USOO7374757B2
`
`(12) United States Patent
`Papadopoulos et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,374,757 B2
`*May 20, 2008
`
`(54) MODIFIED CHIMERIC POLYPEPTIDES
`WITH IMPROVED PHARMACOKINETIC
`PROPERTIES
`
`(75) Inventors: Nicholas J. Papadopoulos,
`Lagrangeville, NY (US); Samuel Davis,
`New York, NY (US); George D.
`Yancopoulos, Yorktown Heights, NY
`(US)
`(73) Assignee: Regeneron Pharmaceuticals, Inc.,
`Tarrytown, NY (US)
`
`*) Notice:
`
`Subject to any disclaimer, the term of this
`y
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 489 days.
`This patent is Subject to a terminal dis
`claimer.
`
`(21) Appl. No.: 11/016,097
`
`(22) Filed:
`
`Dec. 17, 2004
`
`(65)
`
`Prior Publication Data
`US 2005/O163798 A1
`Jul. 28, 2005
`
`Related U.S. Application Data
`(62) Division of application No. 10/009,852, filed as appli
`cation No. PCT/US00/14142 on May 23, 2000, now
`Pat. No. 7,070,959.
`(60) Provisional application No. 60/138,133, filed on Jun.
`8, 1999.
`
`(51) Int. Cl.
`(2006.01)
`A6 IK 38/18
`(2006.01)
`C07K I4/7
`(2006.01)
`CI2N 5/62
`(52) U.S. Cl. ............................... 424/134.1; 424/192.1;
`514/2; 514/12:530/350,536/23.4
`(58) Field of Classification Search ..................... None
`See application file for complete search history.
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`1/1998 Kendall et al.
`5,712.380 A
`1/2000 Charnock-Jones et al.
`6,011,003 A
`6,100,071 A * 8/2000 Davis-Smyth et al. ..... 435/69.7
`2005/0043236 A1* 2/2005 Daly et al..................... 514/12
`2006/0058234 A1* 3/2006 Daly et al..................... 514/12
`FOREIGN PATENT DOCUMENTS
`
`WO
`
`WO97/.44453
`
`11, 1997
`
`WO
`WO
`
`WO98, 13071
`WO99/03996
`
`4f1998
`1, 1999
`
`OTHER PUBLICATIONS
`
`Terman, B.I., et al., “Identification of a new endothelial cell growth
`factor receptor tyrosine kinase”. Oncogene (1991) 6:1677-1683.
`Terman, B.I., et al., “Identification of the KDR tyrosine kinase as a
`receptor for vascular endothelial cell growth factor'. Biochem
`Biophys Res Comm (1992) 187(3): 1579-1586.
`Tsutsumi. Y., et al. "PEGylation of interleukin-6 effectively
`increases
`its
`thrombopoietic potency'. Thrombosis and
`Haemostasis (1997) 77(1): 168-173.
`Dunca, R. and Spreafico. F., “Polymer Conjugates'. Drug Delivery
`Systems (1994) 27(4):290-306.
`Hileman, R.E., et al., “Glycosaminoglycan-protein interactions:
`definitions of consensus sites in glycosaminoglycan binding pro
`teins”, BioEssays (1998) 20:156-167.
`deVries, Carlie, et al., “The fins-like tyrosine kinase, a receptor for
`vascular endothelial growth factor'. Science (1992) 225:989-991.
`Sharifi, J., et al., “Improving monoclonal antibody pharmacokinet
`ics via chemical modification'. Quart J Nucl Med (1998) 42:242
`249.
`Jensen-Pippo, K.E., et al., “Enteral bioavailability of human granu
`locyte colony stimulating factor conjugated with poly(ethylene
`glycol)”, (1996) Pharm Res 13(1):102-107.
`Tanaka, K., et al., “Characterization of the extracellular domain in
`vascular endothelial growth factor receptor-1 (Flt-1 Tyrosine
`kinase)', (1997) Jpn J Cancer Res 88:867-876.
`Yang, J.C., et al., “The use of polyethylene glycol-modified
`interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic
`renal cell carcinoma and melanoma', (1995) Cancer 76(4): 687
`694.
`Davis-Smyth, T., et al., 1996, “The second immunoglobulin-like
`domain of the VEGF tyrosine kinase receptor Flt-1 determines
`ligand binding and may initiate a signal transduction cascade'. The
`EMBO Journal 15(18):4919-4927.
`* cited by examiner
`Primary Examiner Christine J Saoud
`Assistant Examiner—Jon M Lockard
`(74) Attorney, Agent, or Firm—Gregg Valeta, Esq.
`
`(57)
`
`ABSTRACT
`
`Modified chimeric polypeptides with improved pharmaco
`kinetics are disclosed. Specifically, modified chimeric Flt 1
`receptor polypeptides that have been modified in Such a way
`as to improve their pharmacokinetic profile are disclosed.
`Also disclosed are methods of making and using the modi
`fied polypeptides including but not limited to using the
`modified polypeptides to decrease or inhibit plasma leakage
`and/or vascular permeability in a mammal.
`
`7 Claims, 55 Drawing Sheets
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 1 of 55
`Fig.1.
`
`US 7,374,757 B2
`
`1 2 3 4 5 6 7 8 9
`
`O
`
`- Pn.
`
`9.3
`
`5.2
`
`1 OO
`
`1 O
`
`O.O1
`
`O.
`
`1
`g/ml
`-H- rTE-2-FC
`......a...... acetylated Flt-1 (1-3)-FC
`----O---- unmodified Flt-1 (1-3)-Fc
`
`
`
`O.OO
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 2 of 55
`
`US 7,374,757 B2
`
`
`
`NO-SAT
`
`SALT-WASH
`
`SALT-WASH
`
`--
`VEGF
`Fit-1 (1-3)-FC -
`TIE-2-FC
`Heparin
`
`--
`--
`M
`
`-
`
`--
`
`13 14 15 16
`
`la
`7 18 1920
`
`222324
`
`--
`--
`+ acetylated + pegylated
`
`--
`--
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 3 of 55
`
`US 7,374,757 B2
`
`
`
`C)
`
`d
`2, 1
`C 6
`vs
`we
`N1
`,
`
`5 S.
`S 9
`cu
`O >
`S is E 3
`
`C CS
`
`s
`
`s
`
`s
`
`AISuedeodo
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 4 of 55
`
`US 7,374,757 B2
`
`
`
`
`
`. h
`(s
`Ol
`CD
`C
`-H
`CD C) 9 co
`co or 2
`
`
`
`
`
`y - v- N
`.
`.
`.
`t.
`
`It -O Ol
`d5 d5
`g
`E E 92 is
`cus
`S 5
`SSN
`S E is as
`S. 2 QP
`D D C n
`
`//
`
`
`
`/
`
`ci
`
`CN
`
`te
`
`s
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet S of 55
`
`US 7,374,757 B2
`
`Fig.6A.
`1 2 3 4 5 6 7 8 9 10
`
`Fig.6B.
`11 12 13 14 15 1617 18 1920
`
`
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 6 of 55
`
`US 7,374,757 B2
`
`
`
`Fig.7
`
`q
`- a
`asparurve
`
`P
`
`C
`a.
`
`-H rTIE-2-FC
`O
`KX....... unmodified Flt-1 (1-3)-FC
`----O---. acetylated Flt-1 (1-3)-Fo (10X)
`4. OfA---- acetylated Flt-1 (1-3)-Fo (20X)
`-------. acetylated Flt-1 (1-3)-Fc (30X)
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 7 Of 55
`
`US 7,374,757 B2
`
`Fig.8.
`
`0.5 ug/ml
`
`1.0 g/ml
`
`5.0 ug/ml
`
`--Degree of step-acetylation of Flt-1 (1-3)-Fo protein -->
`+ + + + + + + + + + + +
`
`-
`
`--
`
`ae
`
`s
`
`as
`
`a
`
`580
`
`
`
`380
`
`18O
`
`80
`
`-20
`
`VEGF
`0.2 pug/ml
`Unmodified
`Fit-1 (1-3)
`-FC
`
`Acetylated
`Fit-1 (1-3)
`
`ar
`
`H
`
`--
`
`H
`
`--
`
`--
`
`-
`
`--
`
`-
`
`-H
`
`--
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 8
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 8 of 55
`
`US 7,374,757 B2
`
`
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 9 of 55
`
`US 7,374,757 B2
`
`Fig.10A.
`
`10
`
`20
`s
`ATG GTC AGC TAC TGG GAC ACC GGG GTC CTG CTG TGC
`GCG CG
`TAC CAG TCG ATG ACC CTG TGG CCC CAG GAC GAC ACG
`CGC GAC
`Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys
`Ala Leu
`
`30
`
`40
`
`70
`t
`r
`t
`r
`ACA GGA TCT AGT TCA GGT TCA AAA TTA AAA GAT CCT
`GAA CTG
`CCT AGA TCA AG. CCA AGT
`CTT GAC
`TTT AAT TTT CIA GGA
`TGT
`Gly Ser Ser
`Gly Ser
`Lys Leu Lys Asp Pre
`Glu Lieu.
`Th
`Se
`
`100
`
`90
`
`30
`t
`ACA CTG CAT CTC CAA
`CAC
`ATC ATG CAA
`NGC AGG
`GGC CAG
`GCA
`TAG TAC GT
`ACG TCC
`TGT GAC GTA GAG GT
`
`CGT CCG GC
`Cys Arg
`Gly Glin
`Ile Met Glin
`Thr Leu. His Leu Glin
`Ala
`
`40
`
`150
`
`160
`
`y
`
`His
`
`50
`
`60
`
`AGC TGT. CTG
`CT CTC
`TCG ACA GAC
`GAA GAG
`Ser Cys Lieu
`e Lued
`
`10
`
`120
`
`TTA AAA GGC
`ACC CAG
`TGG GC
`AAT II CCG
`Leu Lys Gly
`Thr Gnd
`
`180
`
`170
`t
`CAT AAA
`GAA GCA GCC
`CTT CGT CGG
`GTA TTT
`His LysX
`Gli Ala Ala
`
`90
`
`200
`
`20
`
`220
`
`230
`
`t
`TCT TIG cor
`AGG CTG
`AGT AAG GAA AGC GAA
`
`GAA AIG GIG
`AGA AAC GGA
`TCC GAC
`TCA TTC CTT, TCG CTT
`
`CTT TAC CAC
`Ser Glu
`Glu.
`Ser Lys Glu
`Arg Lieul
`Met Val
`Ser Le Pro
`
`y
`
`r
`
`250
`y
`
`GGA AGA AA
`CCT TOT TTA
`Gly Arg Asn
`
`y
`
`y
`
`250
`
`270
`
`280
`r
`ACC G
`ITC IGC AGT ACT, TTA
`AAA CAA
`TGG AAC
`AAG ACG TCA
`GA AAT
`TTT GTT
`Lys Glin
`Phe Cys Ser
`Thr Leu
`Thr el
`
`240
`r
`
`r
`
`ATA ACT AAA TCT GCC
`AGA CGG
`TAT TGA TTT
`Ile Thr Lys
`Ser Alab
`
`290
`
`300
`
`ACA GCT CAA GCA AAC
`TGT, CGA GT CGT TG
`Thr Ala Gin
`Ala ASn>
`
`30
`r
`y
`ACT GGC TC
`TGA CCG AAG
`Thr Gly Phe
`
`His
`
`320
`
`330
`
`340
`
`350
`
`360
`
`At
`AAG AAG AAG GAA ACA
`CC ACT TOA
`AAA. TA CA
`GCT, GA
`AGC GC
`Tic TTC TTC CTT TGT
`GGA GA AGT
`CGA CAT
`CG ACG
`TTT ATA GAT
`Iys Llys Lys Gill. Thr)
`LyS Tyr Lieu.
`Ser Cys
`Pro
`Set
`Ala Val
`
`r
`
`380
`
`390
`
`370
`A.
`r
`t
`A.
`GTA GAG AG TAC AGT
`TCT GCA ATC
`AGA CCT TTC
`ATT AGT GAT
`ACA GGT
`
`TAT ATA TTT
`CAT CTC TAC AIG TCA
`TGT CCA CT GGA AAG
`AGA CG TAG
`TAA TCA CA
`ATA
`A. AAA
`Arg Pro Phe
`Val Glu Met Tyr Ser2
`Thr Gly
`Ile Ser Asp
`Glu
`Ser Ala Ile
`e Phe
`
`400
`vir
`
`y
`
`A.
`
`40
`
`420
`
`430
`
`440
`
`450
`
`460
`
`470
`
`480
`
`k
`k
`t
`ATT CCC TGC CGG GTT
`GAG CTC GTC
`GGA AGG
`ATC CCC GAA
`AG ACT GAA
`
`ATT ATA CAC
`TAA GGG ACG GCC CAA
`TAC TGA CT CCT, TCC CTC GAG CAG
`TAG GGG CTI
`
`AA TAT GTG
`Gly Arg
`lie Pro Cys Arg Vald
`Glu Leu Val
`Ile Pro Glu
`Met Thr Gu
`Ile His
`Ile
`
`y
`
`Glu
`
`490
`
`500
`
`510
`f
`A.
`'t
`A.
`ACT TTA AAA AAG TTT CCA CTT GAC ACT TTG ATC CCT GAT
`TCA CCT AAC
`ATC
`ACT GIT
`TGA AAT TTT TTC AAA GGT GAA CTG TGA AAC AG GGA CTA
`AGT GGA TG
`TAG
`GA CAA
`Lys Phe Pro Leu Asp Thr Lieu. Ile Pro Asp2
`Thr Leu Lys
`The Val
`Ile
`Ser Pro Asn
`
`520
`y
`
`t
`
`530
`
`540
`
`yir
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`May 20, 2008
`Fig.1OB.
`
`Sheet 10 Of 55
`
`US 7,374,757 B2
`
`r
`
`y
`
`y
`
`y
`
`570
`y
`
`580
`-r
`
`y
`
`y
`
`590
`
`600
`
`GGA AAA CGC ATA ATC
`ACG TAC AAA
`GGC TTC ATC ATA TCA AAT GCA
`TGG GAC AGT AGA AAG
`TGC ATG TTT
`CCT TTT GCG TAT TAG
`CCG AAG TAG TAT AGT TTA CGT
`ACC CTG TCA TCT, TTC
`Thr Tyr Lyss
`Gly Lys Arg Ile Ile
`Gly Phe Ile Ile Ser Asn Ala
`Trp Asp Ser Arg Lys
`
`60
`
`620
`
`660
`630
`r
`r
`t
`A.
`k
`AAT GGG CAT TIG TAT AAG
`GGG CTT
`ACA AAC TAT
`ACC TOT GAA GCA ACA
`ATA
`TTA CCC GTA AAC ATA TTC
`TGT TTG ATA
`CCC GAA
`GAC
`CAG
`TAT
`TGG ACA CTT CGT TGT
`ASn Gly His Leu Tyr Lys
`Thr Asn Tyr2
`Gly Leu
`Thr Cys Glu Ala Thr
`Ile
`Val
`Glu
`Leu
`
`640
`
`650
`
`670
`
`ACA CAT CGA
`GTA GCT
`His Arg
`
`730
`
`CTT AGA
`TTA
`GAA TCT
`AA
`Lieu. Arg
`Ieu
`
`Lys
`
`g
`
`CAA ATG
`GTI IAC
`Glin Met
`Val
`
`680
`
`690
`
`y
`
`700
`710
`GTC CAA ATA AGC ACA CCA
`ACC AAT ACA AC ATA
`GA
`CAG GTT TAT TCG TGI GGT
`CTA
`TGG TTA TGT TAG TAT
`Val Glin le Ser Thr Pro
`Thr Asn Thr le le
`
`t
`
`720
`t
`r
`CCA GTC
`GGT CAG
`Pro Wall
`
`780
`
`750
`740
`r
`s
`r
`TGT ACT GCT ACC ACT CCC
`AAT
`CAT ACT CTT GTC CTC
`ACA TGA CGA TGG GA. GGG
`TTA
`GTA GA GAA CAG GAG
`Cys Thr Ala Thr Thr Pro
`His Thr Leu Val Lieu
`Asn
`
`760
`y
`
`770
`
`AAC ACG
`TTG GC
`Asn Thr2
`
`Lieu
`
`790
`
`800
`
`81.0
`
`B20
`y
`
`830
`y
`
`840
`
`y
`
`AGA GCT. TCC GTA
`AAA AA AAG
`TGG AG TAC CCT GAT
`TCT CGA AGG CAT
`TTT, TTA TTC
`ICC GCT
`ACC CA AG GGA CA
`Arg Arg>
`Arg Ala Ser Val
`Lys ASn Lys
`Trp Ser Tyr Pro Asp
`Glu
`
`850
`
`ATT
`GAC CAA
`TAA
`CTG GTT
`Asp Gln
`Ile
`
`900
`870
`860
`A.
`1.
`k
`1.
`Air
`TTC TAC AGT
`GAC AAA
`GTT CTT ACT ATI
`AA
`AA TCC CAT GCC AAC
`CAA GAA GA 'AA
`AAG ATG TCA
`CIG TTT
`TA
`TTA AGG GTA CGG TG
`Asp LyS>
`Phe Tyr Ser
`Val Leu. Thir Ile
`ASn Ser His Ala ASn
`e
`
`t
`
`y
`
`890
`
`90
`
`920
`
`930
`
`AG
`AAC AAA
`GTC
`TAC
`TTG TTT
`ASn Lys
`Glin
`Met
`
`AAA GGA CTT TAT ACT
`TTT CCT GAA ATA TGA
`Lys Gly Leu Tyr Thr
`
`970
`
`98O
`
`990
`
`940
`A.
`
`950
`
`96.O
`
`y
`
`k
`AG GGA CCA CA
`CGT GA AGG
`TTC AAA
`AAG TTT
`TCA CCT GGT AGT
`GCA CAT NCC
`Phe Lys)
`Arg Val Arg
`Ser Gly Pro Ser
`
`LOOO
`
`1010
`
`102O
`t
`r
`t
`GGC GAG CCC AAA TCT TOT
`GCA GGC CCG
`CCG CTC GGG TTT AGA ACA
`CGT CCG GGC
`Gly Glu Pro Lys Ser Cys
`Ala Gly Pro
`
`GTT AAC ACC TCA GTG CAT ATA TAT GAT
`CAA TTG TGG AGT CAC GTA TAT ATA CTA
`LyS
`Val Asn Thr Ser Val His Ile Tyr Asp
`Ser
`
`r
`
`1040
`
`1050
`
`t
`
`1060
`k
`
`1070
`
`1080
`
`t
`
`y
`
`GAC AAA ACT CAC ACA TGC CCA CCG TGC CCA
`GCA CCT GAA CTC CTG GGG GGA CCG TCA GTC
`CTG TTT TGA GTG TGT ACG GGT GGC ACG GGT
`CGT GGA CTT GAG GAC CCC CCT GGC AGT CAG
`Asp Lys Thr His Thr Cys Pro Pro Cys Pro
`Ala Pro Glu Leu Leu Gly Gly Pro Ser Vald
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 11
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`May 20, 2008
`Fig.10C.
`
`Sheet 11 Of 55
`
`US 7,374,757 B2
`
`100
`
`1090
`r
`TTC CCC CCA AAA CCC
`AAG GGG GGTTTT GGG
`GAG
`AAG
`Phe Pro Pro Lys Pro
`Lel
`Phe
`
`110
`
`y
`
`1120
`
`1130
`
`1140
`
`y
`
`GAG GTC ACA
`ACC CCT
`CGG
`CIC ATG ATC. TCC
`GAC ACC
`CTC CAG TOST
`TGG GGA
`GCC
`GAG TAC TAG AGG
`CTG TGG
`Arg
`Asp Thr
`Glu Val Thr
`Tr Pro
`Leu Met le Ser
`
`Iys
`
`50
`
`160
`
`70
`
`A.
`
`y
`
`18O
`A.
`
`GTG GTG
`CAC CAC
`CAC
`Val Val
`Val
`
`CCT GAG GTC AAG
`GTG AGC
`GAA GAC
`CAC
`cAC TCG
`cTT CTG
`GGA CTC CAG TTC
`GTG
`Pro-Glu Val Lys
`Glu Asp
`His
`Val Ser
`
`90
`
`200
`
`r
`TAC GTG GAC
`AAC TGG
`ATG CAC CTG
`TTG ACC
`Tyr Val Asp
`Asn Trp
`
`1220
`
`120
`t
`GAG GIG
`AA GCC CAT
`CAC
`CTC CAC
`Gly Val
`Glu Val
`
`
`TTA CGG
`Asn Ala
`
`His
`
`1230
`
`ye
`
`240
`y
`
`CCG CGG GAG GAG
`ACA AAG
`GGC GCC CTC CTC
`TGT, TTC
`Thr Lys
`Pro Arg Glu Glu
`
`Lys
`
`250
`t
`
`260
`A.
`k
`AGC ACG TAC
`TAC AAC
`TCG TGC AIG
`AIG TTG
`Ser Thr Tyr
`Tyr Asn
`
`1290
`
`1300
`
`310
`
`320
`
`280
`t
`
`t
`GAG TAC AAG
`GGC AAG
`AAT
`CTG CAC CAG GAC TGG CTG
`
`CTC ACC GTC
`CTC ATG TTC
`CCG TTC
`GAC GTG GTC CTG ACC GAC
`TTA
`GAG TGG
`Gly Lys
`Glu Tyr Lys2
`Leu. His Glin Asp Trp Leu
`As
`Leu Thr
`Val
`
`1270
`y
`
`CGT GTG GTC AGC
`GCA CAC CAG TCG
`Arg Val Val Ser
`
`330
`y
`
`TGC AAG GTC TCC
`ACG TC CAG AGG
`CyS Lys Val Ser
`
`1390
`
`k
`GGG CAG CCC CGA
`CCC GTC GGG GCT
`Gly Glin Pro Arg
`
`1450
`y
`
`t
`AAC CAG GTC AGC
`TTG GTC CAG TCG
`ASn Glin Val Ser
`
`51O.
`y
`
`w
`GAG AGC AAT
`CTC TCG TA
`Glu Ser Asn
`
`340
`
`350
`
`360
`
`t
`CCA GCC CCC ATC GAG AAA
`AAA GCC
`CIC
`GGT CGG GGG TAG CTC TTT
`TTT CGG
`Pro Ala Pro Ile Glu, LyS
`Lys Alia
`Leu
`
`370
`t
`
`380
`
`AAA GCC AAA
`ATC TCC
`TTT CGG TTT
`TAG AGG
`Lys Ala Lys)
`Ile Ser
`
`1410
`
`1420
`1400
`r
`r
`k
`TAC ACC CTG CCC CCA TCC
`CCA CAG
`AG TGG GAC GGG GGT AGG
`CAC
`GGT GNC
`Tyr Thr Leu Pro Pro Ser
`Val
`Pro Gin
`
`460
`
`470
`y
`
`480
`A.
`
`r
`GTC AAA GGC TTC TAT COC
`CTG
`ACC TGC
`CAG TTT CCG AAG ATA GOGG
`TGG ACG
`Val Lys Gly Phe Tyr Pro
`Thr Cys
`
`Lieu
`
`1430
`
`1440
`r
`A.
`CTG ACC AAG
`GA GAG
`GAC TGG TTC
`CTA CTC
`Asp Glu
`Leu. Thr Lys2
`
`1490
`
`1500
`
`GAC ATC
`GCC GTG GAG
`CTG TAG
`CGG CAC CTC
`Asp Ile
`Ala Val Glu2
`
`1520
`
`530
`
`k
`
`1550
`
`1560
`1540
`k
`A.
`CTG GAC TCC
`CCC GTG
`AAC AACTAC AAG ACC ACG CCT
`GGG CAC
`TG TG ATG TTC TGG TGC GGA
`Asn Asn Tyr Lys Thr Thr Pro
`Pro Val
`
`CAG CCG
`GTC GGC
`Gln Pro
`
`Glu
`
`Leu Asp Ser>
`
`1570
`yk
`
`y
`
`158O
`r
`
`y
`
`1590
`t
`r
`k
`AGG TCG CAG CAG GGG
`AAG CTC ACC GTG GAC AAG AGC
`CTC TAC AGC
`GGC. TCC TTC
`TCC ACC GTC GTC CCC
`TTC GAG TGG CAC CTG TTC TCG
`CCG AGG AAG AAG GAG ATG TCG
`Arg Trp Glin Glin Gly>
`Lys Leu Thr Val Asp Lys Ser
`Gly Ser Phe Phe Leu Tyr Ser
`
`SOO
`r
`
`r
`
`1610
`
`1620
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 12 Of 55
`
`US 7,374,757 B2
`
`Fig.1OD.
`
`630
`
`640
`
`16SO
`
`1660
`
`1670
`
`1680
`
`AAC GTC TTC TCA TGC TCC GTG ATG CAT GAG GCT. CTG CAC AAC CAC TAC ACG CAG AAG AGC
`TTG CAG AAG AGT ACG AGG CAC TAC GTA CTC CGA GAC GTG G GTG ATG TGC GTC TTC TCG
`Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Serd
`
`690
`
`700
`
`s
`CTC CC CTG TCT CCG GGT AAA IGA
`GAG AGG GAC AGA. GGC COA. T ACT
`Leu Ser Leu Ser Pro Gly Lys * * * >
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 13
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 13 Of 55
`
`US 7,374,757 B2
`
`
`
`19 || ||ff66 926
`
`08/
`
`?ueuquuÐUuSueu L
`
`º || -61
`
`‘e’e 19 enb?un
`
`S S
`
`
`
`
`
`
`
`
`
`
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 14 of 55
`
`US 7,374,757 B2
`
`
`
`&
`
`3s
`
`S3
`
`S.
`
`S
`
`S
`
`9
`
`8888 8888 888
`u?in c5 cit c cici fui
`AloudolpAH
`
`C C C C C C C C C C C.
`Low cocq - d ... c. co Y up
`AloudolpAH
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 15
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`May 20, 2008
`Fig.13A.
`
`Sheet 15 of 55
`
`US 7,374,757 B2
`
`r
`
`r
`
`y
`
`r
`
`
`GTC CTG
`GTC AGC TAC TGG GAC ACC GGG
`ATG
`GAC
`CAG
`CAG TCG ATG ACC CTG TGG CCC
`TAC
`Val Ser Tyr Trp Asp Thr Gly
`Val
`Ieu
`Met
`
`30
`
`40
`
`50
`
`60
`
`y
`st
`TGC GCG CTG CTC AGC TGT. CTG CTT CTC
`ACG CGC GAC GAG TCG ACA GAC GAA GAG
`Cys Ala Leu. Leu Ser Cys Leu Leu Leux
`Leu
`
`70
`
`80
`
`90
`
`120
`OO
`r
`k
`y
`CCT GAA CTG AGT TTA AAA GGC ACC CAG
`GAT
`TA AAA
`GGA TCT AGT TCA GGT TCA AAA
`ACA
`GGA CTT GAC TCA AAT TTT CCG TGG GTC
`CTA
`AAT TTT
`CCT AGA TCA AGT CCA AGT TTT
`Pro Glu Leu Ser Leu Lys Gly Thr Gln)
`Asp
`Gly Ser Ser Ser Gly Ser Lys
`Leu Lys
`
`10
`
`ge
`
`30
`
`140
`st
`A.
`CAA TGC AGG GGG GAA GCA GCC CAT AAA
`CAT
`ATC AG CAA GOA. GGC CAG ACA
`CAC
`GTT ACG TCC CCC CTT CGT CGG GTA TTT
`GAG
`GA
`GAC
`TAG TAC GTT CGT CCG GTC TGT
`GTG
`Gln Cys Arg Gly Glu Ala Ala His Lys2
`His
`His Ile Met Glin Ala Gly Glin
`Leu
`Thr
`Leu
`
`150
`
`60
`
`17 O
`
`180
`
`190
`y
`
`200
`
`20
`
`TGG TCT TTG CCT GAA ATG GTG
`ACC AGA AAC GGA CTT TAC CAC
`Trip Ser Lieu Pro Glu Met Val
`
`Sea
`
`260
`250
`t
`t
`s
`k
`TGT GGA AGA AAT GGC AAA CAA
`ACA CCT TCT TTA CCG TT GTT
`Cys Gly Arg Asn Gly Lys Gln
`
`Glu
`
`270
`
`AGT
`
`Phe
`
`Ser
`
`220
`
`230
`
`240
`
`st
`GAA AGG CTG AGC ATA ACT AAA TCT, GCC
`CTT TCC GAC TCG TAT TOSA TTT AGA CGG
`Glu Arg Leu Ser Ile Thr Lys Ser Alad
`
`y
`
`290
`
`300
`
`r
`
`28O
`r
`AAC ACA GCT CAA GCA AAC
`TTA ACC TNG
`TTG TGT, CGA GTT CGT TTG
`AAT TGG AAC
`ASn Thr Ala Glin Ala Asn
`Leu. Thir Lell
`
`30
`
`320
`t
`A.
`TAT
`CAC ACT GGC TTC TAC AGC TGC
`ATA
`GTG TGA CCG AAG ATG CG ACG
`LyS
`His Thr Gly Phe Tyr Ser Cys
`
`330
`
`380
`
`370
`y
`A.
`k
`GAA TCT, GCA AC TAT ATA TTT
`AT
`CIT AGA CGT TAG ATA TAT. AAA
`TAA
`Glu Ser Ala Ile Tyr Ile Phe
`le
`
`430
`
`440
`
`r
`k
`ATG
`GAA ATC CCC GAA ATT ATA CAC
`CTT TAG GGG CTT TAA TAT GTG
`TAC
`Glu Ilie Pro Glu Ile Ile His
`
`340
`
`350
`
`360
`
`w
`TCA AAG AAG AAG GAA ACA
`GTA CCT ACT
`AGI ITC TTC TTC CTT TGT
`CAT GGA TGA
`Ser Lys Lys Lys Glu Thr)
`Val Pro Thr
`
`400
`
`40
`
`420
`y
`
`TTC GTA GAG ANG TAC AGT
`GGT AGA CCT
`AAG CAT CTC TAC ATG TCA
`CCA TC GGA
`Phe Val Glu Met Tyr Ser2
`Gly Arg Pro
`
`460
`
`470
`
`480
`A:
`GTC ATT CCC TGC CGG GTT
`AGG GAG CC
`CAG TAA GGG ACG GCC CAA
`TCC CTC GAG
`Gly
`Val Ile Pro Cys Arg Val)
`Arg Glu Lieu
`
`490
`sk
`
`y
`
`500
`t
`
`r
`
`510
`s
`
`k
`
`k
`ACG TCA CCT AAC ATC ACT GTT ACT TTA AAA AAG TTT CCA CTT GAC ACT TTG ATC CCT GAT
`TGC AGT GGA TTG TAG TGA CAA TGA AAT TTT TTC AAA GGT GAA CTG TGA AAC TAG GGA CTA
`Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Lieu Ile Pro Asp>
`
`520
`
`530
`
`540
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 16
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 16 of 55
`
`US 7,374,757 B2
`
`Fig.13B
`
`560
`
`r
`
`580
`
`A.
`
`570
`550
`t
`t
`k
`r
`TC AC ATA
`AGA AAG GGC.
`ATC TGG GAC AGT
`GGA AAA CGC ATA
`TCT TTC CCG AAG TAG TAT
`TAG ACC CTG TCA
`CCT TTT GCG TAT
`Arg Lys Gly Phe Ile Ile
`Gly Lys Arg Ile
`Ile Trp Asp Ser
`
`590
`y
`
`600
`y
`k
`AAT GCA ACG TAC AAA
`TTA CGT TGC ATG TTT
`AGT
`Asn Ala Thr Tyr Lys2
`Ser
`
`610
`
`620
`
`630
`
`f
`
`Glu
`
`r
`GCA ACA GTC AAT GGG CAT
`CG ACC GT GAA
`ATA GGG CT
`CGT TGT CAG TTA. CCC GTA
`GAC TGG ACA CT
`TAT CCC GAA
`Ala Thr Val ASn Gly. His
`Ile Gly Lieu
`Lieu. Thr Cys Glu
`
`640
`Ar
`
`570
`
`690
`680
`y
`t
`t
`t
`AC ATA GA GTC CAA ATA
`CAA ACC AAT ACA
`CAT CGA
`TAG TAT CA CAG GT TAT
`GTT TGG TTA TGT
`GA GCT
`Ile Ile Asp Val Glin Ile
`His Arg
`Glin Thr Asn. Thr
`
`OO
`r
`
`650
`
`660
`
`ACA AAC TAT
`"AT AAG
`TGT TTG ATA
`ATA TTC
`Thr Asn Tyr
`Tyr Lys
`
`720
`
`70
`r
`t
`CGC CCA GTC
`ACA CCA
`GCG GGT CAG
`TGT GGT
`Arg Pro Vald
`Thr Pro
`
`730
`
`740
`r
`
`750
`
`760
`k
`
`CT AGA
`TTA
`GAA TCT
`AAT
`Leu Arg
`Lieu
`
`GTC CTC AAT TGT ACT GCT
`CAT ACT CIT
`CAG GAG TA ACA GA CGA
`GTA GA GAA
`Cys Thr Ala
`Val Lieu.
`His Thr Leu
`Asn
`
`770
`
`780
`t
`TTG AAC ACG
`ACT CCC
`AAC TG TGC
`GA. GGG
`Pro
`Leu. ASn Thr)
`
`790
`
`CAA ATG
`GTT AC
`Gln Met
`
`800
`y
`
`820
`81.0
`w
`r
`ATT GAC CAA
`CCT GAT
`GAA
`TAC
`GG AGT
`TAA CTG GIT
`GGA CIA
`CTT
`AG
`ACC TCA
`Ile Asp Gln
`Pro Asp
`Glu
`Trip Ser
`
`830
`
`840
`y
`
`k
`CAT GCC AAC
`AAT TCC
`GTA CGG TTG
`TTA AGG
`His Ala Asn)
`Asn Ser
`
`850
`
`870
`r
`r
`CAG AAC AAA
`ATG
`GAC AAA
`CIT ACT
`GTT
`ATT
`TAC AGT
`GTC TTG TTT
`TAC
`CTG TTT
`TAA
`GAA GA
`ATG TCA
`Glin Asn. Lys
`Asp IyS
`Tyr Ser
`Val
`Ile
`Leu Thr
`
`t
`
`ATA
`TAT
`Ile
`
`890
`
`900
`r
`
`y
`
`AAA GGA
`CTT TAT ACT
`TTT CCT
`GAA ATA TGA
`Lys Gly
`Lieu Tyr Thr
`
`910
`
`GTA AGG
`CAT TCC
`Val Arg
`
`930
`
`940
`vk
`r
`GTG CAT AA TAT GAT
`GTT AAC ACC TCA
`TTC AAA
`GGA CCA
`CAC GTA TATATA CTA
`CAA TTG TGG AGT
`AAG TTT
`CCT GGT
`Val His Ile Tyr Asp>
`Phe Lys
`Val Asn. Thir Sea
`Gly Pro Ser
`Ser
`
`950
`
`960
`
`970
`
`98O
`
`990
`
`1000
`wir
`
`OO
`r
`
`t
`
`1020
`
`y
`
`r
`
`GGC CCG
`CCG GGC
`Gly Pro
`
`AAA ACT CAC ACA TGC CCA CCG TGC CCA
`GAC
`TCT TGT
`AAA
`GAG CCC
`TTT TGA GTG TGT ACG GG GGC ACG GGT
`AGA ACA
`TTT
`CTC GGG
`Lys Thr His Thr Cys Pro Pro Cys Prox
`Lys
`Ser Cys
`Glu Pro
`
`ASp
`
`O30
`
`1040
`
`1050
`
`1060
`
`1070
`
`1080
`
`CTC TC CCC CCA AAA CCC AAG GAC ACC
`TTC
`TCA GTC
`GGG GGA CCG
`GAA CTC
`GAG AAG GGG GGT TTT GGG TTC CTG TGG
`AAG
`AGT CAG
`CCC CCT GGC
`CTT GAG
`Leu Phe Pro Pro Lys Pro Lys Asp Thrx
`Leu Gly Gly Pro
`Phe
`Ser Val
`Glu Leu
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 17
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`May 20, 2008
`Fig.13C.
`
`Sheet 17 of 55
`
`US 7,374,757 B2
`
`1090
`
`ATC. TCC
`ATG
`TAG AGG
`TAC
`Ile Ser
`Met
`
`Leu
`
`ill.0
`y
`
`r
`
`100
`A.
`GIG GIG
`ACC CCT
`GTC ACA GC GTG
`GAG
`CAC CAC
`CAG TGT ACG CAC
`TGG GGA
`CTC
`Val Thr Cys Val
`Val Val
`Thr Pro
`Glu
`
`YA
`
`y
`
`ill40
`
`130
`t
`CAC GAA GAC
`GG AGC
`cAc TCG
`GTG CTT. CTG
`His Glu Asp)
`Val Ser
`
`1150
`
`60
`
`170
`
`118O
`
`190
`
`1200
`
`GGA
`Pro
`
`Pro
`
`GTC AAG
`CAG TTC
`Val Lys
`
`210
`
`GAG GAG
`CTC CIC
`Glu Glu
`
`r
`r
`AAG ACA AAG
`CAT AAT GCC
`GAG. GTG
`GG GAC GGC GTG
`AAC TGG
`TAC
`TTC TGT, TTC
`GA TA CGG
`CTC CAC
`CAC CTG CCG CAC
`TTG ACC
`ATG
`Lys Thr Lys)
`Val Asp Gly Val
`His ASn Ala
`Asn Trip
`Glu Val
`
`1220
`
`1230
`
`y
`
`y
`
`1260
`t
`r
`GTC
`GTC CTG CAC
`CIC ACC
`GTC AGC
`ACG TAC CGT GTG
`AC AAC
`AGC
`CAG GAC GTG
`GAG GG
`CAG TCG
`TGC AG GCA CAC
`ATG TTG
`Val Leu. His>
`Thr Tyr Arg Val
`Val
`Leu Thr
`Val Ser
`Tyr Asn
`Ser
`
`1240
`
`250
`
`1270
`
`1280
`
`1290
`r
`
`1300
`
`r
`
`30
`
`1320
`
`GTC TCC
`TAC AAG GC AAG
`GGC AAG
`TGG CTG,
`CAG AGG
`ATG TTC ACG TTC
`ACC GAC
`CCG TTC
`TA
`Gly Lys
`Tyr Lys Cys Lys
`Val Ser
`Trip Leu
`Glu
`ASn
`
`CTC CCA GCC
`AAA GCC
`GAG GGT CGG
`TTT CGG
`Lys Ala
`Leu Pro Ala)
`
`Glin
`
`1330
`
`1340
`
`1350
`"r
`
`350
`
`GAG AAA
`CCC
`ACC
`ATC TCC
`ATC
`TAG AGG
`CTC TTT
`TAG
`Glu Lys
`Ile Ser
`Ile
`
`Pro
`
`CCC CGA
`GGG CAG
`GCC AAA
`GGG GCT
`CCC GTC
`CGG TTT
`Gly Glin
`Ala Lys
`Pro Arg
`
`390
`
`1400
`
`40
`
`1420
`
`CCC
`CCA TCC
`GGT AGG
`GAC
`Leu
`to Ser
`Pro
`
`GAT GAG
`CTA CTC
`Asp Glu.
`
`GTC AGC
`ACC AAG.
`CAG TCG
`GTC
`TGG TTC
`Thr Lys
`Val Ser
`Asn Glin
`
`Leu
`
`450
`
`460
`
`1470
`
`y
`
`1480
`g
`
`370
`
`1380
`t
`r
`GTG
`TAC ACC
`CCA CAG
`AIG TGG
`GGT GTC
`Tyr Thre
`Val
`Pro Glin
`
`1430
`1440
`t
`r
`r
`GTC AAA
`ACC TGC
`TGG ACG
`CAG TTT
`Leu Val Lys)
`Thr Cys
`
`1490
`
`1500
`
`TAT CCC
`ATA GCG
`AAG
`Gly
`Tyr Pro
`Phe
`
`GAC ATC
`CTG TAG
`Asp Ile
`
`GG GAG
`CAC CTC
`Val Glu
`Ala
`
`AGC AAT
`TCG TA
`Ser Asn
`
`AAC AAC
`CAG CCG
`TTG TTG
`GTC GGC
`Glu ASn Asn)
`Glin Pro
`
`150
`
`1520
`
`TAC
`ATG
`
`ACC ACG
`TGG GC
`
`CCC GTG
`GGG CAC
`Pro Wall
`
`530
`ye
`
`r
`
`GAC TCC
`CG AGG
`Asp Ser
`
`1540
`
`TCC TTC
`CCG
`AGG AAG
`Gly
`Ser Phe
`
`550
`
`1560
`
`t
`
`t
`
`AAG CTC AGC
`CTC TAC
`TTC GAG
`TCG
`GAG AG
`Lys Leux
`Leu Tyr
`Ser
`
`1570
`
`1580
`
`1590
`
`GAC AAG
`CIG TTC
`Asp Lys
`
`CAG GGG
`AGG, TGG
`GTC CCC
`GTC
`TCC ACC
`Glin Gly ASn
`Arg Trip
`Glin
`Ser
`
`Thr
`
`160
`r
`
`y
`
`1620
`r
`A.
`A.
`CAT GAG
`TCC GTG ATG
`GTC TTC TCA
`GTA CTC
`ACG AGG CAC TAC
`CAG AAG AGT
`Cys Ser Val Met
`His Glux
`Val Phe Ser
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 18
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 18 of 55
`
`US 7,374,757 B2
`
`Fig.13D.
`
`1630
`
`1640
`
`1650
`1660
`k
`y
`A.
`y
`r
`GCT. CTG CAC AAC CAC TAC ACG CAG AAG AGC CTC. TCC CTG TCT CCG GGT AAA TGA
`CGA GAC GTG TTG GTG ATG TGC GTC TTC TCG GAG AGG GAC AGA GGC CCA TTT ACT
`Ala Lieu. His Asn His Tyr Thr Glin Lys Ser Leu Ser Leu Ser Pro Gly Lys * * * >
`
`670
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 19
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`May 20, 2008
`Fig.14A.
`
`Wr
`
`y
`
`rt
`
`yr
`
`Sheet 19 of 55
`
`US 7,374,757 B2
`
`30
`
`40
`
`50
`y
`
`60
`
`y
`
`GTC AGC TAC TGG
`GAC
`AIG
`CAG CG ATG ACC
`TAC
`Val Ser Tyr Trip
`Met
`
`AGC TGT CTG CTT
`CTC
`CTC
`CTG TGC GCG CTG
`ACC
`TCG ACA GAC GAA
`GAG
`GAG
`GAC ACG CGC GAC
`TGG
`CAG
`GAC
`CCC
`Gly
`Leu Cys Ala Leu
`Ser CyS Leu Leu
`Lell
`Leo
`Val
`Thr
`Leu
`
`70
`
`80
`
`90
`
`100
`
`O
`
`20
`
`GGT
`AGA
`GGA
`GGA TCT AG TCC
`ACA
`CCA
`CCT
`CCT AGA NCAAGG
`TGT
`Gly Gly
`
`Gly Ser Ser Ser
`
`GAA ATC CCC GAA
`AGT
`ATT
`ATG TAC
`GTA GAG
`CTT TAG GGG CTI
`TAA
`TAC AIG
`CAT CTC
`Ilex
`Glu Ile Pro Glu
`Met Tyr
`Val Glu
`Ser
`Phe
`
`130
`.
`
`k
`
`140
`
`150
`
`160
`
`170
`y
`
`80
`
`w
`ACG TCA CCT AAC
`GTT
`ATC
`ATT CCC TGC CGG
`GTC
`TGC AGT GGA TTG
`TAG
`TAA GGG ACG GCC
`Ile Pro CyS Arg
`Thir Ser Pro Asn
`Iled
`Wall
`Val
`
`GGA AGG
`CAC ATG ACT GAA
`ATA
`GTG TAC TGA CTT
`CCT TCC
`TAT
`Gly Arg
`His Met Thr Glu
`Glu
`Ile
`
`190
`r
`
`y
`
`k
`
`200
`
`20
`
`220
`
`AAG TTT
`AAA
`GTT ACT TTA
`ITT
`CAA TGA AAT
`TTC AAA
`Iys Phe
`Val Thr Lieu
`
`Pro
`
`ATC CCT
`ACT TTG
`TGA AAC
`TAG GGA
`le Pro
`Thir Leu
`
`230
`240
`k
`w
`GGA AAA CGC ATA
`ATC
`CCT TTT GCG TAT
`TAG
`Gly Lys Arg Ile
`Ilex
`
`260
`'k
`ATC
`GGC TTC
`ATA
`TAT
`TAG
`CCG AAG
`Gly Phe
`Ile
`Ile
`
`280
`
`290
`
`300
`
`ACG TAC
`AAT GOA
`TGC ATG
`TTA CGT
`Thr Tyr
`Asn Ala
`
`GAA ATA GGG CTT
`CTG
`CTT TAT CCC GAA
`Glu Ile Gly Leu
`Leu)
`
`330
`
`320
`wr
`
`340
`r
`ACA AAC
`TAT AAG
`CAT
`GTC AA
`TGT TIG
`ATA TTC
`GTA
`CAG TTA
`Tyr Lys
`Gly. His
`Thir ASIn
`Leu
`Val ASr.
`
`360
`
`350
`r
`'t
`CIC ACA CAT CGA
`GAG TGT GTA GCT
`Leu Thr His Arg
`Gln2
`
`380
`
`390
`
`400
`
`420
`A.
`
`k
`
`410
`k
`t
`GGC
`AAA TTA CTTAGA
`GTC
`ACA COA CGC CCA
`CCG
`TTT AAT GAA TCT
`TGT. GGT GCG GGT
`Gly>
`Lys Lieu. Leu Arg
`Val
`Thr Pro Arg Pro
`Ser
`
`250
`
`GAC AGT AGA
`CTG TCA ICT
`Asp Ser Arg
`
`30
`y
`
`GT GAA GCA
`ACA CT CG
`CyS Glu Ala
`
`370
`t
`
`t
`
`ACC
`
`CAAATA
`GAT GTC
`ATA
`AAT ACA ATC
`GTT TAT
`CTA CAG
`TAT
`TTA TGT TAG
`Asp Val
`Glin Ile
`ASn Thr Ie
`Ie
`
`430
`
`r
`CAT ACT CTT GTC
`GTA TGA GAA CAG
`His Thr Leu Val
`
`440
`
`450
`
`460
`r
`r
`ACT CCC TG AAC
`ACC
`ACT GCT
`AAT TGT
`GA GGG AAC TS
`TGA CGA
`TTA ACA
`Thr Pro Leu ASn
`Asn Cys
`Thr Ala
`
`490
`
`500
`
`510
`
`TGG AGT TAC CCT
`ACC TCA ATG GGA
`Trp Ser Tyr Pro
`
`r
`r
`AAT TCC CAT GCC
`AGC
`GAC CAA
`GAA ATT
`TA AGG GTA CGG
`CTG GIT
`CTT TAA
`Asp Gln
`Asn Ser His Ala
`Glu Ile
`
`Ser
`
`470
`
`480
`
`AGA GT CAA ATG ACC
`TCT CAA GTT TAC TGG
`Arg Val Glin Met Thr2
`
`530
`
`540
`y
`t
`ATA TTC TAC AGT, GTT
`TAT AAG ATG TCA CAA
`Ile Phe Tyr Ser Vala
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 20
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 20 of 55
`
`US 7,374,757 B2
`
`Fig.14B.
`
`560
`*
`
`ATG CAG
`
`TAC GTC
`Met Glin
`
`AAC
`TTG
`Asn
`
`620
`*
`
`TCT GIT
`AGA CAA
`Ser Val
`
`Asn
`
`*
`
`5B0
`*
`
`570*
`GAC AAA GGA CTT TAT ACT
`GAA ATA
`TGA
`CTs
`ect
`TTT
`Thr
`Leu Tyr
`ASP
`Lys
`Gly
`
`*
`
`590
`
`TGT CGT
`ACA GCA
`Cys Arg
`
`GTA
`CAT
`Val
`
`650
`
`630
`*
`
`TCA
`AGT
`Ser
`
`690
`
`640
`*
`
`GTG
`Cac
`val
`
`CAT
`GTA
`His
`
`ATA TAT
`TAT ATA
`Tle Tyr
`
`GAT
`CTA
`ASD
`
`AAA GCA
`TTT CGT
`Lys Ala
`
`ccs
`Gly
`
`700
`*
`
`710
`
`550
`*
`ATT GAC
`TAA CTG
`Ile Asp
`
`610
`*
`TCA TIC
`AGT AAG
`Ser Phe
`
`670
`*
`
`ABATCT
`TIT AGA
`Lys Ser
`
`730
`*
`
`CCG TCA
`GGC AGT
`Pro Ser
`
`750
`*
`
`*
`
`ACT
`TGA
`Thr
`
`Leu
`
`GGT
`Pro
`
`cece
`
`Glu
`
`Pro
`
`Gly
`
`acc
`
`680
`*
`
`GAC AAA
`cTG TIT
`Asp Lys
`
`740
`*
`
`TTC CTC
`AAG GAG
`Phe Leu
`
`BOO
`*«
`
`ACT
`
`ACA TGC
`TGT
`ACG
`
`CCA
`
`Pro
`
`Pro Cys
`
`Gca CCT
`
`GAA
`
`GGcT
`Pro
`
`Ala Pro
`
`Glu
`
`Leu Leu>
`
`Phe
`
`Pro
`
`B10
`
`760
`
`770
`
`780
`
`cece
`
`Pro
`
`AAG GAC
`TIC CTG
`Lys Asp
`
`Acc
`
`Thr
`
`cTC ATG
`GAG TAC
`Leu Met
`
`ATC
`TAG
`Tle
`
`Ser Arg>
`
`820
`
`830
`
`840
`
`AGC
`TCG
`Ser
`
`CAC GAA
`GTG CTT
`His Glu
`
`CCT GAG
`
`GTc
`
`Pro Glu
`
`Val
`
`GAG GTC
`cTc CAG
`Glu val
`
`Pro
`
`TOC GTG
`ACG CAC
`Cys Val
`
`GTG
`CAC
`val
`
`caACc
`Val
`
`850
`*
`
`860
`*
`
`ga8
`
`acc
`Trp
`
`TAC GTG
`ATG CAC
`Tyr Val
`
`GAC
`cis
`Asp
`
`GoC GTG
`ccG CAC
`Gly val
`
`ere
`Glu
`
`TAC
`ATG
`
`AAC
`
`Asn
`
`910
`*
`AGC ACG
`TCG TEC
`Ser Thr
`
`370
`
`920
`*
`
`TAC
`ATG
`
`CGT GTG
`GCA CAC
`Arg Val
`
`val
`
`980
`*
`
`CAC
`Val
`
`AAT
`TTA
`Asn
`
`Asp
`
`870
`
`GTA
`His
`
`930
`
`otc
`
`Val
`
`990
`
`GAG TAC
`CTC ATG
`Glu Tyr
`
`BAG
`TTC
`Lys
`
`TGC AAG
`ACG TTC
`Cys Lys
`
`GTC
`
`val
`
`1030
`
`1040
`
`AGG
`Ser
`
`Asn
`
`1050
`
`Gly
`
`ATC
`TAG
`Tle
`
`AAA GCC
`TIT CGG
`Lys Ala
`
`GGG CAG
`cee GTC
`Gly Gin
`
`CGA
`oct
`Arg
`
`GAA
`cTT
`Glu
`
`Pro
`
`Lys
`
`GGT
`Pro
`
`.GTC
`Gln
`
`GTG TAC
`CAC ATG
`Val Tyr
`
`acc
`
`ems CCC
`
`Leu Pro
`
`cTe
`Asp
`
`Lys Phe>
`
`B80
`
`890
`
`900
`
`TTC TOT
`Lys Thr
`
`940
`
`CCG CGG
`Goce Gcc
`Pro Arg
`
`950
`
`cre
`Glu
`
`cTe GTc
`Glu Gin>
`
`ace
`
`GTC CTG
`CAG GAC
`Val Leu
`
`oTG
`His
`
`CAG GAC
`GTC CTG
`Gln Asp
`
`TGG
`acc
`Trp
`
`1000
`
`1010
`
`CTC CCA
`GAG GGT
`Leu Pro
`
`CGG
`Ala
`
`CGG
`Ala
`
`ccc ATC
`GGG TAG
`Pro Ile
`
`1060
`
`1070
`
`*
`
`960
`*
`
`CTG AAT
`GAC TTA
`Leu Asn>
`
`1020
`*
`*
`AAA ACC
`GAG
`TTT TG
`crc
`Glu Lys Thr>
`
`1080
`*
`«
`CCA TCC CGG
`GGT AGG GcCc
`Pro Ser Arg>
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`Joining Petitioner: Apotex
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`
`Sheet 21 of 55
`
`US 7,374,757 B2
`
`Fig.14C.
`
`090
`
`100
`1130
`r
`w
`t
`y
`s
`GAT GAG CTG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GC AAA GGC TTC TAT CCC AGC
`CTA CTC GAC TGG TTC TTG GTC CAG TCG GAC TGG ACG GAC CAG TTT CCG AAG ATA GGG TCG
`Asp Gu Leu Thr Lys Asn Glin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
`
`110
`
`1120
`
`1140
`
`1150
`
`60
`170
`r
`s
`t
`k
`A.
`t
`'r
`GAC ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG AAC, AAC TAC AAG ACC ACG CCT
`CTG TAG CGG CAC CTC ACC CTC TCG TTA CCC GTC GGC CTC TTG TTG ATG TTC TGG TGC GGA
`Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Glin Pro Glu Asn Asn Tyr Lys Thr Thr Pro
`
`180
`
`11.90
`
`200
`
`120
`
`1220
`
`1230
`
`1240
`260
`k
`r
`t
`g
`r
`CCC GTG CTG GAC TCC GAC GGC. TCC TTC TTC CTC TAC AGC AAG CTC ACC GTG GAC AAG AGC
`GGG CAC GAC CTG AGG CTG CCG AGG AAG AAG GAG ATG TCG TTC GAG TGG CAC CTG TC TCG
`Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Llys Ser>
`
`1250
`
`280
`
`1270
`1290
`300
`r
`s
`r
`s
`y
`t
`t
`y
`AGG TGG CAG CAG GGG AAC GTC TTC TCA TGC TCC GTG ATG CAT GAG GCT. CTG CAC AAC CAC
`TCC ACC GTC GTC CCC TTG CAG AAG AGT ACG AGG CAC TAC GTA CTC CGA GAC GTG TTG GIG
`Arg Trp Glin Glin Gly. Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu. His Asn His>
`
`310
`
`320
`
`1340
`
`1330
`t
`t
`k
`TAC ACG CAG AAG AGC CTC. TCC CTG TCT CCG GGT AAA TGA
`AIG TGC GTC TTC TCG GAG AGG GAC AGA GGC CCA TTT ACT
`Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys * * * >
`
`1350
`
`Mylan Exhibit 1022
`Mylan v. Regeneron, IPR2021-00881
`Page 22
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`May 20, 2008
`Fig.15A.
`
`10
`
`30
`
`ATG
`TAC
`Met
`
`Sheet 22 of 55
`
`US 7,374,757 B2
`
`r
`AGC TGT
`CTT CTC
`CG GC GCG CG CTC
`CTG
`GTC CTVG
`ACC GGG
`AGC AC TGG
`GAC
`GAA GAG
`GAC
`TCG ACA
`GAC ACG CGC GAC GAG
`CAG GAC
`TGG CCC
`TCG AG ACC
`Ser Cys
`Thr Gly
`Leu. CyS Ala Lieu Lel
`Ser Tyr Trp
`Leu Lieud
`Leu
`Val Lieu.
`
`40
`t
`
`y
`
`r
`
`SO
`
`60
`
`yr
`
`70
`
`80
`
`90
`
`100
`
`y
`
`r
`
`O
`r
`
`120
`
`CCC
`GAA ATC
`GAA AT
`GTA GAG ATG AC AGT
`GGT AGA
`CCT TIC
`TCT AGT TCC
`CTT TAG
`CTT TAA
`CAT CTC TAC ATG TCA
`GGA AAG
`AGA TCA AGG
`CCA.
`Gly Gly
`Glu Ilex
`Val Glu Met Tyr Ser
`Glu Ile
`Pro Phe
`PO
`Ser Ser Ser
`
`30
`
`40
`
`50
`
`160
`
`t
`
`170
`
`80
`
`ATG ACT GAA
`ATA
`GGA AGG
`TAC TGA CTT
`GTG
`TAT
`CCT TOC
`Gly Arg
`le
`Met Thr
`His
`Glu
`Glu
`
`ACG TCA
`CCT
`AAC ATC
`AT CCC TGC CGG GT
`CTC GTC
`NGC AG GGA
`G AG
`TAA GGG ACG GCC CAA
`GAG CAG
`Cys Arg Val
`Thir Ser
`Pro ASn Ilex
`le Pro
`Lieu Val
`
`90
`
`2OO
`
`ACT TA
`TGA AA
`Thr Leu
`
`AAG TTT
`TNC AAA
`Lys Phe
`
`Pro
`
`220
`
`r
`
`k
`
`230
`210
`ar
`t
`t
`ATC ccT GAT
`GGA AAA
`CTT GAC
`ACT TTG
`AG GGA CA
`CCT TTT
`TGA AAC
`GAA CTG
`Gly Lys
`Ile Pro Asp
`Leu. Asp
`Thr Lieu
`
`240
`y
`t
`ATA ATC
`TAT TAG
`Arg
`Ile Ilex
`
`AGT AGA
`TCA TCT
`Ser Arg
`
`30
`
`GAA GCA
`cTT ccT
`Glu Ala
`
`ACC
`
`260
`
`270
`k
`ATA TCA
`GGC ITC
`ATC
`TTA
`TAT AGT
`TAG
`CCG AAG
`Gly Phe
`Ile Ser
`Ile
`Asn
`
`330
`
`320
`A.
`
`t
`AT
`CAT TIG
`GNC AAT
`ATA
`GTA AAC
`CCC
`CAG TA
`Gly
`His Leu
`Wall Asn
`
`280
`
`290
`
`300
`
`CTT. CTG
`GAA ATA
`GGG
`ACG AC AAA
`GAA GAC
`CTT TAT
`TGC ATG ITT
`Gly
`Thr Tyr Lys
`Glu Ile
`Lieu. Leu)
`
`340
`r
`
`y
`
`350
`k
`
`360
`t
`
`k
`
`CA CGA CAA
`CTC ACA
`ACA AAC TAT
`GTA GCT GTT
`GAG TGT
`TGT TTG ATA
`His Arg Glind
`Thr Asn Tyr
`