(12) United States Patent
`Gorman et al.
`
`(54) ALTERED ANTIBODIES AND THEIR
`PREPARATION
`
`(75)
`
`Inventors: Scott David Gorman, Cambridge
`(GB); Michael Ronald Clark,
`Cambridge (GB); Stephen Paul
`Cobbold, Cambridge (GB); Herman
`Waldmann, Cambridge (GB)
`(73) Assignee: Glaxo Wellcome Inc., Research
`Triangle Park, NC (US)
`
`( * )
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 clays.
`
`Appl. No.:
`PCT Filed:
`PCT No.:
`§371 (c)(l),
`(2), (4) Date: May 17, 1993
`(87) PCT Pub. No.: W092/05274
`PCT Pub. Date: Apr. 2, 1992
`
`Foreign Application Priority Data
`(30)
`(GD) ............................................. 9020282
`Sep. 17, 1990
`(51) Int. Cl.7 ......................... C07K 16/00; C12P 21/04;
`C12P 21/08; C07H 21/04
`(52) U.S. Cl . ................................ 530/387.3; 530/387.l;
`530/387.7; 530/388.22; 530/388.75; 530/388.7;
`530/389.6; 435/69.7; 536/23.4; 536/23.53
`(58) Field of Search
`...................... 424/85.8; 435/70.21,
`435/172.2, 69.7, 240.27, 252.3, 320.l, 240.l;
`530/300, 328, 329, 330, 326, 327, 867,
`387.3, 387.1, 387.7, 388.75, 389.7, 389.6,
`388.22; 536/23.4, 23.53
`
`(56)
`
`EP EP EP EP EP EP EP WO WO WO
`
`200412
`239400
`328404
`365209
`380018
`409242
`403156
`8601533
`9007861
`9107492
`
`10/1986
`9/1987
`2/1989
`l0/1989
`l/1990
`7/1990
`12/t990
`3/1986
`7/1990
`5/1991
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`
`US006767996Bl
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,767,996 Bl
`Jul. 27, 2004
`
`9109966
`9109967
`
`7/1991
`7/1991
`
`WO WO
`OTHER PUBLICATIONS
`Mathieson et al N. Eng. J. Mel 323:250-254 1990.*
`Harris et al TibTech 11:42-46 1993.*
`Osbaod ei al Imm. Today 11:193-195 1990.*
`Dillman el al Aon. lot. Med. 111:592-603 1989.*
`Hird et al Genes & Cancer 1990 Wiley & Soos Pub Cb 17. *
`Waldmann 252: 1657-1661 1991. *
`Roberts el al., Nature, 328, 1987, pp.731-734.
`Sharon, Proc. Natl. Acad. Sci. USA, 87, 1990, pp.
`4814-4817.
`
`11 Claims, 33 Drawing Sheets
`
`(21)
`
`(22)
`(86)
`
`08/030,175
`
`Sep. 16, 1991
`
`PCT/GB91/01578
`
`Tao, et al., Journal of /11111111nolog>�
`143(8), 1989, pp.
`239, 1988, pp. 1534-1536.
`2595-2601.
`Yerhoeyeo et al., Science,
`252, 1991, pp. 1657-1662.
`Waldmann, Science,
`Ward et al., Nature, 341, 1989, pp. 544-546.
`Jones et al., Nature, 321 (1986), pp. 522-525.
`Lazar ct al., Molecular and Cellular Biology, 8(3),
`1247-1252, 1988.
`Bruggemann, et al., J. Exp. Med., 1987, pp. 135 1-1361.
`111 (1990), pp.
`Burgess, el a.I., The Journal of Cell Biology,
`2129-2138.
`Byrn et al., Nature, 344, 1990, pp. 667-670.
`
`Crowe et al., Nucleic Acid Research, 17, 1989, p. 7992.
`Daugherty el al., Nucleic Acids Research, 19, 1991, pp.
`2 471-2476.
`Gorman et a l., Proc. Natl. Acad. Sci. USA, 88, 1991, pp.
`4181-4185.
`
`Kett.lcborough, et al., Protein Engineering, 4:7, 1991, pp.
`773-784 (ABST.).
`Lewis, et al., Gene, 101, 1991, pp. 297-302.
`Orlandi et al., Proc. Nall. Acad. Sci. USA, 86, 1989, pp.
`3833-3847.
`Queen et al., Proc. Natl. Acad. Sci. USA, 86, 1989, pp.
`10029-10033.
`Reichmann, L., et al., Nature, 332, 1988, 323-327.
`* cited by examiner
`References Cited
`Primary Examiner-Donald E. Adams
`Agem, or Firm-Nixon & Vaoderbye P.C.
`U.S. PATENT DOCUMENTS
`(74) Allorney,
`3/1987 Kung el al. ................... 424/85
`4,652,447 A
`4,695,459 A
`9/1987 Steinman ..................... 424/95
`(57)
`ABSTRACT
`An altered antibody cb.ain is produced io wbich the CDR's
`FOREIGN PATENT DOCUMENTS
`of the variable domain of the chain are derived from a first
`DNA encoding tbc variable domain of the first species arc
`mammalian species. The framework-encoding regions of
`mutated so that the mutated framework·encodiog regions
`encode a framework derived from a second different mam­
`malian species. The or each constant domain of the antibody
`chain, if present, are also derived from the second mamma­
`lian species.
`
`1 of 62
`
`BI Exhibit 1134
`
`

`

`HirxiIII
`AAGCTTATGAATATGCAAATCCTCTGAATCTACATGGTAAATATAGGTTTGTCTATACC
`
`Fig. 1
`
`1
`
`5 9
`
`60 ACAAACAGAAAAACATGAGATCACAGTTCTCTCTACAGTTACTGAGCACACAGGACCTCA
`
`11 9
`
`I L F L V A T A T
`M G W S C
`I
`-19
`120 CCATGGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCTACAGGTAAGGGGTGCA
`
`- 5
`179
`
`180 CAGTAGCAGGCTTGAGGTCTGGACATATATATGGGTGACAATGACATCCACTTTGCCTTT 239
`I Q L T Q S P V S L S A
`G V H S D
`-4
`1 3
`240 CTCTCCACAGGTGTCCACTCCGACATCCAGCTGACCCAGTCTCCAGTTTCCCTGTCTGCA 2 9 9
`CDRl
`S L G E T V N I E C IL A
`S D L
`S E D I Y
`33
`14
`300 TCTCTGGGAGAAACTGTCAACATCGAATGTCTAGCAAGTGAGGACATTTACAGTGATTTA 359
`
`Cj
`•
`00
`.
`�
`�
`..... (D
`= .....
`
`� c: :-N
`�" N
`�
`
`00 =­� � ... �
`� ...
`�
`
`e
`\J)
`°'
`�
`°'
`-....)
`\o
`"°
`°'
`co
`,....
`
`2 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 1A
`CDR 2
`� w
`Y IN
`34
`53
`G K s p Q L L I
`y Q Q K p
`T
`T D
`360 GCATGGTATCAGCAGAAGCCAGGGAA ATCTCCTCAACTCCTGATCTATAA TACAGATACC 419
`
`L Q N I G v p s R F s G s G s G T Q y s L
`73
`54
`420 TTGCAAAATGGGGTCCCTTCACGGTTTAGTGGCAGTGGATCTGGCACACAGTATTCTCTA 479
`CDR 3
`K I N s L Q s E D v A T y F c IQ Q y N N
`93
`74
`480 AA AA TAA ACAGCCTGCAATCTGAA GATGTCGCGACTTATTTCTGTCAA CA ATATAA CA AT 539
`y p w Tf F G G G T K L E I
`108
`94
`K R
`540 TATCCGTGGACGTTCGGTGGAGGGACCAAGCTGGAGATCAA ACGTGAGTAGA ATTTAAAC 599
`
`600 TTTGCTTCCTCAGTTGGATCC
`
`BanHI
`
`620
`
`d
`•
`00
`•
`""C
`� ......
`(D
`=
`......
`
`-i:: :-N
`�.....:J N Q
`Q �
`00 =-� �
`.... N 0 ....,
`�
`�
`
`e VJ
`�el'. -....J
`el'. -....J
`\o
`"°
`el'.
`Cd ......
`
`3 of 62
`
`BI Exhibit 1134
`
`

`

`-19
`1
`
`w s c I
`M G
`Hi.OOIII
`AAGCTTGGCTCTACAGTTACTGAGCACACAGGACCTCACCATGGGATGGAGCTGTATC
`
`Fig. 2
`
`-14
`58
`
`-13
`I L F L v A T A T G v H s D I Q M T Q s
`7
`59 ATCCTCTTCTTGGTAGCAACAGCTACAGGTGTCCACTCCGACATCCAGATGACCCAGAGC 118
`CDR
`1
`s Q
`s v G D R v T I T c IK A
`p s s L s A
`27
`8
`119 CCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACCATCACCTGTAAAGCAAGTCAG 178
`y Q Q K p G K A p K L L
`N I D K y L
`N jW
`28
`179 AATATTGACAAATACTTAAACTGGTACCAGCAGAAGCCAGGTAAGGCTCCAAAGCTGCTG
`CDR 2
`s
`I Y fN T N N L Q rl G v p s R F s G s G
`48
`239 ATCTACAATACAAACAATTTGCAAACGGGTGTGCCAAGCAGATTCAGCGGTAGCGGTAGC
`
`67
`298
`
`47
`238
`
`G T D F T F T
`I s s L Q p E D I A T y y
`68
`87
`299 GGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGCCAGAGGACATCGCCACCTACTAC 358
`
`�
`•
`00
`•
`�
`�
`..... �
`=
`.....
`
`�
`E.
`. N
`�-..J
`N �
`�
`
`rJ)
`-.... (">
`("> .....
`� 0
`-� �
`
`� �
`0\
`... -....l 0\
`-....l \o "° 0\
`co �
`
`4 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 2A
`c 11
`T I F
`107
`Q H
`G Q G T K v E
`88
`359 TGCTTGCAGCATATAAGTAGGCCGCGCACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 418
`
`I K
`
`CDR 3
`
`I s R p R
`
`108
`s D E Q L K s
`127
`R T v A A p
`s v F I F p p
`419 CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT 478
`
`s v v c L L N N F y p R E A K v Q
`147
`128
`479 GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAG 538
`
`G T A
`
`s v T E Q D
`w K v D N A L Q s G N s Q E
`16 7
`148
`539 TGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGAC 598
`
`187
`168
`s K A D y E
`s K D
`s L s s T L T L
`s T y
`599 AGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAG 658
`
`K H K v y A c E v T H Q G L s
`188
`s p v T K
`659 AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAG
`
`s F N R G E C Tnn Hind.III
`208
`719 AGCTTCAACAGGGGAGAGTGTTAGAAGCTT
`
`207
`
`214
`748
`
`d
`•
`00
`•
`""C
`�
`...... (D
`= ......
`
`�.....::i
`
`-i:: :-
`N
`N Q Q �
`00 =-� � .... �
`0 ...., �
`�
`
`e
`VJ
`0-,
`
`... -..-l
`
`0-,
`-..-l
`\o
`"°
`0-,
`Cd ......
`
`5 of 62
`
`BI Exhibit 1134
`
`

`

`-19
`1
`
`Fig. 3
`HirrlIII
`AAGCTTGGCTCTACAGTTACTGAGCACACAGGACCTCACCATGGGATGGAGCTGTATC
`
`M G W S C I
`
`-14
`58
`
`I L F L V A T A T G V H S D
`I Q M T Q S
`7
`-13
`59 ATCCTCTTCTTGGTAGCAACAGCTACAGGTGTCCACTCCGACATCCAGATGACCCAGAGC 118
`CDR 1
`R V T I T C l L A
`S E
`27
`P S S L S A S V G D
`8
`119 CCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACCATCACCTGTCTAGCAAGTGAG 178
`I Y S D L Aj W Y Q Q K P G K A P K L L
`47
`D
`28
`179 GACATTTACAGTGATTTAGCATGGTACCAGCAGAAGCCAGGTAAGGCTCCAAAGCTGCTG 238
`CDR 2
`I y I N T D T L Q N I G v p
`s
`s R F s G
`s G
`67
`48
`239 ATCTACAATACAGATACCTTGCAAAATGGTGTGCCAAGCAGATTCAGCGGTAGCGGTAGC 298
`
`S L Q P E D I A T Y Y
`I
`G T D F T F T
`S
`87
`68
`299 GGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGCCAGAGGACATCGCCACCTACTAC 358
`CDR 3
`
`c I Q Q y N N y p w TI F G Q G T K v E
`
`I K
`88
`107
`359 TGCCAACAGTATAACAATTATCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 418
`
`Cj
`•
`00
`.
`�
`�
`..... (D
`= .....
`
`� c: :-N
`�" N
`�
`
`00 =­� � ... ti\ � ...
`
`�
`
`e
`\J)
`°'
`�
`°'
`-....)
`\o
`"°
`°'
`co
`,....
`
`6 of 62
`
`BI Exhibit 1134
`
`

`

`108
`
`128
`
`148
`
`168
`
`208
`
`Fig. 3A
`R T v A A p s v F I F p p s D E Q L K s
`419 CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT 478
`G T A s v v c L L N N F y p R E A K v Q
`479 GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAG 538
`w K v D N A L Q
`s G N s Q E s v T E Q D
`539 TGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGAC 598
`s K D s T y s L s s T L
`s K A D y E
`T L
`599 AGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAG 658
`188 K H K v y A c E v T H Q G L s s p v T K 207
`659 AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAG 718
`s F N R G E C Trm HirrlIII
`719 AGCTTCAACAGGGGAGAGTGTTAGAAGCTT
`
`127
`
`147
`
`167
`
`187
`
`214
`
`748
`
`Cj
`•
`.
`00
`�
`� ..... (D
`= .....
`
`� c:
`:-N
`�"
`N 0 0 �
`00 =-�
`�
`... 0-.
`� ... � �
`
`e \J)
`°'
`�
`°' -....) '"
`"°
`"°
`°'
`co ,....
`
`7 of 62
`
`BI Exhibit 1134
`
`

`

`HirrlIII
`
`Fig. 4
`
`1
`
`AAGCTTATGAATATGCAAATCCTCTGAATCTACATGGTAAATATAGGTTTGTCTATACC
`
`59
`
`60 ACAAACAGAAAAACATGAGATCACAGTTCTCTCTACAGTTACTCAGCACACAGGACCTCA
`
`119
`
`-19
`
`M G W S C
`I L F L V A T A T
`120 CCATGGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCTACAGGTAAGGGGCTCA
`
`I
`
`-5
`
`179
`
`180 CAGTAGCAGGCTTGAGGTCTGGACATATATATGGGTGACAATGACATCCACTTTGCCTTT
`
`239
`
`-4
`
`G V H S Q V Q L Q E S G G G L V Q
`
`240 CTCTCCACAGGTGTCCACTCCCAGGTCCAACTGCAGGAGTCTGGTGGAGGCTTAGTGCAG
`CDR 1
`
`S )N Y G
`P G R S L K L S C A A S G L T F
`300 CCTGGAAGGTCCCTGAAACTCTCCTGTGCAGCCTCTGGACTCACTTTCAGTAACTATGGC 359
`CDR 2
`I
`s H
`360 ATGGCCTGGGTCCGCCAGGCTCCAACGAAGGGGCTGGAGTGGGTCGCAACCATTAGTCAT 419
`
`14
`
`34
`
`M A I w v R Q A p T K G L E w v A I T
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-F-N
`�.....:J � = �
`
`00 =­� � .... .....:J 0 ...., � �
`
`e VJ
`�el'.
`-..-l
`el'.
`-..-l
`\o
`"°
`el'.
`Cd ......
`
`13
`
`299
`
`33
`
`53
`
`8 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 4A
`D G s D T y F R D s v K G I R F T
`54
`73
`I
`s R D
`420 GATGGTAGTGACACTTACTTTCGAGACTCCGTGAAGGGCCGATTCACTATCTCCAGAGAT 479
`
`N G K S T L Y L Q M D
`93
`S L R S E D T A T
`74
`480 AATGGAAAAAGCACCCTATACCTGCAAATGGACAGTCTGAGGTCTGAGGACACGGCCACT 539
`y y c A R r o-- G � T
`r A �c-i RJD w G Q G T r
`9 4
`540 TATTACTGTGCAAGACAAGGGACTATAGCAGGTATACGTCACTGGGGCCAAGGGACCACG
`
`1 1 3
`599
`
`118
`V T V S
`114
`S
`600 GTCACCGTCTCCTCAGGTGAGTCCTTACAACCTCTCTCTTCTATTCAGCTTAAATAGATT 659
`
`660 TTACTGCATTTGTTGGGGGGGAAATGTGTGTATCTGAATTTCAGGTCATGAAGGACTAGG 719
`
`720 GACACCTTGGGAGTCAGAAAGGGTCATTGGGAGCCCGGGCTGATGCAGACAGACATCCTC 779
`
`Ba.nHI
`780 AGCTCCCAGACTTCATGGCCAGAGATTTATAGGGATCC
`
`8 17
`
`e
`•
`•
`rJ'l
`�
`�
`.....
`(D
`= .....
`
`� c :-N
`�""' N
`�
`
`rJ) =­� � � 00 0 ..., � �
`
`�
`rJ')
`°'
`� 0\ -....l
`
`'\:>
`\C
`°'
`eo """"
`
`9 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 5
`
`-12
`59
`
`29
`179
`
`-19 HirrlIII
`M G W S
`I L
`C I
`1 AAGCTTTACAGTTACTGAGCACACAGGACCT CACCATGGGATGGAGCTGTAT CAT CCT C
`F L V A T A T G V H S Q V Q L Q E S G P
`9
`-11
`60 TT CTTGGTAGCAACAGCTACAGGTGT CCACT CCCAGGT CCAA CTGCAGGAGAGCGGT CCA 119
`10 G L V R P S Q T L S L T C T V S G F T F
`120 GGT CTTGTGAGACCTAGCCAGACCCTGAGCCTGACCTGCACCGTGT CTGGCTT CACCTT C
`CDR 1
`T I D F y M N I w v R Q p p G R G L E w I G
`30
`180 ACCGATTT CTACATGAACTGGGTGAGACAGCCACCTGGACGAGGT CTTGAGTGGATTGGA
`CDR 2
`I F I R D K A K G y T T E y N .. p s v K--G] R
`50
`240 TTTATTAGAGACA AAGCTA AAGGTTACACAACAGAGTACAAT CCAT CTGTGA AGGGGAGA
`
`49
`239
`
`69
`299
`
`e
`•
`.
`00
`�
`�
`..... (D
`= .....
`
`� c: :-N
`�" N
`�
`
`00 =­� � ... \C � ...
`
`�
`
`e \J)
`°'
`�
`°' -....) '"
`"°
`"°
`°'
`co ,....
`
`10 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. SA
`s v T
`v T M L v D T s K N
`70
`Q F s L R L
`300 GTGACAATGCTGGTAGACACCAGCAAGAACCAGTTCAGCCTGAGACTCAGCAGCGTGACA
`CDR 3
`RIE
`A A D T A v y y c A
`G H T A A p F D
`90
`360 GCCGCCGACACCGCGGTCTATTATTGTGCAAGAGAGGGCCACACTGCTGCTCCTTTTGAT
`110 � w G Q G s L v T v
`s A s T K G p
`420 TACTGGGGTCAAGGCAGCCTCGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTC
`
`s
`
`s
`
`s v
`
`s T s G G T A A L G c L
`F p L A p
`130
`480 TTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTG
`
`s K
`
`s
`
`s G A L T s
`150 v K D y F p E p v T v s w N
`540 GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC
`
`d
`•
`00
`•
`""C
`�
`...... (D
`= ......
`
`�.....::i
`
`-i::
`:-N
`N Q Q
`�
`00 =-� �
`..... Q 0 -
`� �
`
`....
`
`e VJ
`��
`-..-l
`�
`-..-l
`\o
`"°
`�
`Cd ......
`
`89
`359
`
`109
`419
`
`129
`479
`
`149
`539
`
`169
`599
`
`11 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 58
`G V H T F P A V L Q S S G L Y S L S S V
`170
`600 GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
`S L G T Q T Y I C N V N H K
`V T V P S S
`190
`660 GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAG
`
`s c D K T H T
`210
`p s N T K v D K K v E p K
`720 CCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACA
`
`s v F L F p p
`c p p c p A p E L L G G p
`230
`780 TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCA
`
`250
`K p K D T L M
`I s R T p E v T c v v v D
`840 AAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC
`
`('.j
`•
`00
`•
`�
`� � �
`= �
`
`-c: -. N � ,.
`
`�
`�
`
`00 =-t'> t'> ..... � �
`0 -� �
`
`� rJ)
`9' -.....) °' -.....)
`\o "" °'
`
`�
`lo-"
`
`189
`659
`
`209
`719
`
`229
`779
`
`249
`839
`
`269
`899
`
`12 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. SC
`
`270
`V S H E D P E V K F N W Y V D G V E V H
`900 GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCAT
`N A K T K P R E E Q Y N S T Y R V V
`290
`S V
`960 AATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
`
`289
`959
`
`309
`1019
`
`329
`310
`L T v L H Q D w L N G K E y K c K v
`1020 CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAAC 1079
`s K A K G Q p R E
`330
`K A L p A p I E K T
`I
`1080 AAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAA
`
`349
`1139
`
`s N
`
`350
`369
`P Q V Y T L P P
`S R D E L T K N Q V
`S L
`1140 CCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG 1199
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-F-N
`�.....::i � = �
`00 =-� � ....
`.... N 0 -� �
`
`e VJ
`��
`-..-l
`�
`-..-l
`\o
`"°
`�
`Cd ......
`
`13 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 50
`s N G
`I A v E w E
`T c L v K G F y p
`370
`s D
`1200 ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG
`
`389
`
`1259
`
`s D G
`Q p E N N y K T T p
`s F F
`390
`p v L D
`1260 CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC
`
`409
`
`1319
`
`s R w Q Q G N v F
`L y s K L T v D K
`s c
`410
`1320 CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGC
`
`429
`
`1379
`
`s v H H E A L H N H y T Q K s L
`s p
`s L
`430
`1380 TCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
`
`448
`
`1439
`
`G K Trm
`Hi.IXIII I
`449
`1440 GGTAAATGAGTGCGACGGCCCCAAGCTT
`
`450
`
`1467
`
`d
`•
`00
`•
`""C
`� ...... (D
`=
`......
`
`�.....::i
`
`-i:: :-
`N
`N Q Q �
`00
`=-� � ....
`.... �
`0 -� �
`
`e
`VJ
`0-,
`�
`0-,
`-....J
`\o
`"°
`0-,
`Cd ......
`
`14 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 6
`
`- 1 9 HirrlIII
`M G W S C I I L
`1
`AAGCTTTACAGTTACTGAGCACACAGGACCTCACCATGGGATGGAGCTGTATCATCCTC
`F L V A T A T G V H S Q V Q L Q E S G P
`-11
`60 TTCTTGGTAGCAACAGCTACAGGTGTCCACTCCCAGGTCCAACTGCAGGAGAGCGGTCCA
`10 G L V R P S Q T L S L T C T V S G F T F
`120 GGTCTTGTGAGACCTAGCCAGACCCTGAGCCTGACCTGCACCGTGTCTGGCTTCACCTTC
`CDR 1
`T I N y G M -!J w v R Q p p G R G L E w I G
`30
`180 ACCAACTATGGCATGGCCTGGGTGAGACAGCCACCTGGACGAGGTCTTGAGTGGA!TGGA
`CDR 2
`Ir I s H n G s n r Y F R n s v K cl R v r
`so
`240 ACCATTAGTCATGATGGTAGTGACACTTACTTTCGAGACTCTGTGAAGGGGAGAGTGACA
`
`-12
`59
`
`9
`1 1 9
`
`29
`1 79
`
`49
`239
`
`69
`299
`
`('.j
`•
`00
`•
`�
`� � �
`= �
`
`-c: -. N �
`
`,.
`�
`�
`
`00 =­t'> t'> ..... � � 0 -
`
`�
`
`� rJ)
`°'
`�
`°'
`-...J
`
`\o "" °'
`
`�
`lo-"
`
`15 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. SA
`70 M L V D T S K N Q F S L R L S S V T A A
`300 AT GCT GGTA GA CA CCA GCAAGAA CCA GTT CA GCCT GA GA CT CA GCA GCGTGA CA GCCGCC
`CDR 3
`D T A v y y c A R I Q G T I A G I R H I w G
`90
`360 GA CA CCGCGGT CTATTATT GT GCAA GA CAAGGCA CTATA GCT GGTATA CGT CA CT GGGGT
`
`110
`Q G s L v T v s s A s T K G p s v F p L
`420 CAA GGCA GCCT CGT CA CA GT CT CCT CA GCCT CCA CCAAGGGCCCAT CGGT CTT CCCCCT G
`
`130 A p s s K s T s G G T A A L G c L v K D
`480 GCA CCCT CCT CCAA GA GCA CCT CT GGGGGCA CA GCGGCCCT GGGCT GCCT GGT CAA GGA C
`
`150
`y F p E p v T v s w N s G A L T s G v H
`540 TA CTT CCCCGAA CCGGT GA CGGT GT CGT GGA ACT CA GGCGCCCT GA CCA GCGGCGT GCA C
`
`89
`359
`
`1 09
`419
`
`129
`479
`
`1 49
`539
`
`1 69
`599
`
`L!
`•
`00
`•
`""C
`� ..... �
`= .....
`
`-c :-N ... ......::i
`� = �
`
`(J) =-('> � .... � <JI 0 ...., � �
`
`e \J)
`$"--....) °' -....)
`
`\o
`'°
`°'
`co
`to-a
`
`16 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 68
`s v v T v
`T F p A v L Q s s G L y
`170
`s L s
`600 ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTG
`
`s s L G T Q T y I c N v N H K p
`190
`s N
`p
`s
`660 CCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC
`
`T K v D K K v E p K s c D K T H T c p p
`210
`720 ACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCG
`
`c p A p E L L G G p s v F L F p p K p K
`230
`780 TGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG
`
`s R T p E v T
`D T L M I
`250
`s H
`c v v v D v
`8'40 GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAC
`
`1 89
`659
`
`209
`719
`
`229
`779
`
`249
`839
`
`269
`899
`
`�
`•
`00
`•
`�
`�
`..... �
`=
`.....
`
`�
`F-N
`�-..J
`�
`rJ) :::r (">
`� � O'I 0 -�
`� � 0\ � 0\ -..l \o "° 0\
`
`co �
`
`17 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 6C
`E D P E V K F N W Y V D G V E V H N A K
`270
`900 GAAGACCCT GAGGT CAAGTT CAACT GGT ACGT GGACGGCGT GGAGGT GCAT AAT GCCAAG
`
`T K P R E E Q Y N S T Y R V V S V L T V
`290
`960 ACAAAGCCGCGGGAGGAGCAGT ACAACAGCACGT ACCGT GT GGT CAGCGT CCT CACCGT C
`
`3 1 0 L H Q D W L N G K E Y K C K V S N K A L
`1020 CT GCACCAGGACT GGCT GAAT GGCAAGGAGT ACAAGTGCAAGGT CT CCAACAAAGCCCT C
`
`P A P I E K T I S K A K G Q P R E P Q V
`330
`1080 CCAGCCCCCAT CGAGAAAACCAT CT CCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT G
`
`Y T L P P S R D E L T K N Q V S L T C L
`350
`1140 T ACACCCT GCCCCCAT CCCGGGAT GAGCT GACCAAGAACCAGGT CAGCCT GACCT GCCT G
`
`Cj
`•
`00
`•
`�
`� """' ('D
`= """'
`
`-c � N ... ""
`� Q �
`
`rJ) =-(") � f"'O' .... "" 0 � � �
`
`� VJ
`0-.
`� 0-. -....J ... "°
`"°
`0-.
`� .....
`
`289
`959
`
`309
`1 0 1 9
`
`329
`1079
`
`349
`1139
`
`369
`1 1 99
`
`18 of 62
`
`BI Exhibit 1134
`
`

`

`370
`
`1200
`
`Fig. 60
`v K G F y p s D I A v E w E s N G Q p E
`GTCAAA GGCTTCTA TCCCA GCGA CA TCGCCGTGGA GTGGGA GA GCAATGGGCA GCCGGA G
`
`390
`G s F F L y s
`N N y K T T p p v L D s D
`1260 AA CAA CTA CAA GA CCA CGCCTCCCGTGCTGGA CTCCGA CGGCTCCTTCTTCCTCTA CA GC
`
`410
`K L T v D K s R w Q Q G N v F s c s v M
`1320 AA GCTCA CCGTGGA CAA GA GCA GGTGGCA GCA GGGGAA CGTCTTCTCA TGCTCCGTGA TG
`
`430
`H E A L H N H y T Q K s L s L s p G K Trm
`1380 CA TGA GGCTCTGCA CAA CCA CTA CA CGCA GAAGA GCCTCTCCCTGTCTCCGGGTAAA TGA
`
`HiirlIII
`1440 GTGCGA CGGCCCCAA GCTT
`
`389
`1259
`
`409
`1319
`
`429
`1379
`
`448
`1439
`
`1458
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-i:: :-N
`�.....:J N Q Q �
`00 =-� � ....
`"""" QO 0 -� �
`
`e VJ
`�el'.
`-..-l
`el'.
`-..-l
`\o
`"°
`el'.
`Cd ......
`
`19 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 7
`
`-19 HirrlIII
`.M G W S C I I L
`AAGCTTTACAGTTACT GAGCACACAGGACCT CACCAT GGGAT GGAGCT GTAT CAT CCT C
`1
`
`G P
`F L V A T A T G V H S Q V Q L Q E S
`-11
`60 TT CTT GGTAGCAACAGCTACAGGT GT CCACT CCCAGGT CCAACT GCAGGAGAGCGGTCCA
`
`G F T F
`C T V S
`G L V R P S Q T L S L T
`1 0
`120 GGT CTT GT GAGACCTAGCCAGACCCT GAGCCT GACCT GCACCGT GT CT GGCTT CACCTT C
`CDR 1
`G M A I w v R Q p p
`s ( N y
`G R
`G
`G L E w I
`30
`1 80 AGCAACTAT GGCAT GGCCT GGGT GAGACAGCCACCT GGACGAGGT CTT GAGT GGATT GGA
`CDR 2
`1 r r
`s v K cJ R v r
`so
`s H n c s n T y F R n
`240 ACCATTAGT CAT GAT GGTAGT GACACTTACTTT CGAGACT CT GT GAAGGGGAGAGT GACA
`
`-12
`59
`
`9
`119
`
`29
`1 79
`
`49
`239
`
`69
`299
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-F-N
`�.....::i � = �
`
`00 =­� � .... ..... \0 0 -�
`
`e VJ
`
`��
`-..-l
`�
`-..-l
`\o
`"°
`�
`Cd ......
`
`20 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 7A
`
`M L V D T S K N Q F S L R L S S V T A A
`70
`300 AT GCT GGTAGACACCAGCAAGAACCAGTT CAGCCT GAGACT CAGCAGCGT GACAGCCGCC
`CDR 3
`90 D T A v y y c A R I Q G T I A G I R H I w
`G
`360 GACACCGCGGT CTATTATT GT GCAAGACAAGGCACTATAGCT GGTATACGT CACT GGGGT
`
`G p s v F p L
`Q G s L v T v s s A s T K
`110
`420 CAAGGCAGCCT CGT CACAGT CT CCT CAGCCT CCACCAAGGGCCCAT CGGT CTT CCCCCT G
`
`130 A p s s K s T s G G T A A L G c L v K D
`480 GCACCCT CCT CCAAGAGCACCT CT GGGGGCACAGCGGCCCT GGGCT GCCT GGT CAAGGAC
`
`Y F P E P V T V S W N S
`G A L T S G V H
`150
`540 TACTT CCCCGAACCGGT GACGGT GT CGT GGAACTCAGGCGCCCT GACCAGCGGCGTGCAC
`
`89
`359
`
`109
`419
`
`129
`479
`
`149
`539
`
`169
`599
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-i:: :-N
`� Q �
`
`�.....:J
`
`00 =-�
`� .... N Q 0 -
`
`� �
`
`e VJ
`�el'. -..-l
`el'. -..-l
`\o
`"°
`el'.
`Cd ......
`
`21 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 78
`T F p A v L Q s s G L y s L s s v v T v
`170
`600 ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTG
`
`p s s s L G T Q T y I c N v N H K p s N
`190
`660 CCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC
`
`T K v D K K v E p K s c D K T H T c p p
`210
`720 ACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCG
`
`230
`c p A p E L L G G p s v F L F p p K p K
`780 TGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG
`
`D T L M I s R T p E v T c v v v D v s H
`250
`840 GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAC
`
`189
`659
`
`209
`719
`
`229
`779
`
`249
`839
`
`269
`899
`
`('.j
`•
`00
`•
`�
`� � �
`= �
`
`-c: -. N � ,. N Q Q �
`00 =-t'> t'> ..... N ...
`0 -� �
`
`� rJ)
`9' -.....) °' -.....)
`'to "" °'
`
`�
`lo-"
`
`22 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 7C
`E D P E V K F N W Y V D G V E V H N A K
`270
`900 GAA GA CCCT GA GGT CAA GTT CAACT GGTA CGT GGA CGGCGT GGA GGT GCATAAT GCCAAG
`
`T K P R E E Q Y N S T Y R V V S V L T V
`290
`960 A CAAA GCCGCGGGA GGA GCA GTA CAACA GCA CGTA CCGT GT GGT CA GCGT CCT CA CCGT C
`
`L H Q D W L N G K E Y K C K V S N K A L
`310
`1020 CT GCA CCA GGA CT GGCT GAAT GGCAA GGA GTA CAA GT GCAA GGT CT CCAA CAAA GCCCT C
`
`P A P I E K T I S K A K G Q P R E P Q V
`330
`1080 CCA GCCCCCAT CGA GAAAA CCAT CT CCAAAGCCAAA GGGCA GCCCCGA GAA CCA CA GGT G
`
`Y T L P P S R D E L T K N Q V S L T C L
`350
`1140 TA CA CCCT GCCCCCAT CCCGGGAT GA GCT GA CCAA GAA CCA GGT CA GCCT GA CCT GCCT G
`
`289
`959
`
`309
`1019
`
`329
`1079
`
`349
`1139
`
`369
`1199
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-F-N
`�.....:J � = �
`
`00 =-� � .... N N 0 -� �
`
`e VJ
`�el'. -..-l
`el'. -..-l
`\o
`"°
`el'.
`Cd ......
`
`23 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 70
`V K G F Y P S D I A V E W E S N G Q P E
`370
`1200 GT CA AAGGCTT CTAT CCCA GCGA CAT CGCCGT GGA GT GGGA GA GCAAT GGGCA GCCGGA G
`
`N N Y K T T P P V L D S D G S F F L Y S
`390
`1260 AACAA CTA CAA GA CCA CGCCT CCCGT GCT GGA CT CCGA CGGCT CCTT CTT CCT CTA CA GC
`
`K L T v D K s R w Q Q G N v F s c s v M
`410
`1320 AA GCT CA CCGT GGA CAA GA GCA GGT GGCA GCA GGGGAA CGT CTT CT CAT GCT CCGT GAT G
`
`430
`H E A L H N H y T Q K s L s L s p G K T rm
`1380 CAT GA GGCT CT GCA CAA CCA CTA CA CGCA GAA GA GCCT CT CCCT GT CT CCGGGTAAAT GA
`
`�
`•
`00
`•
`�
`= ..... �
`=
`389 .....
`1259 -= -.
`409 N --"" N
`1319 Q Q ,,.
`429 00 :r
`1379
`('> ('> ..... N � 0
`448 ...., � �
`1439
`
`HirrlIII
`1440 GT GCGA CGGCCCCAAGCTT
`
`1458
`
`e
`
`"': -...l O'I -...l
`\o \0 O'I
`
`co
`�
`
`24 of 62
`
`BI Exhibit 1134
`
`

`

`p G R s L R L s c s s s G F I F
`
`Fig. 8
`Q v Q L v E s G G G v v Q
`CDR 1
`s I s
`y A
`CDR 2
`Air
`I w D
`
`�w
`
`v R Q A p G K G L E w v
`
`1
`
`14
`
`34
`
`54 D G s D Q H y A D s v K Gj R F T I s R D
`
`74
`
`94
`
`N s K N T L F L Q M D s L R p E D T G v
`CDR 3
`y F c A RID G G H G F c s s A s c F G p
`
`114 �w G Q G T p v T v s s
`
`d
`•
`00
`•
`""C
`� ......
`(D
`= ......
`
`-
`i::
`-
`. N
`N Q
`Q
`�
`
`�.....::i
`
`13
`
`33
`
`53
`
`73 00 =-� � .... N �
`
`93
`
`0 -
`� �
`
`113
`
`126 e VJ
`��
`-..-l
`�
`-..-l
`
`\o "° �
`Cd ......
`
`25 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 9
`HirrlIII
`AAGCTTATGAATATGCAAAT CCT CTGAAT CTA CATGGTA ;\ATATAGGTTTGT CTATA CC 59
`
`1
`
`60 A CAAA CAGAAAAACATGAGAT CA CAGTT CT CT CTA CAGTTA CT CAGCA CA CAGGA CCT CA 119
`
`-5
`M G W S C I I L F L V A T A T
`-19
`120 CCATGGGATGGAGCTGTAT C�T CCT CTT CTTGGTAGCAACAGCTA CAGGTAAGGGGCT CA 179
`
`180 CAGTAGCAGGC.TTGAGGT CTG.GA CATATATAT GGGTGA CAATGA CAT CCA CTTTGCCTTT 239
`
`-4
`G V H S Q V Q L V E S G G G V V Q
`13
`240 CT CT CCA CAGG.TGT CCA CT CCCAGGT CCAA CTGGTGGAGT CTGGTGGAGGCGTGGTGCAG 299
`CDRl
`P G R S L R L S C S S S G F I F S [N Y G
`33
`14
`300 CCTGGAAGGT CCCTGAGA CT CT CCTGTT CCT CCT CTGGATT CAT CTT CAGTAA CTATGGC 359
`CDR2
`34 M A J w v R Q A p G K G L E w v A I T I s H
`53
`360 ATGGCCTGGGT CCGCCAGGCT CCAGGCAAGGGG CTGGAGTGGGT CGCAA CCATTAGT CAT 419
`
`d
`•
`00
`•
`1-'d
`� ..... �
`= .....
`
`� c
`. N
`�.......}
`� Q �
`
`00 =­� � -N (Ii 0 -�
`
`e rJ)
`
`.9'
`-...J
`O'I
`-...J
`\o
`\0
`O'I
`t:d l>-l
`
`26 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 9A
`D G s D T y F R D s v K G I R F T
`73
`54
`420 GATGGTAGTGACACTTACTTTCGAGACTCCGTGAAGGGCCGATTCACTATCTCCAGAGAT 479
`
`s R D
`
`I
`
`N S K N T L F L Q M D
`S L R P E D T G V
`74
`480 AATAGCAA.AAACACCCTATTCCTGCAAATGGACAGTCTGAGGCCCGAGGACACGGGCGTG
`CDR 3
`I R H I w G Q G T p
`y F c A R I Q G T
`94
`I A G
`540 TATTTCTGTGCAAGACAAGGGACTATAGCAGGTATACGTCACTGGGGCCAAGGGACCCCC
`
`93
`539
`
`113
`599
`
`118
`V T V S S
`114
`600 GTCACCGTCTCCTCAGGTGAGTCCTTACAACCTCTCTCTTCTATTCAGCTTAAATAGATT 659
`
`660 TTACTGCATTTGTTGGGGGGGAAATGTGTGTATCTGAATTTCAGGTCATGAAGGACTAGG 719
`
`720 GACACCTTGGGAGTCAGAAAGGGTCATTGGGAGCCCGGGCTGATGCAGACAGACATCCTC 779
`
`BaJTHI
`780 AGCTCCCAGACTTCATGGCCAGAGATTTATAGGGATCC
`
`817
`
`e
`•
`00
`.
`�
`�
`..... (D
`= .....
`
`� c: :-N
`�" N
`�
`
`00 =­� � ... N °' 0 ...., V) V)
`
`e
`\J)
`°'
`�
`°'
`-....)
`\o
`"'°
`°'
`co
`,.....
`
`27 of 62
`
`BI Exhibit 1134
`
`

`

`-1 9 HirrlIII
`M G W S C I I L F -11
`60
`1 AAGCTTTACAGTTACTCAGCACACAGGACCTCACCATGGGATGGAGCTGTATCATCCTCT
`
`Fig. 1 0
`
`('.j
`•
`00
`•
`�
`� � �
`= �
`
`-10
`
`L V A T A T
`61 TCTTGGTAGCAACAGCTACAGGTAAGGGGCTCACAGTAGCAGGCTTGAGGTCTGGACATA
`
`-4
`
`G V H S Q V
`121 TATATGGGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTC
`
`3
`
`Q L V E S G G G V V Q P G R S L R L S C
`181 CAACTGGTGGAGTCTGGTGGAGGCGTGGTGCAGCCTGGAAGGTCCCTGAGACTCTCCTGT
`CDR 1
`
`23
`
`s
`s
`241 TCCTCCTCTGGATTCATCTTCAGTAACTATGGCATGGCCTGGGTCCGCCAGGCTCCAGGC
`
`s G F I F s I N y G M A I w v R Q A p G
`
`CDR 2
`I S H D G
`S D T Y F R D
`301 AAGGGGCTGGAGTGGGTCGCAACCATTAGTCATGATGGTAGTGACACTTACTTTCGAGAC
`
`K G L E W V A I T
`
`43
`
`-c: -.
`-5
`N �
`120 �
`Q �
`
`2
`
`180
`
`22
`240
`
`42
`300
`
`62
`360
`
`00 =­t'> t'> ..... N � 0 -�
`
`� rJ)
`9' -.....) °'
`
`-.....)
`\o
`""
`°'
`�
`lo-"
`
`28 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 1 0A
`s v K G I R F T I
`s R D N
`63
`s K N T L F L Q
`36 1 TCCGTGAAGGGCCGATTCACTATCTCCAGAGATAATAGCAAAAACACCCTATTCCTGCAA
`CDR 3
`
`M D s L R p E D T G v y F c A R I Q G T
`83
`I
`421 ATGGACAGTCTGAGGCCCGAGGACACGGGCGTGTATTTCTGTGCAAGACAAGGGACTATA
`
`I R H] W G Q G T P V T V S S
`1 03
`A G
`481 GCAGGTATACGTCACTGGGGCCAAGGGACCCCCGTCACCGTCTCCTCAGGTGAGTCCTTA
`
`82
`420
`
`102
`480
`
`1 2 2
`
`540
`
`541 CAACCTCTCTCTTCTATTCAGCTTAAATAGATTTTACTGCATTTGTTGGGGGGG . .\AATGT
`
`600
`
`60 1 GTGTATCTGAATTTCAGGTCATGAAGGACTAGGGACACCTTGGGAGTCAGAAAGGGTCAT
`
`661 TGGGAGCCCGGGCTGATGCAGACAGACATCCTCAGCTCCCAGACTTCATGGCCAGAGATT
`
`BanHI
`
`7 2 1 TATAGGGATCC
`
`660
`
`7 20
`
`7 3 1
`
`�
`•
`00
`•
`�
`�
`..... �
`=
`.....
`
`�
`F-N
`�-..J
`�
`rJ) :::" (">
`� N QQ 0 -�
`� � 0\ � 0\ -..l \o "° 0\
`
`co �
`
`29 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 1 1
`HirxlIII
`1 AA GCTTAT GAATAT GCAAAT CCT CT GAAT CTACAT GGTAAATATAGGTTT GT CTATACC
`
`5 9
`
`60 ACAAACAGAAAAACAT GAGAT CACAGTT CT CT CTACAGTTACT CAGCACACAGGACCT CA
`
`1 19
`
`C I I L F L V A T A T
`G W S
`- 1 9
`M
`1 20 CCAT GGGAT GGAGCT GTAT CAT CCT CTT CTTG GTAGCAA CAGCTACAGGTAA GGGGCT CA
`
`- 5
`
`1 7 9
`
`1 80 CAGTAGCAGGCTT GAGGT CT GGACATATATAT GGGT GACAAT GACAT CCACTTT GCCTTT 2 3 9
`
`G V H S Q V Q L V E S G G G V V Q
`-4
`1 3
`240 CT CT CCACAGGT GT CCACT CCCAGGT CCAA CT GGT GGAGT CT GGT GGAGGCGT GGT GCAG 2 9 9
`CDR 1
`s I N y G
`s c
`G F I F
`s
`s
`p G R s L R L
`s
`3 3
`1 4
`300 CCT GGAAGGTCCCT GAGACTCTCCT GTTCCT CCTCT GGATTCATCTTCAGTAACTAT GGC 3 5 9
`CDR 2
`M A I w v R Q A p G K G L E w v A LT I
`34
`s H
`360 AT GGCCT GGGT CCGCCAGGCT CCAGGCAA GGG GCT GGAGT GGGT CGCAA CCATTAGT CAT
`
`4 1 9
`
`5 3
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-F-N
`�.....::i � = �
`
`00 =­� � .... N \C 0 -�
`
`e VJ
`
`��
`-..-l
`�
`-..-l
`
`\o "° �
`Cd ......
`
`30 of 62
`
`BI Exhibit 1134
`
`

`

`L!
`•
`00
`•
`""C
`� ..... �
`= .....
`
`-c :-N ... ......::i
`� = �
`
`(J) =­('> � .... � = 0 ....,
`
`�
`
`e \J)
`
`$"--....)
`
`°'
`-....)
`\o
`'°
`°'
`co
`to-a
`
`Fig. 1 1 A
`S V K G] R F T
`5 4
`S D T Y F R D
`I
`S R D
`D G
`420 GATGGTAGTGACACTTACTT�CGAGACTCCGTGAAGGGCCGATTCACTATCTCCAGAGAT
`
`73
`479
`
`93
`S L R P E D T G V
`74
`N
`S K N T L F L Q M D
`480 AATAGCAAAAACACCCTATTCCTGCAAATGGACAGTCTGAGGCCCGAGGACACGGGCGTG 539
`C D R 3
`y F c A R I Q G T
`I R H I w G Q G T T
`113
`9 4
`I A G
`540 TATTTCTGTGCAAGACAAGGGACTATAGCAGGTATACGTCACTGGGGCCAAGGGACCACG 599
`
`118
`V T V
`114
`S
`S
`600 GTCACCGTCTCCTCAGGTGAGTCCTTACAACCTCTCTCTTCTATTCAGCTTAAATAGATT 659
`
`660 TTACTGCATTTGTTGGGGGGGAAATGTGTGTATCTGAATTTCAGGTCATGAAGGACTAGG
`
`719
`
`720 GACACCTTGGGAGTCAGAAAGGGTCATTGGGAGCCCGGGCTGATGCAGACAGACATCCTC
`
`779
`
`BauHI
`780 AGCTCCCAGACTTCATGGCCAGAGATTTATAGGGATCC
`
`817
`
`31 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 1 2
`M G W
`- 1 9 Hin:IIII
`1 AAGCTTTACAGTTACTCAGCACACAGGACCTCACCATGGGATGGAGCTGTATCATCCTCT
`
`S C
`
`I
`
`I L F - 1 1
`60
`
`L V A T A T
`- 1 0
`6 1 TCTTGGTAGCAACAGCTACAGGTAAGGGGCTCACAGTAGCAGGCTTGAGGTCTGGACATA
`
`- 4
`G V H S Q V
`1 2 1 TATATGGGTGACAATGACATCCACTTTGCCTTTCTCTCCACAGGTGTCCACTCCCAGGTC
`
`2 3
`
`s s s G F
`
`Q L V E S G G G V V Q P G R S L R L S C
`3
`1 8 1 CAACTGGTGGAGTCTGGTGGAGGCGTGGTGCAGCCTGGAAGGTCCCTGAGACTCTCCTGT
`CDR 1
`s IN y G M /\] w v R Q A p G
`I F
`2 4 1 TCCTCCTCTGGATTCATCTTCAGTAACTATGGCATGGCCTGGGTCCGCCAGGCTCCAGGC
`CDR 2
`I s H D G s D T y F R D
`3 0 1 AAGGGGCTGGAGTGGGTCGCAACCATTAGTCATGATGGTAGTGACACTTACTTTCGAGAC
`
`4 3
`
`K G L E w v A I T
`
`63
`
`S V K G) R F T I
`
`S R D N S K N T L F L Q
`
`3 6 1 TCCGTGAAGGGCCGATTCACTATCTCCAGAGATAATAGCAAAAACACCCTATTCCTGCAA
`
`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-F-N
`�.....::i � = �
`
`00 =­� � .... � """"' 0 -�
`
`e VJ
`
`��
`-..-l
`�
`-..-l
`
`\o "° �
`Cd ......
`
`-5
`
`1 20
`
`2
`1 8 0
`
`2 2
`2 4 0
`
`4 2
`
`3 0 0
`
`6 2
`
`360
`
`8 2
`4 2 0
`
`32 of 62
`
`BI Exhibit 1134
`
`

`

`Fig. 1 2A
`
`fQ G T
`M D S L R P E D T G V Y F C A R
`83
`I
`421 ATGGACAGTCTGAGGCCCGAGGACACGGGCGTGTATTTCTGTGCAAGACAAGGGACTATA
`I R HI w G Q G T T v T v s s
`A G
`1 03
`481 GCAGGTATACGTCACTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGGTGAGTCCTTA
`
`CDR 3
`
`1 02
`
`480
`
`122
`540
`
`541 CAACCTCTCTCTTCTATTCAGCTTAAATAGATTTTACTGCATTTGTTGGGGGGGAAATGT
`
`600
`
`601 GTGTATCTGAATTTCAGGTCATGAAGGACTAGGGACACCTTGGGAGTCAGAAAGGGTCAT
`
`6 6 1 TGGGAGCCCGGGCTGATGCAGACAGACATCCTCAGCTCCCAGACTTCATGGCCAGAGATT
`
`BairHI
`7 2 i TATAGGGATCC
`
`660
`
`720
`
`7 3 1
`
`Cj
`•
`00
`.
`�
`�
`..... (D
`= .....
`
`� c: :-N
`�" N
`�
`
`00 =­� � ... � N 0 ...., � �
`
`e
`\J)
`°'
`�
`°'
`-....)
`\o
`"°
`°'
`co
`,....
`
`33 of 62
`
`BI Exhibit 1134
`
`

`

`d
`•
`00
`•
`""C
`� ...... (D
`= ......
`
`-F-N
`�.....:J � = �
`
`00 =­� � .... � � 0 -�
`
`e VJ
`�el'.
`-..-l
`el'.
`-..-l
`\o
`"°
`el'.
`Cd ......
`
`00/492
`0 .5 5 0 0
`
`Fig. 1 3
`
`... �-
`
`I l
`
`--- --
`� �
`.�··
`�
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`
`- �
`
`0 .5 0 0 0
`
`0 .4 5 0 0
`
`0 .4000
`
`0 .3500
`
`0 . 30 0 0
`
`0 .2500
`
`0 . 20 00
`
`0 . 1 500
`
`0 . 1 00 0
`
`0 .0 5 0 0
`
`0 .0 0 0 0 ��
`ff
`
`--
`
`-/'
`
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`
`.�
`
`/ / �
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`/
`fl v
`� _/
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`1 00
`
`0. 39 0.097 0 .024 0.0061
`
`25 6.25 1 56
`A NTIBODY CONC. ug I ml
`AVIDITY EXPER IM ENT
`113 ! Y NB46, 1 . 8
`• C 0 4VHK O L -THR
`
`34 of 62
`
`BI Exhibit 1134
`
`

`

`us 6,767,996 l3 1
`
`1
`ALTERED ANTIBODIES ANO THEffi
`PREPARATION
`
`5
`
`This application is a 371 of PCT/GB91/01578, filed Sep.
`16, 1991.
`The present invention relates to altered antibodies and
`their preparation. The invention is typically applicable to the
`production of humanised antibodies.
`Antibodies typically comprise rwo heavy chains linked
`together by disulphide bonds and two light chains. Each 10
`light chain is linked to a respective heavy chain by disul­
`phide bonds. Each heavy chain has al one end a variable
`domain followed by a number of constant domains. Each
`light chain has a variable domain at ooc cod aod a constant
`
`domain al its other encl. The light chain variable domain is JS
`
`aligned with the variable domain of the heavy chain. The
`light chain constant domain is aligned with the first constant
`domain of the heavy chain. Tbc constant