Leu Gln Ala Arg Tyr Leu Val Asp Gly Leu Trp Gly Gln Gly Pro Phe 
    530                 535                 540                 


Tyr Glu Lys Asn Arg Leu Thr Trp Phe Asp Glu Gly Thr Ala Glu Phe 
545                 550                 555                 560 


Phe Ala Gly Ser Thr Arg Thr Ser Gly Val Leu Pro Arg Lys Ser Ile 
                565                 570                 575     


Leu Gly Tyr Leu Ala Lys Asp Lys Val Asp His Arg Tyr Ser Leu Lys 
            580                 585                 590         


Lys Thr Leu Asn Ser Gly Tyr Asp Asp Ser Asp Trp Met Phe Tyr Asn 
        595                 600                 605             


Tyr Gly Phe Ala Val Ala His Tyr Leu Tyr Glu Lys Asp Met Pro Thr 
    610                 615                 620                 


Phe Ile Lys Met Asn Lys Ala Ile Leu Asn Thr Asp Val Lys Ser Tyr 
625                 630                 635                 640 


Asp Glu Ile Ile Lys Lys Leu Ser Asp Asp Ala Asn Lys Asn Thr Glu 
                645                 650                 655     


Tyr Gln Asn His Ile Gln Glu Leu Ala Asp Lys Tyr Gln Gly Ala Gly 
            660                 665                 670         


Ile Pro Leu Val Ser Asp Asp Tyr Leu Lys Asp His Gly Tyr Lys Lys 
        675                 680                 685             


Ala Ser Glu Val Tyr Ser Glu Ile Ser Lys Ala Ala Ser Leu Thr Asn 
    690                 695                 700                 


Thr Ser Val Thr Ala Glu Lys Ser Gln Tyr Phe Asn Thr Phe Thr Leu 
705                 710                 715                 720 


Arg Gly Thr Tyr Thr Gly Glu Thr Ser Lys Gly Glu Phe Lys Asp Trp 
                725                 730                 735     


Asp Glu Met Ser Lys Lys Leu Asp Gly Thr Leu Glu Ser Leu Ala Lys 
            740                 745                 750         


Asn Ser Trp Ser Gly Tyr Lys Thr Leu Thr Ala Tyr Phe Thr Asn Tyr 
        755                 760                 765             


Arg Val Thr Ser Asp Asn Lys Val Gln Tyr Asp Val Val Phe His Gly 
    770                 775                 780                 


Val Leu Thr Asp Asn Ala Asp Ile Ser Asn Asn Lys Ala Pro Ile Ala 
785                 790                 795                 800 


Lys Val Thr Gly Pro Ser Thr Gly Ala Val Gly Arg Asn Ile Glu Phe 
                805                 810                 815     


Ser Gly Lys Asp Ser Lys Asp Glu Asp Gly Lys Ile Val Ser Tyr Asp 
            820                 825                 830         


Trp Asp Phe Gly Asp Gly Ala Thr Ser Arg Gly Lys Asn Ser Val His 
        835                 840                 845             


Ala Tyr Lys Lys Ala Gly Thr Tyr Asn Val Thr Leu Lys Val Thr Asp 
    850                 855                 860                 


Asp Lys Gly Ala Thr Ala Thr Glu Ser Phe Thr Ile Glu Ile Lys Asn 
865                 870                 875                 880 


Glu Asp Thr Thr Thr Pro Ile Thr Lys Glu Met Glu Pro Asn Asp Asp 
                885                 890                 895     


Ile Lys Glu Ala Asn Gly Pro Ile Val Glu Gly Val Thr Val Lys Gly 
            900                 905                 910         


Asp Leu Asn Gly Ser Asp Asp Ala Asp Thr Phe Tyr Phe Asp Val Lys 
        915                 920                 925             


Glu Asp Gly Asp Val Thr Ile Glu Leu Pro Tyr Ser Gly Ser Ser Asn 
    930                 935                 940                 


Phe Thr Trp Leu Val Tyr Lys Glu Gly Asp Asp Gln Asn His Ile Ala 
945                 950                 955                 960 


Ser Gly Ile Asp Lys Asn Asn Ser Lys Val Gly Thr Phe Lys Ser Thr 
                965                 970                 975     


Lys Gly Arg His Tyr Val Phe Ile Tyr Lys His Asp Ser Ala Ser Asn 
            980                 985                 990         


Ile Ser Tyr Ser Leu Asn Ile Lys  Gly Leu Gly Asn Glu  Lys Leu Lys 
        995                 1000                 1005             


Glu Lys  Glu Asn Asn Asp Ser  Ser Asp Lys Ala Thr  Val Ile Pro 
    1010                 1015                 1020             


Asn Phe  Asn Thr Thr Met Gln  Gly Ser Leu Leu Gly  Asp Asp Ser 
    1025                 1030                 1035             


Arg Asp  Tyr Tyr Ser Phe Glu  Val Lys Glu Glu Gly  Glu Val Asn 
    1040                 1045                 1050             


Ile Glu  Leu Asp Lys Lys Asp  Glu Phe Gly Val Thr  Trp Thr Leu 
    1055                 1060                 1065             


His Pro  Glu Ser Asn Ile Asn  Asp Arg Ile Thr Tyr  Gly Gln Val 
    1070                 1075                 1080             


Asp Gly  Asn Lys Val Ser Asn  Lys Val Lys Leu Arg  Pro Gly Lys 
    1085                 1090                 1095             


Tyr Tyr  Leu Leu Val Tyr Lys  Tyr Ser Gly Ser Gly  Asn Tyr Glu 
    1100                 1105                 1110             


Leu Arg  Val Asn Lys 
    1115             


<210>  2
<211>  1021
<212>  PRT
<213>  Clostridium histolyticum

<400>  2

Met Lys Arg Lys Cys Leu Ser Lys Arg Leu Met Leu Ala Ile Thr Met 
1               5                   10                  15      


Ala Thr Ile Phe Thr Val Asn Ser Thr Leu Pro Ile Tyr Ala Ala Val 
            20                  25                  30          


Asp Lys Asn Asn Ala Thr Ala Ala Val Gln Asn Glu Ser Lys Arg Tyr 
        35                  40                  45              


Thr Val Ser Tyr Leu Lys Thr Leu Asn Tyr Tyr Asp Leu Val Asp Leu 
    50                  55                  60                  


Leu Val Lys Thr Glu Ile Glu Asn Leu Pro Asp Leu Phe Gln Tyr Ser 
65                  70                  75                  80  


Ser Asp Ala Lys Glu Phe Tyr Gly Asn Lys Thr Arg Met Ser Phe Ile 
                85                  90                  95      


Met Asp Glu Ile Gly Arg Arg Ala Pro Gln Tyr Thr Glu Ile Asp His 
            100                 105                 110         


Lys Gly Ile Pro Thr Leu Val Glu Val Val Arg Ala Gly Phe Tyr Leu 
        115                 120                 125             


Gly Phe His Asn Lys Glu Leu Asn Glu Ile Asn Lys Arg Ser Phe Lys 
    130                 135                 140                 


Glu Arg Val Ile Pro Ser Ile Leu Ala Ile Gln Lys Asn Pro Asn Phe 
145                 150                 155                 160 


Lys Leu Gly Thr Glu Val Gln Asp Lys Ile Val Ser Ala Thr Gly Leu 
                165                 170                 175     


Leu Ala Gly Asn Glu Thr Ala Pro Pro Glu Val Val Asn Asn Phe Thr 
            180                 185                 190         


Pro Ile Leu Gln Asp Cys Ile Lys Asn Ile Asp Arg Tyr Ala Leu Asp 
        195                 200                 205             


Asp Leu Lys Ser Lys Ala Leu Phe Asn Val Leu Ala Ala Pro Thr Tyr 
    210                 215                 220                 


Asp Ile Thr Glu Tyr Leu Arg Ala Thr Lys Glu Lys Pro Glu Asn Thr 
225                 230                 235                 240 


Pro Trp Tyr Gly Lys Ile Asp Gly Phe Ile Asn Glu Leu Lys Lys Leu 
                245                 250                 255     


Ala Leu Tyr Gly Lys Ile Asn Asp Asn Asn Ser Trp Ile Ile Asp Asn 
            260                 265                 270         


Gly Ile Tyr His Ile Ala Pro Leu Gly Lys Leu His Ser Asn Asn Lys 
        275                 280                 285             


Ile Gly Ile Glu Thr Leu Thr Glu Val Met Lys Val Tyr Pro Tyr Leu 
    290                 295                 300                 


Ser Met Gln His Leu Gln Ser Ala Asp Gln Ile Lys Arg His Tyr Asp 
305                 310                 315                 320 


Ser Lys Asp Ala Glu Gly Asn Lys Ile Pro Leu Asp Lys Phe Lys Lys 
                325                 330                 335     


Glu Gly Lys Glu Lys Tyr Cys Pro Lys Thr Tyr Thr Phe Asp Asp Gly 
            340                 345                 350         


Lys Val Ile Ile Lys Ala Gly Ala Arg Val Glu Glu Glu Lys Val Lys 
        355                 360                 365             


Arg Leu Tyr Trp Ala Ser Lys Glu Val Asn Ser Gln Phe Phe Arg Val 
    370                 375                 380                 


Tyr Gly Ile Asp Lys Pro Leu Glu Glu Gly Asn Pro Asp Asp Ile Leu 
385                 390                 395                 400 


Thr Met Val Ile Tyr Asn Ser Pro Glu Glu Tyr Lys Leu Asn Ser Val 
                405                 410                 415     


Leu Tyr Gly Tyr Asp Thr Asn Asn Gly Gly Met Tyr Ile Glu Pro Glu 
            420                 425                 430         


Gly Thr Phe Phe Thr Tyr Glu Arg Glu Ala Gln Glu Ser Thr Tyr Thr 
        435                 440                 445             


Leu Glu Glu Leu Phe Arg His Glu Tyr Thr His Tyr Leu Gln Gly Arg 
    450                 455                 460                 


Tyr Ala Val Pro Gly Gln Trp Gly Arg Thr Lys Leu Tyr Asp Asn Asp 
465                 470                 475                 480 


Arg Leu Thr Trp Tyr Glu Glu Gly Gly Ala Glu Leu Phe Ala Gly Ser 
                485                 490                 495     


Thr Arg Thr Ser Gly Ile Leu Pro Arg Lys Ser Ile Val Ser Asn Ile 
            500                 505                 510         


His Asn Thr Thr Arg Asn Asn Arg Tyr Lys Leu Ser Asp Thr Val His 
        515                 520                 525             


Ser Lys Tyr Gly Ala Ser Phe Glu Phe Tyr Asn Tyr Ala Cys Met Phe 
    530                 535                 540                 


Met Asp Tyr Met Tyr Asn Lys Asp Met Gly Ile Leu Asn Lys Leu Asn 
545                 550                 555                 560 


Asp Leu Ala Lys Asn Asn Asp Val Asp Gly Tyr Asp Asn Tyr Ile Arg 
                565                 570                 575     


Asp Leu Ser Ser Asn Tyr Ala Leu Asn Asp Lys Tyr Gln Asp His Met 
            580                 585                 590         


Gln Glu Arg Ile Asp Asn Tyr Glu Asn Leu Thr Val Pro Phe Val Ala 
        595                 600                 605             


Asp Asp Tyr Leu Val Arg His Ala Tyr Lys Asn Pro Asn Glu Ile Tyr 
    610                 615                 620                 


Ser Glu Ile Ser Glu Val Ala Lys Leu Lys Asp Ala Lys Ser Glu Val 
625                 630                 635                 640 


Lys Lys Ser Gln Tyr Phe Ser Thr Phe Thr Leu Arg Gly Ser Tyr Thr 
                645                 650                 655     


Gly Gly Ala Ser Lys Gly Lys Leu Glu Asp Gln Lys Ala Met Asn Lys 
            660                 665                 670         


Phe Ile Asp Asp Ser Leu Lys Lys Leu Asp Thr Tyr Ser Trp Ser Gly 
        675                 680                 685             


Tyr Lys Thr Leu Thr Ala Tyr Phe Thr Asn Tyr Lys Val Asp Ser Ser 
    690                 695                 700                 


Asn Arg Val Thr Tyr Asp Val Val Phe His Gly Tyr Leu Pro Asn Glu 
705                 710                 715                 720 


Gly Asp Ser Lys Asn Ser Leu Pro Tyr Gly Lys Ile Asn Gly Thr Tyr 
                725                 730                 735     


Lys Gly Thr Glu Lys Glu Lys Ile Lys Phe Ser Ser Glu Gly Ser Phe 
            740                 745                 750         


Asp Pro Asp Gly Lys Ile Val Ser Tyr Glu Trp Asp Phe Gly Asp Gly 
        755                 760                 765             


Asn Lys Ser Asn Glu Glu Asn Pro Glu His Ser Tyr Asp Lys Val Gly 
    770                 775                 780                 


Thr Tyr Thr Val Lys Leu Lys Val Thr Asp Asp Lys Gly Glu Ser Ser 
785                 790                 795                 800 


Val Ser Thr Thr Thr Ala Glu Ile Lys Asp Leu Ser Glu Asn Lys Leu 
                805                 810                 815     


Pro Val Ile Tyr Met His Val Pro Lys Ser Gly Ala Leu Asn Gln Lys 
            820                 825                 830         


Val Val Phe Tyr Gly Lys Gly Thr Tyr Asp Pro Asp Gly Ser Ile Ala 
        835                 840                 845             


Gly Tyr Gln Trp Asp Phe Gly Asp Gly Ser Asp Phe Ser Ser Glu Gln 
    850                 855                 860                 


Asn Pro Ser His Val Tyr Thr Lys Lys Gly Glu Tyr Thr Val Thr Leu 
865                 870                 875                 880 


Arg Val Met Asp Ser Ser Gly Gln Met Ser Glu Lys Thr Met Lys Ile 
                885                 890                 895     


Lys Ile Thr Asp Pro Val Tyr Pro Ile Gly Thr Glu Lys Glu Pro Asn 
            900                 905                 910         


Asn Ser Lys Glu Thr Ala Ser Gly Pro Ile Val Pro Gly Ile Pro Val 
        915                 920                 925             


Ser Gly Thr Ile Glu Asn Thr Ser Asp Gln Asp Tyr Phe Tyr Phe Asp 
    930                 935                 940                 


Val Ile Thr Pro Gly Glu Val Lys Ile Asp Ile Asn Lys Leu Gly Tyr 
945                 950                 955                 960 


Gly Gly Ala Thr Trp Val Val Tyr Asp Glu Asn Asn Asn Ala Val Ser 
                965                 970                 975     


Tyr Ala Thr Asp Asp Gly Gln Asn Leu Ser Gly Lys Phe Lys Ala Asp 
            980                 985                 990         


Lys Pro Gly Arg Tyr Tyr Ile His  Leu Tyr Met Phe Asn  Gly Ser Tyr 
        995                 1000                 1005             


Met Pro  Tyr Arg Ile Asn Ile  Glu Gly Ser Val Gly  Arg 
    1010                 1015                 1020     


