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`4 of 947
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`Celltrion, Inc., Exhibit 1002
`
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`Celltrion, Inc., Exhibit 1002
`
`

`

`t1ft•.aPCrJPTr· 11uov-··,,.."'
`~
`
`08/1Li620h us
`s·
`tnnex b's~. page I
`.cant's Guide - Volume II - National Chaptc
`~ SS MAIL: BB214759358US
`MAILED:
`17 NOVEMBER 1993
`U.S. DEPAR;:!T~M~EN~;'f~O~F ~CO~M~M~E~RC~E~P~AT~E!!"!t."T~AN~'O~T~RA~D~E~M""!AR~l:~O~F~FIC~E~ATT~OR~N~.EY'~S~DOC~~ .. ET~N~U~M~BE~R;;..;.,;;;;;,;;;,;~..;;,,;;.;.;;.._
`
`PCT
`
`R
`
`-• •
`
`•
`
`fllljU
`FOl<M rro.1 )?0
`(REV 11-9iJ
`
`-- -r
`
`709Pl
`PRIORITY DATE CLAIMED
`14 June 1991 14.06.91
`
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`NTERNATIONAL Al'l'LICATION NO.
`PCT/US92/05126
`TITLE OF INVENTION
`METHOD FOR MAK.ING HUMANIZED ANTIBODIES
`Al'PLICANT(S) FOR DO/EO/US
`Paul J. CARTER Leonard G. PRESTA
`ppli~nt herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items under 35 U.S.C. 371:
`I. CD This express request to immediately begin national examination procedures (35 U.S.C. 37 J (f)).
`2. C!I The U.S. National Fee (35 U.S.C. 37l(c)(l)) and other fees as follows:
`(2) NUMBER FILED
`(3) NUMBER EXTRA
`-20 =
`23
`3
`-3 =
`10
`7
`
`(4) RATE
`x $22.00
`X$74.00
`+ $230.00
`
`(5) CALCULATIONS
`$
`
`518.00
`230.00
`
`'BAsrc NATXONAL FEE (37 CFR 1.492(a)(1)-(5))l
`. 0 For filing with EPO or JPO search report (37CFR I .492{a){5)).....
`0
`
`Intemational preliminary examination fee paid to USPTO (37 CFR 1.482)
`................................................................................................
`S640.00
`No international preliminary examination fee paid to USPTO (37 CFR 1.482)
`but international search fee paid to USPTO {37 CFR I .445(a)(2))..
`$710.00
`
`S830.00
`
`Neither international preliminary examination fee (37 CFR 1.482) nor
`international search fee (37CFR I .445(a)(2)) paid to USPTO.......
`$950.00
`
`International preliminary examination fee paid to USPTO (37 CFR 1.482)
`and all claims satisfied provisions of PCT Articles 33(2)-33(4)...
`$90.00
`
`950.00
`
`Surcharge ofSIJ0.00 for fumishing the National fee or oath or
`0 30 months from the earliest
`declaration later thanO 20
`claimed priority date (37 CFR l .492(e)).
`
`TOTAL OF ABOVE CALCULATIONS
`
`= 1,. 764.00
`
`Affidavit must be filed also.
`
`SUBTOTAL
`D 20 D 30
`
`+
`
`TOTAL NATIONAL FEE $1~764.00
`
`+
`
`40.00
`
`TOTAL FEES ENCLOSED 51,,804.00
`
`a. 0 A check in the amount of S
`to cover the above fees is enclosed.
`b. ~ Please charge my Deposit Accourit No. 07-0630
`in the amount of $ 1, 804. 00
`to cover the above fees.
`A duplicate copy of this sheet is enclosed.
`c. ~ The Commissioner is hereby authorized to c_ha~Jl8Y additional fees which may be required, or credit any
`O/-U-b3 '
`overpayment to Deposit Account No.
`A duplicate copy of this sheet is enclosed.
`
`(January 1993)
`
`6 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`-
`
`Ji"..
`
`I .
`i i\~;i;,. fr\ )ri·
`. US
`Annex U~.VI,,page.2.-. ·
`
`.
`.
`Applicant's Guide - Volume II - National Cl
`
`r- US
`
`.. .
`
`3.
`
`A copy of the International Application as filed (35 U.S.C. 37l(c)(2))
`a. bl is transmitted herewith (required only if not transmitted by the International bureau).
`b. ~ is not required, as the application was filed in the United States receiving Office (RO/US).
`c. D has been transmitted by the International Bureau.
`
`4. D A translation of the International Application into English (35 U.S.C. 37 l(c)(2)).
`
`5.
`
`Amendments to the claims of the International Application under PCT Anicle 19 (35 U.S.C. 371(c){3))
`a D
`are transmitted herewith (required only if not transmitted by the International Bureau).
`b. D
`have been transmitted by the International Bureau.
`
`7.
`
`6. D A translation of the amendments to the claims under PCT Anicle 19 (35 U.S.C. 371(c)(3)).
`IKJ An oath or declaration of the inventor (35 U.S.C. 37l(c)(4)).
`8. D A translation of the annexes to the International Preliminary Examination Report under PCT Article 36
`(35 U.S.C. 371(c)(5)).
`
`Other docwnent(s) or information included:
`9. D An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`
`10. ~ An assignment document for recording.
`PLEASE MAIL THE RECORQED ASSIGNMENT DOCUMENT TO :
`a. Cl the person whose signature, name and address appears at the bottom of this page.
`b. D
`the following:
`
`11.
`
`e.
`
`The above checked items are being transmited:
`a. 0
`before the eighteenth ( 18) month publication.
`b. D after publication of the Article 20 communication but before twenty (20) months from the priority date.
`c. D after twenty (20) months but before twenty-two (22) months (surcharge and/or processing fee included).
`d. O after twenty-two (22) months (surcharge and /or processing fee included).
`·
`NOTE: Petition to revive (37 CFR l.137(a) or (b)) is necessary ifJS U.S.C. 371 requirements submitted
`after 22 months and NO propel' dema11d for Intematio11al Preliminary Examination was made by 19 months
`from the earliest claimed prioriry date.
`!XI by thirty (30) months and a proper· demand for International Preliminary Examination was made by the 19th
`month from the earliest claimed priority date.
`f. O after thirty (30) months but before thirty-two (32} months and a proper demand for International Preliminary
`Examination was made by the 19th month from the earliest claimed priority date (surcharge and/or processing
`fee included).
`g. D after thirty-two (32) months (surcharge and/or processing fee included).
`NOTE: Petition to revive (37 CFR 1.137(a) or (b)) is necessary if JS U.S.C. 371 requirements submitted
`after 32 months and a proper demand for International Preliminary Examination was made by 19 months
`from the earliest claimed priority date.
`
`12.
`
`\
`
`At the time of transmittal, the time limit for amending claims under Article 19:
`IE has expired and no amendments were made.
`a.
`b. D has not yet expired.
`13. D Certain requirements under 35 U.S.C. 371 were previously submitted by the applicant on ________ _
`namely:
`14_ Submitted herewith arei
`Amendment:
`
`Sequence Diske~t:e, Sequence Listing, Preliminary
`
`Janet: E. Hasak
`NAME
`ADDRESS Genent:ech, Inc
`460 Loint San Bnmo Boulenai;d
`Sout: San Francisco, CA 94080-4990
`REGISTRATION NUMBER
`28,.616
`
`SIONA TURI!
`
`">"'1P10.lJ90(REv 11·92)
`
`Et~l 6 I i.~::
`n Ir{ I I"),.: n.:i-.:.:]
`
`7 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`I
`
`• CERTIFICATION UNDER 37 CFR 1.10
`
`HB214759358US: Express Mail Number
`
`17 NOVEMBER 1993 : Date of Deposit
`
`I hereby certify that this request to initial national processing, including: TRANSMITTAL
`LETTER, PRELIMINARY AMENDMENT, SEQUENCE LISTING & DISKETTE, COMBINED
`DECLARATION & POWER OF ATTORNEY, ASSIGNMENT and COPY OF PRELIMINARY
`EXAMINATION REPORT is being deposited with the United States Postal Service "Express
`Mail Post Office to Addressee" service under 37 CFR 1.10 on the date indicated above and
`is addressed to the Commissioner of Patents and Trademarks, Washington, D.C. 20231.
`
`Carol Koehler
`
`8 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`405
`
`H0405
`
`50
`40
`30
`20
`10
`OIVMTQSHKFMSTSVGORVSITCJCASQOVHTAVAWYQQKPGHSPKLLIYSASFRYT
`I
`1111
`I
`I
`I
`11
`111
`1111
`I
`I
`I
`I
`I I
`I l l
`OIQMTQSPSSLSASVGORVTITCRASQOVHTAVAWYQQKPGKAPKLLIYSASFLES
`1111
`I
`I
`1111
`I
`I
`OIQMTQSPSSLSASVGORVTITCRASQOVSSYLAWYQQKPGKAPKLLIYAASSLES
`
`405
`
`H0405
`
`100
`90
`80
`70
`60
`GVPDRFTGNRSGTOFTFTISSVQAEOLAVYYCQQHYTTPPTFGGGTKLEIKRA
`I I I I
`I
`I I
`I
`I
`I
`I
`I I
`I
`I t I I
`I
`I
`I
`I
`GVPSRFSGSRSGTDFTLTISSLQPEOFATYYCQQHYTTPPTFGQGTJCVEIKRT
`I
`1111
`I
`I
`1111
`I
`GVPSRFSGSGSGTOFTLTISSLQPEOFATYYCQQYNSLPYTFGQGTKVEIKRT
`
`9 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`•
`
`•
`
`PCT/US 92105126
`N/14&~&
`
`II
`II
`
`II
`II
`
`I
`I
`
`I
`I
`
`I
`I
`
`I
`I
`
`I
`I
`
`I
`I
`
`II
`II
`
`II
`II
`
`10
`20
`30
`40
`50 A
`EVQLQQSGPELVKPGASLKLSCTASGFNIXDTYIHWVKQRPEQGLEWIGRIYPTN
`EVQLVESGGGLVQPGGSLRLSCAASGFNIKD'l'YIHWVRQAPGKGLEWVARIYPTN
`EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVAVISENG
`---------
`
`Ill 1111
`111 1111
`
`I 1111
`I 1111
`
`v8 -cDa2
`
`60
`70
`80 ABC '·
`90
`100ABC
`GYTRYOPKFQOKATITAOTSSNTAYLQVSRLTSEOTAVYYCSRWGGDGFYAMDYW
`GYTRYAOSVKGRFTISAOTSKNTAYLQMNSLRAEOTAVYYCSRWGGDGFYAMDVW
`SOTYYADSVKGRFTISROOSKNTLYLQMNSLRAEDTAVYYCARDRGGAVSYFOVW
`
`11111111
`11111111
`
`I
`I
`
`I
`I
`
`111 ti
`111 II
`
`II I
`It
`I
`
`I
`I
`
`I
`I
`
`I
`I
`
`I
`I
`
`I
`I
`
`II 111111
`II 111111
`
`'-
`
`.. "'·
`
`t,-"
`
`,
`
`•' :-
`
`405
`
`HU405
`
`405
`
`HU405
`
`HUVHIII
`
`405
`
`HU405
`
`110
`GQGASVTVSS
`I I
`I I
`GQGTLVTVSS
`
`HUVHIII
`
`GQGTLVTVSS
`
`10 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`. .,.
`
`... . .
`
`•
`
`Anneal hu VL or huV8 oligomers to pAKl template
`
`1. Ligate
`2. Isolate assembled oligomers
`3. Anneal to pAKl template (XhoJ-, Stuf+)
`4. Extend and ligate
`
`I
`
`Xhol
`
`1. Transform E. coli
`2. Isolate phagemid pool
`3. Enrich for hu'l and huV8 (Xho I~ Stul-)
`4. ·Sequence verify
`
`pAK2
`
`11 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`~T/US 9 2 I .Q 5 1 2 6
`6f/;~.26,6
`
`100
`
`c: g.g 80
`-
`8 t!
`~'2 o::.
`-e 5 c. 60
`
`~=
`~8
`
`40
`
`I
`
`hu.MAb4DS-1
`
`huMAb4DS-8
`
`muMAb4DS
`
`4
`
`12
`8
`[MAb4D5 variant] µg/ml
`
`16
`
`12 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`If T!US 9 2 I 0 5 1 2 6
`'TT/US 92/0512 6
`' t1?//4'~~
`‘ Jay/4am
`
`'
`
`
`
`--
`
`. . . .-·
`
`13 of 947
`
`Celltrion, |nc., Exhibit 1002
`
`13 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`i' \(";·
`\.
`.._.
`'
`
`!
`
`~ .
`
`1r1us 921os12 6
`o if J Lite, z..o ~
`
`VL
`muxCD3
`huxCD3vl
`huKI
`
`20
`10
`40
`30
`• • • • • •
`DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKP
`**
`*
`*
`DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKP
`# #
`#
`DIQMTQSPSSLSASVGDRVTITCRASQSISNYLAWYQQKP
`
`CDR-Ll
`
`muxCD3
`huxCD3vl
`huKI
`
`60
`50
`80
`70
`••••••
`DGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEO
`****
`*
`*
`*
`* **
`GKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQP
`## ·#
`#
`GKAPKLLIYAASSLESGVPSRFSGSGSGTDFTLTISSLQP
`
`CDR-L2
`
`muxCD3
`huxCD3vl
`hulCI
`
`90
`100
`•••••••
`EDIATYFCQQGNTLPWTFAGGTKLEIK
`*
`*
`**
`*
`EDFATYYCQQGNTLPWTFGQGTKVEIK
`# #
`EDFATYYCQQYNSLPWTFGQGTKVEIK
`
`CDR-L3
`
`Vs
`muxCD3
`huxCD3vl
`huIII
`
`10
`20
`40
`30
`• • • • •
`EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQS
`**
`**
`*
`* ***
`*
`* *
`EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQA
`## ## # #
`EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQA
`
`CDR-Hl
`
`a
`50
`60
`70
`•
`• •••••••••
`muxCD3
`HGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAY
`*
`*
`**
`*
`**** ** **
`**
`huxCD3vl PGKGLEWVALINPYKGVTTYADSVKGRFTISVDKSKNTAY
`## #### # #
`# #
`#
`huIII
`PGKGLEWVSVISGDGGSTYYADSVKGRFTISRDNSKNTLY
`
`CDR-H2
`
`muxCD3
`huxCD3vl
`huIII
`
`80 abc
`90
`lOOabcde
`110
`••••••••
`MELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGAGTTVTVSS
`****
`**
`*
`*
`*
`LQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS
`########### #
`LQMNSLRAEDTAVYYCARGRVGYSLSGLYDYWGQGTLVTVSS
`D E T
`S
`.
`
`CDR-H3
`
`fl<JURt- 5
`
`14 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`'
`
`if ?T!US 9 2 /-0 5 1 2 6
`· o~/14rczorc,
`
`l'XGURB 6A
`
`H52H4-160
`
`pH52-8.0
`
`H52H4-160
`
`pH52-8.0
`
`H52H4-160
`pH52-8.0
`
`H52H4-160
`
`pH52-8.0
`
`H52H4-160
`pHS2-8.0
`
`H52H4-160
`pHS2-8.0
`
`H52H4.-160·
`
`pH52-8.0
`
`10
`20
`30
`QVQLQQSGPELVKPGASVKISCKTSGYTFTE
`·*** ·** **·**·*···** ********
`MGWSCIILFLVATATGVHSEVQLVESGGGLVQPGGSLRLSCATSGYTFTE
`10
`20
`30
`40
`50
`
`40
`50
`60
`70
`80
`YTMHWMKQSHGKSLEWIGGFNPKNGGSSHNQRFMDXATLAVOKSTSTAYM
`******·*· **·***··*·******·********· *··**********
`YTMHWMRQAPGKGLEWVAGINPKNGGTSHNQRFMDRFTISVOKSTSTAYM
`60
`70
`80
`90
`.
`100
`
`90
`100
`110
`120
`130
`ELRSLTSEDSGIYYCARWRGLNYGFDVRYFDVWGAGTTVTVSSASTKGPS
`•• ** ·**···********************** ** ************
`QMNSLRAEDTAVYYCARWRGLNYGFDVRYFDVWGQGTLVTVSSASTKGPS
`110
`120
`130
`140
`150
`
`140
`150
`160
`170
`180
`VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
`****** *·*** ·************************************
`VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
`160
`170
`180
`190
`200
`
`190
`200
`210
`220
`230
`QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVOKKVEPKSCDKTH
`************** **··***** ***·********** ** * *
`QSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVOKTVERJCCC---v
`210
`220
`230
`240
`
`240
`250
`260
`270
`280
`TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK
`*******
`··*************************************·
`ECPPCPAPP-VAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQ
`250
`260
`270
`280
`290
`
`290
`300
`310
`320
`330
`FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
`*******·*************·***·********·***************
`FNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVS
`300
`310
`320
`330
`340
`
`15 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`H52H4-160
`
`pHS2-8.0
`
`H52H4-l60
`
`pHS2-8.0
`
`H52H4-160
`
`pH52-8.0
`
`340
`350
`360
`370
`380
`NKALP!NPIEKTISKAKGQPREPQVYTLPPSREEMT~QVSLTCLVKGFY~-
`* * • * ** * * * * * * * * • * * * ** * • * * * ** * * ** ** ** * * * **** ** * ** * * *
`NKGLPAPIEKTISKTKGQPREPQVYTLPPSREEM'f.'ANQV~LTCLVKGFYP
`350
`360
`370
`390
`38~
`
`400
`390
`410
`420
`430
`SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS
`**********************······················~·····
`SDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSR~Q03NVFS
`410
`400
`420
`430
`440
`
`440
`450
`CSVMHEALHNHYTQKSLSLSPGK
`***********************
`CSVMHEALHNHYTQKSLSLSPGK
`450
`460
`
`16 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`l':IGURB IB
`
`H52L6-158
`
`30
`20
`10
`DVQMTQTTSSLSASLGDRVTINCRASQDINN
`*·****· ******·****** *********
`pH52-9.0 MGWSCIILFLVATATGVHSDIQMTQSPSSLSASVGDRVTITCRASQDINN
`20
`30
`40
`50
`10
`
`80
`70
`60
`50
`40
`H52L6-158 YLNWYQQKPNGTVKLLIYYTSTLHSGVPSRFSGSGSGTDYSLTISNLDQE
`*********
`• ***************************·****·*· *
`YLNWYQQKPGKAPKLLIYYTSTLHSGVPSRFSGSGSGTDYTLTISSLQPE
`60
`70
`80
`90
`100
`
`pH52-9.0
`
`130
`120
`110
`100
`90
`H52L6-158 DIATYFCQQGNTLPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS
`*·***·*******************************************
`DFATYYCQQGNTLPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS
`110
`120
`130
`140
`150
`
`pH52-9.0
`
`180
`170
`160
`150
`140
`H52L6-158 VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
`**************************************************
`VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
`160
`170
`180
`190
`200
`
`pHS2-9.0
`
`HS2L6-158
`
`pH52-9.0
`
`·210
`200
`190
`SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
`*********************************
`SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
`210
`220
`230
`
`I
`
`17 of 947
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`Celltrion, Inc., Exhibit 1002
`
`

`

`... J
`
`-,.- ____ ,__ ,, •. ----·-~·. '.""~_ ..
`
`I
`
`IMMUNOGLOBULIN VARIANTS
`
`:5
`
`10
`
`...... " ·.""'.
`
`15
`
`20
`
`25
`
`rr··
`
`30
`
`This invention relates to methods for the preparation and use of variant antibodies and
`application particularly in the fields of immunology and cancer diagnosis and therapy.
`
`Background of the Invention
`
`Naturally occurring antibodies (immunoglobulins) comprise two heavy chains linked
`together by disulfide bonds and two light chains, one light chain being linked to each of the
`heavy chains by disulfide bonds. Each heavy chain has at one end a variable domain (V H)
`followed by a number of constant domains. Each light chain has a variable domain CVL) at one
`end and a constant domain at its other end; the constant domain of the light chain is aligned
`with the first constant domain of the tieavy chain, and the light chain variable domain is
`aligned with the variable domain of the heavy chain. Particular amino acid residues are
`believed to form an interface between the light and heavy chain variable domains, see e.g.
`Chothia et al., J. Mo/. Biol. 186:651-663 ( 1985); Novotny and Haber, Proc. Natl. A cad. Sci.
`USA 82:4592-4596 {1985).
`The constant domains are not involved directly in binding the antibody to an antigen,
`but are involved in various effector functions, such as participation of the antibody in antibody(cid:173)
`dependent cellular cytotoxicity. The variable domains of each pair of light and heavy chains
`are involved directly in binding the antibody to the antigen. The do.mains of natural light and
`heavy chains have the same general structure, and each domain comprises four framework
`(FR} regions, whose sequences are somewhat conserved, connected by three hyper-variable
`or complementarity determining regions CCDRs) (see Kabat, E. A. et al., Sequences of Proteins
`of lf!lmunological Interest, National Institutes of Health, Bethesda, MD, (1987)). The four
`framework regions largely adopt a P-sheet conformation and the CDRs form loops connecting,
`and in some cases forming part of, the P-sheet structure. The CDRs in each chain are held in
`close proximity by the framework regions and, with the CDRs from the other chain, contribute
`
`18 of 947
`
`Celltrion, Inc., Exhibit 1002
`
`

`

`'!US 9 21 0 5 l 2 6
`
`s
`
`10
`
`15
`
`20
`
`25
`
`30
`
`to the formation of the antigen binding site.
`Widespread use has been made of monoclonal antibodies, particularly those derived
`from rodents including mice, however they are frequently antigenic in human clinical use. For
`example, a major limitation in the clinical use of rodent monoclonal antibodies is an
`anti-globulin response during therapy (Miller, R. A. et al., Blood 62:988-995 (1983); Schroff,
`R. W. et al., Cancer Res. 45:879-885 (1985)).
`The art has attempted to overcome this problem by constructing "chimeric" antibodies
`in which an animal antigen-binding variable domain is coupled to a human constant domain
`(Cabilly et al., U.S. patent No. 4,816,5-67; Morrison, S. l. et al., Proc. Natl. Acad. Sci. USA
`81:6851-6855 (1984); Boulianne, G. L. eta/., Nature 312:643-646 (1984); Neuberger, M. S.
`et al., Nature 314:268-270 {1985)). The term "chimeric" antibody is used herein to describe
`a polypeptide comprising at least the antigen binding portion of an antibody molecule linked
`to at least part of another protein (typically an immunoglobulin constant domain).
`The isotype of the human constant domain may be selected to tailor the chimeric
`antibody
`for participation
`in ·antibody-dependent cellular cytotoxicity
`(ADCC) and
`complement-dependent cytotoxicity (see e.g. Bruggemann, M. et al., J. Exp. Med.
`166:1351-1361 (1987); Riechmann, L. et al., Nature 332:323-327 (1988); Love et al.,
`Methods in Enzymology 178:515-527 (1989); Bindon et al., J. Exp. Med. 168:127-142
`(1988).
`In the typical embodiment, such chimeric antibodies contain about one third rodent (or
`other non-human species) sequence and thus are capable of eliciting a significant anti-globulin
`response in humans. For example, in the case of the murine anti-CD3 antibody, OKT3, much
`of the resulting anti-globulin response is directed against the variable region rather than the
`constant region (Jeffers, G. J. eta/., Transplantation 41:572-578 (1986)).
`In a further effort to resolve the antigen binding functions of antibodies and to minimize
`the use of heterologous sequences in human antibodies, Winter and colleagues (Jones, P. T.
`et al., Nature 321 :522-525 (1986); Riechmann, L. et al., Nature 332:323-327 (1988);
`Verhoeven, M. et al., Science 239:1534-1536 (1988)) have substituted rodent CDRs or CDR
`sequences for the corresponding segments of a human antibody. As used herein, the term
`"humanized" antibody is an embodiment of chimeric antibodies wherein substantially less than
`an intact human variable domain has been substituted by the corresponding sequence from a
`non-human species. In practice, humanized antibodies are typically human antibodies in which
`some CDR residues and possibly some FR residues are substituted by residues from analogous
`sites in rodent antibodies.
`
`19 of 947
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`
`

`

`•
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`3
`
`i/US 9 2 I 0 5 1 2 6
`
`The therapeutic promise of. this approach is supported by the clinical efficacy of a
`humanized antibody specific for the CAMPA TH-1 antigen with two non-Hodgkin lymphoma
`patients, one of whom had previously developed an anti-globulin response to the parental rat
`antibody (Riechmann, L. et al., Nature 332:323-327 (1988); Hale, G. et al., Lancet
`i: 1394-1399 ( 1988)). A murine antibody to the interleukin 2 receptor has also recently been
`humanized (Queen, C. et al., Proc. Natl. Acad. Sci. USA 86:10029-10033 (1989)) as a
`potential immunosuppressive reagent. Additional references related to humanization of
`antibodies include Co et al., Proc. Natl. Acad. Sci. USA 88:2869-2873 (1991 ); Gorman etal.,
`Proc. Natl. Acad. Sci. USA 88:4181-4185 (1991 ); Daugherty et al., Nucleic Acids Research
`19(9):2471-2476 (1991 ); Brown et al., Proc. Natl. Acad. Sci. USA 88:2663-2667 (1991 );
`Junghans et al., Cancer Research 50: 1495-1502 ( 1990).
`In some cases, substituting CDRs from rodent antibodies for the human CDRs in human
`frameworks is sufficient to transfer high antigen binding affinity (Jones, P. T. et al., Nature
`321 :522-525 (1986); Verhoeven, M. eta/., Science239:1534-1536 (1988)), whereas in other
`cases "it has been necessary to · additionally replace one (Riechmann, L. et al., Nature
`332:323-327
`(1988)) or several
`(Queen, C. et al., Proc. Natl. Acad. Sci. USA
`86:10029-10033 (1989)) framework region (FR} residu~s. See also Co eta/., supra.
`For a given antibody a small number of FR residues are anticipated to be important for
`antigen binding. Firstly for example, certain antibodies have been shown to contain a few FR
`residues which directly contact antigen in crystal structures of antibody-antigen complexes
`(e.g., reviewed in Davies, D. R. et al., Ann. Rev. Biochem. 59:439-473 (1990)). Secondly,
`a number of FR residues have been proposed by Chothia, Lesk and colleagues (Chothia, C. &
`Lesk, A. M., J. Mo/. Biol. 196:$01-917 (1987); Chothia, C. et al., Nature 342:877-883
`(1989); Tramontano, A. et al., J. Mo/. Biol. 215:175-H~2 (1990)) as critically affecting the
`conformation of particular CDRs and thus their contribution to antigen binding. See also
`Margolies eta/., Proc. Natl. Acad. Sci. USA 72:2180-2184 (1975).
`It is also known that, in a few instances, an antibody variable domain (either VH or VL)
`may contain glycosylation sites, and that this glycosylation may improve or abolish antigen
`binding, Pluckthun, Biotechnology 9:545-51 (1991 ); Spiegelberg eta/., Biochemistry 9:4217-
`4223 ( 1970); Wallie et al., J. Exp. Med. 168: 1099-1109 ( 1988); Sox et al., Proc. Natl. A cad.
`Sci. USA 66:975-982 (1970); Margni et al., Ann. Rev. lmmunol. 6:535-554 (1988).
`Ordinarily, however, glycosylation has no influence on the antigen-binding properties of an
`antibody, Pluckthun, supra, (1991 ).
`The three-dimensional structure of immunoglobulin chains has been studied, and crystal
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`20 of 947
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`Celltrion, Inc., Exhibit 1002
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`structures for intact immunoglobulins, for a variety of immunoglobulin fragments, and for
`antibody-antigen complexes have been published (see e.g., Saul et al., Journal of Biological
`Chemistry 25:585-97 (1978); Sheriff eta/., Proc. Natl. Acad. Sci. USA 84:8075-79 (1987);
`Segal et al., Proc. Natl. Acad. Sci. USA 71 :4298-4302 (1974); Epp et al., Biochemistry
`14(22):4943-4952 (1975); Marquart et al., J. Mo/. Biol. 141 :369-391 {1980); Furey et al.,
`J. Mo/. Biol. 167:661-692 (1983); Snow and Amzel, Protein: Structure, Function, and
`Genetics 1 :267-279, Alan R. Liss, Inc. pubs. ( 1986); Chothia and Lesk, J. Mo/. Biol. 196:901-
`917 (1987); Chothia eta/., Nature 342:877-883 (1989); Chothia eta/., Science 233:755-58
`( 1986); Huber et al., Nature 264:415-420 ( 1976); Bruccoleri et al., Nature 335:564-568
`(1988) and Nature 336:266 (1988); Sherman eta/., Journal of Biological Chemistry 263:4064-
`4074 (1988); Amzel and Poljak, Ann. Rev. Biochem. 48:961-67 (1979); Silverton et al., Proc.
`Natl. Acad. Sci. USA 74:5140-5144 (1977); and Gregory et al., Molecular Immunology
`24:821-829 (1987). It is known that the function of an antibody is dependent on its three
`dimensional structure, and that amino acid substitutions can change the three-dimensional
`structure of an antibody, Snow and Amzel, supra.
`It has previously been shown that the
`antigen binding affinity of a humanized antibody can be increased by mutagenesis based upon
`molecular modelling (Riechmann, L. et al., Nature 332:323-327 ( 1988); Queen, C. et al., Proc.
`Natl. Acad. Sci. USA 86:10029-10033 (1989)).
`Humanizing an antibody with retention of high affinity for antigen and other desired
`biological activities is at present difficult to achieve using currently available procedures.
`Methods are needed for rationalizing the selection of sites for substitution in preparing such
`antibodies and thereby increasing the efficiency of antibody humanization.
`The proto-oncogene HER2
`(human epidermal growth factor receptor 2) encodes a
`protein tyrosine kinase (p155HER2) that is related to and somewhat homologous to the human
`epidermal growth factor receptor (see Coussens, L. et al., Science 230: 1132-1139 ( 198 5);
`Yamamoto. T. et al., Nature 319:230-234 (1986); King, C. R. et al., Science 229:974-976
`( 1985))~- HER2 is also known in the field as c-erbB-2, and sometimes by the name of the rat
`homolog, neu. Amplification and/or overexpression of HER2 is associated with multiple human
`malignancies and appears to be integrally involved in progression of 25-30% of human breast
`and ovarian cancers (Slamon, D. J. eta/., Science 235:177-182 (1987), Slamon, D. J. eta/.,
`Science 244: 707-71 2 ( 1 989 >). Furthermore, the extent of amplification is inversely correlated
`with the observed median patient survival time (Slamon, supra, Science 1989).
`The murine monoclonal antibody known as muMAb405 (Fendly, B. M. et al., Cancer
`Res. 50: 1550-1558 ( 1990)), directed against the extracellular domain <ECO) of p 185HER2,
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`specifically inhibits the growth of tumor cell lines overexpressing p195HERl in monolayer
`culture or in soft agar {Hudziak, R. M. et al., Molec. Cell. Biol. 9: 1165-1172 ( 1989}; Lupu, R.
`et al., Science 249:1552-1555 (1990)). MuMAb405 also has the potential of enhancing
`tum