US008029791B2
`
`(12) United States Patent
`Papadopoulos et a1.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,029,791 B2
`*Oct. 4, 2011
`
`(54) MODIFIED CHIMERIC POLYPEPTIDES
`WITH IMPROVED PHARMACOKINETIC
`PROPERTIES
`
`(75) Inventors: Nicholas J. Papadopoulos,
`LaGrangeville, NY (U S); Samuel Davis,
`New York, NY (US); George D.
`Yancopoulos, Yorktown Heights, NY
`(Us)
`
`(73) Assignee: Regeneron Pharmaceuticals, Inc.,
`Tarrytown, NY (U S)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 492 days.
`This patent is subject to a terminal dis
`claimer.
`
`(21) Appl.No.: 12/102,666
`
`(22) Filed:
`
`Apr. 14, 2008
`
`(65)
`
`Prior Publication Data
`
`US 2009/0081217 A1
`
`Mar. 26, 2009
`
`Related US. Application Data
`
`(60) Continuation of application No. 11/016,097, ?led on
`Dec. 17, 2004, now Pat. No. 7,374,757, which is a
`division of application No. 10/009,852, ?led as
`application No. PCT/US00/ 14142 on May 23, 2000,
`now Pat. No. 7,070,959.
`
`(60) Provisional application No. 60/138,133, ?led on Jun.
`8, 1999.
`
`(51) Int. Cl.
`(2006.01)
`A61K 38/18
`(2006.01)
`C07K 14/71
`(52) US. Cl. ................. .. 424/1341; 424/1921; 514/11;
`514/133; 514/21.2; 530/350
`(58) Field of Classi?cation Search ...................... .. None
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,712,380 A
`1/1998 Kendall et a1.
`6,011,003 A
`1/2000 Charnock-Jones et al.
`6,100,071 A
`8/2000 Davis-Smyth et a1.
`6,897,294 B2
`5/2005 Davis-Smyth et a1.
`7,279,159 B2 * 10/2007 Daly et a1. ............... .. 424/1341
`7,396,664 B2*
`7/2008 Daly et a1. ................. .. 435/697
`2/ 2005 Daly et al.
`2005/0043236 A1
`12/2005 Davis-Smyth et a1.
`2005/0281831 A1
`3/2006 Daly et al.
`2006/0058234 A1
`
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`WO97/44453
`11/1997
`WO98/13071
`4/1998
`WO99/03996
`1/1999
`
`OTHER PUBLICATIONS
`
`Terman et al., 1991, “Identi?cation of a new endothelial cell growth
`factor receptor tyrosine kinase”, Oncogene 6: 1677-1683.
`Terman et al., 1992, “Identi?cation of the KDR tyrosine kinase as a
`receptor for vascular endothelial cell growth factor”, Biochem
`Biophys Res Comm 187(3):1579-1586.
`Tsutsumi et al., 1997, “PEGylation of interleukin-6 effectively
`increases its thrombopoietic potency”, Thrombosis and Haemostasis
`77(1):168-173.
`Dunca and Sprea?co 1994, “Polymer Conjugates”, Drug Delivery
`Systems 27(4):290-306.
`Hileman et al., 1998, “Glycosaminoglycan-protein interactions: de?
`nitions of consensus sites in glycosaminoglycan binding proteins”,
`BioEssays 20: 156-167.
`Devries et al., 1992, “The fms-like tyrosine kinase, a receptor for
`vascular endothelial growth factor”, Science 225:989-991.
`Shari? et
`al.,
`1998, “Improving monoclonal antibody
`pharmacokinetics via chemical modi?cation”, Quart J Nucl Med
`42:242-249.
`Jensen-Pippo et al.,1996, “Enteral bioavailability of human granulo
`cyte colony stimulating factor conjugated with poly(ethylene gly
`col)”, Pharm Res 13(1)102-107.
`Tanaka et al., 1997, “Characterization of the extracellular domain in
`vascular endothelial growth factor receptor-1 (Flt-1 Tyrosine
`kinase)”, Jpn J Cancer Res 88:867-876.
`Yang et al., 1995, “The use of polyethylene glycol-modi?ed
`interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic
`renal cell carcinoma and melanoma”, Cancer 76(4): 687-694.
`Davis-Smyth 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 * Valeta Gregg; Frank R.
`Cottingham
`
`ABSTRACT
`(57)
`Modi?ed chimeric polypeptides with improved pharmacoki
`netics are disclosed. Speci?cally, modi?ed chimeric Fltl
`receptor polypeptides that have been modi?ed in such a way
`as to improve their pharmacokinetic pro?le are disclosed.
`Also disclosed are methods of making and using the modi?ed
`polypeptides including but not limited to using the modi?ed
`polypeptides to decrease or inhibit plasma leakage and/or
`vascular permeability in a mammal.
`
`9 Claims, 55 Drawing Sheets
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 1 of 55
`
`US 8,029,791 B2
`
`Fig.1.
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`0.001
`
`0.01
`
`0.1
`
`1
`
`10
`
`100
`
`ug/ml
`——{}— rTIE-2-Fe
`often acetylated Fit-1(1-3)-Fe
`----O---- unmodified Fit-1(1-3)-Fe
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`

`

`US. Patent
`
`0a. 4, 2011
`
`Sheet 2 0155
`
`US 8,029,791 B2
`
`g
`+ E mm mm 5
`
`+
`
`+
`
`35.38 +
`
`m? m? w? m?
`
`6mm
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`
`com
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`2:
`
`o
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`i
`
`l
`
`“EMS
`
`“mini Em
`
`PTNME
`
`56%:
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`

`

`US. Patent
`
`0a. 4, 2011
`
`Sheet 3 0155
`
`US 8,029,791 B2
`
`Him. 5 IE $5855 .L1l
`
`
`
`uulm- 5 IE 885mg .III
`
`8-8-3-5 EESQQ ll
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`:Em:
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`v0.0
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`50.0
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`H5O
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`

`

`US. Patent
`
`0a. 4, 2011
`
`Sheet 4 0155
`
`US 8,029,791 B2
`
`l
`
`l
`
`lll'b
`
`55%; + 0.1-6-521 8:605: 1....
`
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`
`0.1.8.: EE 8§a8< 1T
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`/
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`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`

`

`5.85
`5.20
`
`4.55
`
`3.75
`
`Fig.6B.
`
`3.50
`i112 13 14 15 1617 1819 20CNY
`
`U S Patent
`U.S. Patent
`
`0a. 4, 2011
`Oct. 4, 2011
`
`Sheet 5 0155
`Sheet 5 of 55
`
`US 8,029,791 B2
`US 8,029,791 B2
`
`'6A
`Fig.6A.
`
`123 45 67 8
`
`9
`
`10
`
`9.3
`8.65
`8.45
`8.15
`7.35
`6.85
`
`6.55
`
`5.85
`5.20
`4.55
`
`3.75
`3.50
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`

`

`US. Patent
`
`0a. 4, 2011
`
`Sheet 6 0155
`
`US 8,029,791 B2
`
`Fig.7.
`
`0.8
`
`0.6
`
`---
`
`-——[]—— rTIE-2-Fc
`unmodi?ed Flt-1(1-3)-Fc
`---—O---- acetytated Flt-1(1-3)-Fc (10X)
`.... “Am-- acetylated FIt-1(1-3)-Fc (20X)
`"HEB."- acetylated Flt-1 (1 -3)-Fc (30X)
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`

`

`US. Patent
`
`0a. 4, 2011
`
`Sheet 7 0155
`
`US 8,029,791 B2
`
`Fig.8.
`
`580
`
`0.5 pg/ml
`
`1.0 pg/ml
`
`5.0 pg/ml
`
`480 "
`
`,
`
`380 -
`
`RU
`
`280 I
`
`180
`
`80
`
`20 0 10 2o 30
`0
`5
`w
`'
`'
`0o
`l<--- Degree of step-acetylation of F!t-1(1-3)-Fc protein "+1
`VEGF++++++++++++
`0.2ug/ml
`Unmodified
`
`Flt-1(1-3)
`
`-Fc
`Ace'tyiated
`Flt-1 (1-3)
`-Fc
`
`-
`
`+
`
`-
`
`-
`
`-
`
`-
`
`-
`
`_
`
`-
`
`_
`
`_
`
`_
`
`.
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+ +
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 8
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 8 of 55
`
`US 8,029,791 B2
`
`
`
`
`
`+(XOL)94-(€-1)L-pereyAjeor
`
`
`
`0+-(E-L)Lalpey!powun
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`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 9 of 55
`
`US 8,029,791 B2
`
`Fig.10A.
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`ATG GTC AGC TAC TGG GAC ACC GGG GTC CTG CIS TOC Geo CIG CIC Act TOT CTS CIT cre
`TAC CAG TCG ATG ACC CTG TGG CCC CAG GAC GAC ACG CGC GAC GAG TCG ACA GAC GAA GAG
`Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser Cys Leu Leu Leu>
`
`*
`
`70
`*
`
`*
`
`80
`*
`
`*
`
`80
`*
`
`ee
`
`100
`*
`
`*
`
`110
`*
`
`*
`
`120
`v
`
`ACA GGA TCT AGT TCA GGT TCA AAA TTA AAA GAT CCT GAA CTG AGT TTA AAA GGC ACC CAG
`TGT CCT AGA TCA AGT CCA AGT TTT AAT TTT CTA GGA CTT GAC TCA AAT TIT CCG TGG GTC
`Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pre Glu Leu Ser Leu Lys Gly Thr Gln>
`
`*
`
`130
`*
`
`*
`
`140
`*
`
`*
`
`150
`*
`
`*
`
`160
`*
`
`*
`
`170
`*
`
`*
`
`180.
`*
`
`CAC ATC ATG CAA GCA GGC CAG ACA CIG CAT CIC CAA TGC AGG GGG GAA GCA GCC CAT AAA
`GTG TAG TAC GIT CGT CCG GTC TGT GAC GTA GAG GTT ACG TCC CCC CIT CGT CGG GTA TIT
`His Ile Met Gln Ala Gly Gln Thr Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys>
`
`*
`
`190
`*
`
`*
`
`200
`4
`
`210
`*
`
`*
`
`*
`
`220
`*
`
`*
`
`230
`*
`
`240
`*
`
`*
`
`TGG TCT TTG CCT GAA ATG GIG AGT AAG GAA AGC GAA AGG CTG AGC ATA ACT AAA TCT GCC
`ACC AGA AAC GGA CTT TAC CAC TCA TTC CTT TOG CTT TCC GAC TCG TAT TGA TIT AGA CG
`Trp Ser Lau Pro Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Tle Thr Lys Ser Ala>
`
`*
`
`*
`
`*
`
`*
`
`*
`
`290
`*
`
`300
`*
`
`*
`
`250
`*
`
`260
`*
`
`270
`*
`
`280
`*
`
`7G'T GGA AGA AAT GGC AAA CAA TTC TGC AGT ACT TTA ACC TING AAC ACA GCT CAA GCA AAC
`ACA CCT TCT TTA CCG TTT GTT AAG ACG TCA IGA ART TGG AAC TYG TGT CGA GTT COT TIG
`Cys Gly Arg Asn Gly Lys Gln Fhe Cys Ser Thr Leu Thr Leu Asn Thr Ala Gin Ala Asn>
`
`*
`
`310
`*
`
`*
`
`320
`*
`
`330
`*
`
`*
`
`340
`
`*
`
`*
`
`350
`*
`
`360
`*
`
`*
`
`CAC ACT GGC TIC TAC AGC TGC AAA TAT CTA GCT GTA CCT ACT TCA AAG AAG AAG GAA ACA
`GTG TGA CCG AAG ANG TCG ACG TTT ATA GAT CGA CAT GGA IGA AGT TTC TIC TIC CIT TT
`His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val Pro Thr Ser Lys Lys Lys Glu Thr>
`
`*
`
`370
`*
`
`*
`
`360
`*
`
`390
`*
`
`*
`
`*
`
`400
`*
`
`*
`
`410
`*
`
`420
`*
`
`*
`
`GAA TCT GCA ATC TAT ATA TIT ATT AGT GAT ACA GGT AGA CCT TIC GTA GAG ANG TAC AcT
`CTT AGA CGT TAG ATA TAT AAA TAA TCA GTA [GT CCA TCT GGA AAG CAT CTC TAC ATG TCA
`Glu Ser Ala Tle Tyr Ile Phe Ile Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyz Ser>
`
`*
`
`430
`*
`
`*
`
`440
`*
`
`*
`
`450
`*
`
`*
`
`460
`*&
`
`*
`
`470
`*
`
`480
`*
`
`*
`
`GAA ATC CCC GAA ATT ATA CAC ATG ACT GAA GGA AGG GAG CIC GTC ATT CCC TGC CGG GIT
`CTT TAG GGG CIT TAA TAT GIG TAC TGA CTT COT TCC CTC GAG CAG TAA GGG ACG GCC CAA
`Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val>
`
`*
`
`490
`*
`
`*
`
`500
`©
`
`*
`
`510
`*
`
`*
`
`$20
`*
`
`*
`
`530
`*
`
`*
`
`540
`*
`
`ACG TCA CCT AAC ATC ACT GIT ACT TTA AAA AAG TTT CCA CTT GAC ACT TTG ATC CCT GAT
`TGC AGT GGA TTG TAG TGA CAA TGA AAT TTT TIC 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 Leu Ile Pro Asp>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 10 of 55
`
`US 8,029,791 B2
`
`Fig.10B.
`
`*
`
`*
`
`*
`
`5
`
`*
`
`570
`
`x.
`
`580
`*
`
`590
`
`600
`
`GGA AAA
`CcT TTT
`Gly Lys
`
`CGC ATA ATC
`GCG TAT TAG
`Arg Ile fle
`
`TGG GAC
`ACC CTG
`frp Asp
`
`AGT
`
`Ser
`
`AGA
`TT
`Arg
`
`BAG
`TTC
`Lys
`
`Goce TTC
`CCG AAG
`Gly Phe
`
`ATC ATA
`TAG TAT
`Ile Ile
`
`TCA
`AGT
`Ser
`
`AAT GCA AGG TAC AAA
`ToC
`ATG TIT
`TTA CCT
`Thr
`Asn Ala
`Tyr Lys>
`
`610
`*
`
`*
`
`620
`*
`
`630
`
`&
`
`640
`*
`
`650
`*
`
`*
`
`660
`*
`
`ATA
`TAT
`Glu Ile
`
`GGG CTT CTs
`ccc GAA GAC
`
`ACC Tot
`TGG ACA
`
`Gly Leu Leu
`
`Thr Cys
`
`CET
`Ala
`
`Glu
`
`ACA
`TST
`Thr
`
`GTC AAT
`CAG TTA
`Val Asn
`
`GGG CAT
`cee GTA
`
`Gly His
`
`TAT AAG
`ATA TIC
`Tyr Lys
`
`ACA
`
`Thr
`
`AAC TAT
`TTG ATA
`Asn Tyr>
`
`BAC
`Leu
`
`670
`*
`
`*
`
`680
`*
`
`CAT CGA CAA
`GTA GCT GTT
`
`His Arg Gin
`
`ACC AAT
`ToS TTA
`Thr Asn
`
`690
`
`700
`*
`
`710
`*
`
`ATC
`TAG
`Tle
`
`ATA
`TAT
`Tle
`
`GAT GTC
`CTA CAG
`
`Asp Val
`
`CAA ATA
`GTT TAT
`Gin Ile
`
`TGT GGT
`Thr Pro
`
`720
`*
`
`oa
`
`CCA GTC
`Got CAG
`Pro Val>
`
`730
`¥
`
`*
`
`740
`*
`
`750
`
`760
`*
`
`770
`*
`
`780
`*
`
`*
`
`CTT AGA Got
`GAA TOT CCG
`Leu Arg Gly
`
`CAT ACT
`GTA TGA
`His Thr
`
`err
`
`Leu
`
`GTC
`CAG
`Val
`
`eT¢c
`GAG
`Leu
`
`AAT TGT
`TTA ACA
`Asn Cys
`
`ACT GCT
`TGA CGA
`Thr Ala
`
`acT cece
`TGA GGG
`Thr Pro
`
`TTS
`AAT
`Leu
`
`AAC ACG
`TTS TSC
`Asn Thr>
`
`790
`*
`
`*
`
`800
`*
`
`810
`
`820
`*
`
`830
`&
`
`*
`
`840
`*
`
`cect
`GGA
`Pro
`
`GRA
`CTT
`Glu
`
`AGA
`
`Get tee
`CGA AGG
`Ala Ser
`
`GTA
`CAT
`Val
`
`GTT
`CAA
`Vail
`
`CAA ATG ACC
`GTT TAC TGG
`Gin Met Thr
`
`TAC
`TGS AGT
`ACC TCA ATG
`Tyr
`Trp Ser
`
`850
`*
`
`*
`
`860
`*
`
`GAT
`CTA
`Asp
`
`870
`
`ABA
`TTT
`Lys
`
`AAT AAG
`TTA TTC
`Asn Lys
`
`Arg
`
`880
`*
`
`890
`*
`
`AGG CGA
`Tee Ger
`Arg Arg>
`
`$00
`*
`
`*
`
`Got
`
`ATT
`TAA
`Tle
`
`GAC CAA AGC
`CTG GTT TCG
`Asp Gin Ser
`
`ABT TCC
`TIA AGG
`Asn Ser
`
`CAT
`GTA
`His
`
`ace
`
`Ala
`
`ATA
`TAT
`Tie
`
`TTC
`AAG
`Phe
`
`TAC AGT
`ATG TCA
`Tyr Ser
`
`GTT
`
`Val
`
`CTT ACT
`GAA TGA
`Leu Thr
`
`ANT
`TAA
`Ile
`
`GAC ABA
`CTS TIT
`asp Lys>
`
`910
`*
`
`*
`
`920
`*
`
`940
`*
`
`950
`*
`
`ATG
`TAC
`Met
`
`CAG
`ote
`Gin
`
`AAC AAA GAC
`TTG TIT CTS
`Asn Lys Asp
`
`cTT
`
`Leu
`
`TAT
`ATA
`Tyr
`
`TST
`ACA
`cys
`
`Cot
`
`arg
`
`AGT
`
`Ser
`
`*
`
`960
`*
`
`TTC AAA
`AAG TIT
`Phe Lys>
`
`Ser
`
`ABA GGA
`TIT cect
`Lys Gly
`
`970
`*
`
`*
`
`580
`*
`
`TT
`
`Ser
`
`GTT
`CAL
`Val
`
`BAC ACC TCA
`TTS TGG AGT
`Asn Thr Ser
`
`GTtG CAT
`caAc GTA
`Val His
`
`ATA
`TAL
`Ile
`
`1030
`*
`
`*
`
`1040
`*
`
`*
`
`990
`*
`
`TAT GAT
`ATA CTA
`Tyx Asp
`
`1050
`*
`
`*
`
`CGT
`Ala
`
`Lys
`
`GTA AGG
`CAT TCC
`Val Arg
`
`1000
`*
`
`GG CCG
`ccs GEC
`Gly Pro
`
`1060
`*
`
`GGA CCA
`CCT Got
`Gly Pro
`
`1010
`*
`
`1020
`*
`
`*
`
`GAG cCtc
`CTC Gos
`Glu Pro
`
`BAR
`
`Lys
`
`TCT TOT
`AGA ACA
`Ser Cys>
`
`1070
`*
`
`1080
`*
`
`*
`
`AAA
`
`Lys
`
`ACT CAC ACA
`TGA GTG TGT
`Thr His Thr
`
`TGC CCA
`ACG GGT
`Cys Pro
`
`Ces
`oct
`Pro
`
`TGC CCA
`ACG GGT
`Cys Pro
`
`ceT
`GGA
`Pro
`
`GAA CTC
`CTT GAG
`Glu Leu
`
`Ala
`
`Leu
`
`cece cect
`Gly Gly
`
`ccGe
`
`Pro
`
`TCA GTC
`AGT CAG
`Ser Val>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 11
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 11
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 11 of 55
`
`US 8,029,791 B2
`
`Fig.10C.
`
`1090
`*
`
`*
`
`1100
`*
`
`1110
`*
`
`*
`
`1129
`*
`
`*
`
`1130
`"
`
`*
`
`1140
`*
`
`©
`
`cre
`GAS
`Leu
`
`TTC CCC CCA AAA CCC
`BAG GGG GGT TTT GGG
`Phe Pro Pro Lys Pro
`
`AAG
`
`Lys
`
`GAC ACC
`CTS TG
`Asp Thr
`
`CY ATG AT TCC CGG
`GAG TAC TAG AGG GCC
`Leu Met Ile Ser Arg
`
`AcC ccT
`TGG GGA
`Thr Pro
`
`GAG
`CTc
`Glu
`
`GTC ACA
`CAG TGT
`Val Thr>
`
`12150
`*
`
`*
`
`1160
`*
`
`1170
`*
`
`*
`
`*
`
`1180
`*
`
`*
`
`1190
`*
`
`1200
`*
`
`*
`
`GTG
`CAC
`Val
`
`ACG
`Cys
`
`GTG GTG GAC GTG AGC
`Cac CAC CTG Cac TOG
`Val Val Asp Val Ser
`
`CAC
`GTG
`His
`
`GAA GAC
`CTT CiIc
`Glu Asp
`
`CCT GAG GTC AAG
`GGA CTC CAG TIc
`Pro Glu Val Lys
`
`AAG
`Phe
`
`BAC TGG
`TTS ACC
`Asn Trp
`
`TAC
`ATG
`Tyr
`
`GTG GAC
`CAC CG
`Val Asp>
`
`1210
`*
`
`&
`
`1220
`*
`
`1230
`*
`
`*
`
`1240
`*
`
`*
`
`‘*
`
`1250
`*
`
`1260
`*
`
`¥
`
`Gis
`CAC
`Val
`
`GAG GTG CAT AAT GCC
`cTe CRC GTA TTA CGG
`Glu Val His Asn Ala
`
`BAG
`
`Lys
`
`ACA AAG
`GT TTC
`Thr Lys
`
`COG CGS GAG GAS
`Gee ect cre cto
`Pro Arg Glu Glu
`
`Gte
`Gln
`
`TAC ARC
`ATG [TG
`Tyr Asn
`
`Acc
`
`Ser
`
`ACG TAC
`Tac ATG
`Thr Tyr>
`
`1270
`*
`
`*
`
`1280
`*
`
`GTG
`CAC
`Val
`
`GTC ac GTC cic acc
`CAG TCG CAG GAG TGG
`Val Ser Val Leu Thr
`
`ote
`
`Val
`
`1330
`*
`
`*
`
`1340
`*
`
`*
`
`1290
`*
`
`CTG CAC
`GAC GT¢
`Leu His
`
`1350
`*
`
`*
`
`1300
`*
`
`*
`
`*
`
`1310
`*
`
`41320
`*
`
`*.
`
`CAG GAC TGG CTG AAT
`GTC CTG ACC GAC 'TTA
`Gln Asp Trp Leu Asn
`
`GGC AAG
`cee TIC
`Gly Lys
`
`GAG
`er
`Glu
`
`TAC AAG
`ATG TTC
`Tyr Lys>
`
`1380
`*
`
`t
`
`1360
`*
`
`*
`
`GTC TCC ARC AAA GCC
`CAS AGG TIG TTT cGG
`Val Ser Asn Lys Ala
`
`ere
`GAG
`Leu
`
`CCA GCC
`Got Ca¢G
`Pro Ala
`
`Coc ATC GAG AAA
`GGG TAG CIc TTT
`Pro Ile Glu Lys
`
`Cys
`
`1350
`*
`
`*
`
`1400
`*
`
`1410
`*
`
`*
`
`1420
`*
`
`xk
`
`1370
`*
`
`ATC TC
`TAG AGG
`Iie Ser
`
`ABA
`
`Lys
`
`GCC AAA
`cee TTT
`Ala Lys>
`
`1430
`*
`
`1440
`*
`
`*
`
`*
`
`*
`
`cece
`Gly
`
`GI¢
`Glin
`
`CcC CGA GAA CCA CAG
`
`GGG GCT CTT GGT GTC
`Pro Arg Glu Pro Gin
`
`GTG
`CAC
`val
`
`TAC ACC
`Arc Tod
`Tyr Thr
`
`CTG Ccce CcaA Tec
`GAC GGG GGT AGS
`Leu Pra Pro Ser
`
`GAT GAG
`CTA CTC
`Asp Glu
`
`ots
`GAC
`Leu
`
`ACC AAG
`TSG TIC
`Thr Lys>
`
`Gece
`Arg
`
`1450
`*
`
`*
`
`1460
`*
`
`1470
`*
`
`*
`
`1480
`*
`
`*
`
`*
`
`1490
`*
`
`1500
`*
`
`*
`
`ote
`Gin
`
`GTC AGC CTG Acc TGC
`CAG TCG GAC TGG ACG
`Val Ser Leu Thr Cys
`
`cTs
`Gac
`Leu
`
`GTC AAA
`CAG TTT
`Val Lys
`
`Goce TTC TAT CCC AGC
`COG AAG ATA GGG
`Gly Fhe Tyr Pro Ser
`
`GAC ATC
`CTs TAG
`Asp Ile
`
`GTG GAG
`CAC cre
`Val Glu>
`
`CGS
`Ala
`
`1510
`¥
`
`*
`
`1520
`*
`
`1530
`*
`
`*
`
`1540
`*
`
`*
`
`1550
`*
`
`*
`
`ACC
`
`ere
`Glu
`
`AGC AAT GGG CAG CCG
`TOG TTA CCC GTC GGC
`Ser Asn Gly Gin Pro
`
`GAG
`
`Glu
`
`AAC AAC
`TTG TTG
`Asn Asn
`
`TAC AAG ACC ACG CCT
`ATG TIC 166 TSt
`Tyr Lys Thr Thr Pro
`
`ccc GTG
`GGG CAC
`Pro Val
`
`gs
`GAC
`Leu
`
`1560
`*
`
`*
`
`Gae TC
`CTG AGG
`Asp Ser>
`
`1620
`*
`
`*
`
`1570
`*
`
`*
`
`1580
`*
`
`Toc PTC TIC crc TAC
`AGG AAG AAG GAG ATG
`Ser Phe Phe Leu Tyr
`
`AGC
`
`Ser
`
`cece
`Gly
`
`1590
`*
`
`af
`
`AAG CTC
`TTC GAG
`Lys Leu
`
`1600
`*
`
`*
`
`*
`
`1610
`*
`
`ACC GTG GAC AAG AGC
`TOG CAC CTG TTC TCG
`Thr Val Asp Lys Ser
`
`AGG TOG
`TCC ACC
`Arg Trp
`
`CAG CAG GGG
`GTC eT¢ ccc
`Gin Gln Gly>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 12 of 55
`
`US 8,029,791 B2
`
`Fig.10D.
`
`*
`
`1630
`*
`
`*
`
`1640
`*
`
`1650
`*
`
`*
`
`*
`
`1660
`*
`
`*
`
`1670
`*
`
`1680
`*
`
`*
`
`AAC GTC TIC TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC ACG CAG AAG AGC
`TIG CAG AAG AGT ACG AGG CAC TAC GTA CTC CGA GAC GIG TTG GTG ATG TGC GIC TC NG
`Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser>
`
`*
`
`1690
`*
`
`*
`
`1700
`*
`
`crc TCC CTG TCT CCG GGT AAA TGA
`GAG AGG GAC AGA GGC CCA TYT ACT
`
`Leu Ser Leu Ser Pro Gly Lys ***>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 13
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 13
`
`

`

`U.S. Patent
`
`
`
`
`
`SethESLEv669C6cL8\6S40S/189ossSpGREO08
`
`082
`
`
`
`
`easeBUlJejN|eoes7U}SUBIGWUOWUSUE1Buipuigpuebyseynyjeoesyx>
`ufeulopBIsulewop
`
`
`
`NZN9NSNevNENe
`
`“LEBis
`
`Oct. 4, 2011
`
`Sheet 13 of 55
`
`US 8,029,791 B2
`
`SXSSS
`SES
`
`‘2-2Leenbiun
`
`ss8dS}--4SNO
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`SNUILUI9]-9
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`(CL
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`s78SiSSy7SSxS]L-HASNEcCcL
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`
`ss
`
`dS]basNv
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`s™dS}b-udSNZ
`
`=dS}b-L14wewny
`
`|ONplowoulwy
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`
`
`
`
`

`

`US. Patent
`
`0a. 4, 2011
`
`Sheet 14 0155
`
`US 8,029,791 B2
`
`00? ow 0m 0w 0m
`
`.<w if
`
`cm 00 0h 0m 0m av 0m 0m 0 F
`
`.mm If
`
`AumuudwpKH
`
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`
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`
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`
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`
`00.0
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 15
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 15 of 55
`
`US 8,029,791 B2
`
`Fig.13A.
`
`*
`
`*
`
`1
`
`*
`
`30
`
`40
`*
`
`50
`*
`
`*
`
`60
`*
`
`ATG
`TAC
`Met
`
`ote
`CAG
`Val
`
`AGC TAC TGG
`TCG ATG ACC
`Ser Tyr Trp
`
`GAS ACC
`CTs Tac
`Asp Thr
`
`GGG
`cece
`Gly
`
`GTC
`CAG
`Val
`
`Cogs
`GAC
`Leu
`
`cigs
`GAC
`Leu
`
`TGC
`ACG
`Cys
`
`GCG CTG
`CGC GAC
`Ala Leu
`
`ere
`GAG
`Leu
`
`AGC IGT
`OG ACA
`Ser Cys
`
`cis
`GAC
`Leu
`
`cTT crc
`GAA GAGS
`Leu Leu>
`
`70
`*
`
`*
`
`BO
`*
`
`106
`*
`
`110
`*
`
`*
`
`120
`*
`
`ACA
`
`TCT AGT TCA
`AGA TCA AGT
`Ser Ser Ser
`
`GGT TCA
`CCA AGT
`Gly Ser
`
`cect
`Gly
`
`AAT
`Leu
`
`Lys
`
`ccrT
`
`Pro
`
`GAA CTG
`CTT GAC
`Glu Leu
`
`AGT
`TCA
`Ser
`
`TTA AAA
`AAT DTT
`Leu Lys
`
`Goce
`ce
`Gly
`
`ACC CAG
`TSG GTe
`Thr Gln>
`
`CTA
`Asp
`
`130
`*
`
`*
`
`140
`*
`
`Ag
`TAG
`Tle
`
`ATG CAA GCA
`TAC GIT CGT
`Met Gln Ala
`
`GTS
`His
`
`Goc CAG
`CoG GTC
`Gly Gin
`
`ACA
`TOT
`Thr
`
`GAC
`Leu
`
`GAG
`Leu
`
`Gort
`Gin
`
`190
`*
`
`*
`
`200
`*
`
`160
`*
`
`TGC AGG
`ACG ToC
`Cys Arg
`
`220
`*
`
`ace
`Trp
`
`AGA
`Ser
`
`TTS CCT GAR
`AAC GGA CTT
`Leu Pro Glu
`
`ATG GTG
`TAC CAC
`Met Val
`
`AGT
`TCA
`Ser
`
`GAA
`cTT
`Glu
`
`AGG CTG
`TCC GAC
`Arg Leu
`
`TCG
`Ser
`
`250
`*
`
`*
`
`260
`*
`
`acT
`
`TTA
`AAT
`Leu
`
`170
`*
`GAR GCA
`CTT Cot
`Glu Ala
`
`180
`*
`
`*
`
`cece
`GG
`Ala
`
`CAT ABA
`GTA TTT
`His Lys>
`
`230
`*
`
`240
`*
`
`*
`
`ATA ACT
`TAT TGA
`Tle Thr
`
`AMA
`
`Lys
`
`pot Gece
`AGA CGG
`Sex Ala>
`
`290
`*
`
`300
`
`GTT
`Gln
`
`Cet TTS
`Ala Asn>
`
`Ser
`
`AAC
`
`AGA BAT GGT
`TCT TTA Cce
`Arg Asn Gly
`
`AAA CAA
`TIT GTT
`Lys Gin
`
`cer
`Gly
`
`AAG
`Phe
`
`ACG
`cys
`
`310
`*
`
`*
`
`320
`*
`
`280
`*
`ACC TTG
`TGG AAC
`Thr Leu
`
`340
`*
`
`ACA GCT
`TGT CGA
`Thr Ala
`
`Asn
`
`ACT
`
`Thre
`
`GGC TTC TAC
`COG AAG ATG
`Gly Phe Tyr
`
`AGC TGC
`TCG ACG
`Ser Cys
`
`TOT
`Lys
`
`GTG
`His
`
`TAT
`ATA
`
`CTA
`GAT
`Leu
`
`oct
`
`Ala
`
`GTA
`CAT
`Val
`
`cer acT
`GGA TGA
`Pro Thr
`
`TCA
`AGT
`Ser
`
`370
`*
`
`*
`
`380
`*
`
`cTT
`Glu
`
`AGA
`Ser
`
`GCA ATC TAT
`CGT TAG ATA
`Ala Ile Tyr
`
`ATA TIT
`TAT AAA
`Tle Phe
`
`ATT
`TAA
`Tle
`
`AST
`
`Ser
`
`430
`*
`
`*
`
`440
`*
`
`390
`
`GAT
`CTA
`Asp
`
`450
`
`400*
`AGA ccT
`TCT GGA
`Arg Pro
`
`TTC
`
`Phe
`
`GGT
`CCA
`Gly
`
`TOT
`Tor
`
`460
`*
`
`350
`*
`
`ARG AAG
`TTC TIe
`Lys Lys
`
`410*
`GTA GAG
`CaT CTC
`Val Glu
`
`470
`*
`
`360
`
`GAA ACA
`
`Lys
`
`Glu ‘Thr>
`
`ATG
`TAC
`Met
`
`420
`
`TAC AGT
`
`Tyr Ser>
`
`480
`
`GCC CAA
`Arg Val>
`
`560
`
`ATC
`TAG
`Tle
`
`CCC GAA ATT
`GGG CTT TAA
`Pro Glu Ile
`
`ATA CAC
`TAT GTG
`Ile His
`
`ATG
`TAC
`Met
`
`ACT
`TGA
`
`Glu
`
`AGG
`
`Arg
`
`ccr
`Gly
`
`GAG CTC
`CTC GAG
`Glu Leu
`
`GTc
`
`Val
`
`ATT CCC
`TAR GGG
`Tle Pro
`
`Tec
`ACG
`Cys
`
`490
`*
`
`*
`
`500
`*
`
`520
`*
`
`ACG
`
`TCA
`
`Thr
`
`Ser
`
`eccrT AAC ATC
`GGA TIG TAG
`Pro Asn Tle
`
`ACT GTT
`TGA CAA
`Thr Val
`
`ACT
`TGA
`Thr
`
`TTA
`BAT
`Leu
`
`AAG
`
`Lys
`
`Phe
`
`CcA crt
`GGT GAA
`Pro Leu
`
`Gac
`CTs
`Asp
`
`ATC
`TAG
`Tle
`
`ccr GAT
`GGA CTA
`Pro Asp>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 16
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 16
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 16 of 55
`
`US 8,029,791 B2
`
`Fig.13B.
`
`*
`
`550
`*
`
`560
`*
`
`570
`
`*
`
`580
`*
`
`590
`
`*
`
`600
`*
`
`GGA AKA CGC ATA
`CccT TTT GCG TAT
`Gly Lys Arg Ile
`
`ATC
`TAG
`Tle
`
`TGG GAC
`ACC CIG
`Trp Asp
`
`AGT AGA AAG
`TOA TCT TTC
`Ser Arg Lys
`
`GGC TIC ATC ATA
`
`CCG AAG TAG TAT
`Phe
`Ile Ile
`Gly
`
`TCA
`AGT
`Ser
`
`AAT GCA
`TTA CGT
`Asn Ala
`
`ACG TAC AAA
`TOC ATG TIT
`Thr Tyr Lys>
`
`.
`
`610
`*
`
`620
`*
`
`630
`
`640
`*
`
`650
`
`660
`
`GAA ATA GGG CTT
`CYT TAT CCC GAA
`Glu Tle Gly Leu
`
`ete
`GAC
`Leu
`
`ACC TGT
`TGG ACA
`Thr Cys
`
`GAA GCA ACA
`eTr CGT ToT
`Glu Ala
`
`GT¢
`CAG
`Val
`
`AAT
`TTA
`Asn
`
`GOs CAT
`cce GTA
`Gly His
`
`AAC
`Leu
`
`TAT AAG
`ATA TIC
`Tyr Lys
`
`ACA AAC TAT
`TGT TTG ATA
`Thr Asn Tyr>
`
`*
`
`676
`*
`
`680
`*
`
`690
`
`700
`*
`
`710
`
`720
`*
`
`*
`
`CTC ACA CAT CGA
`GAG TCT GTA GCT
`Leu Thr His Arg
`
`ACC AAT
`TOS TIA
`Thr Asn
`
`ACA ATC ATA
`TaT TAG TAT
`Tle Ile
`
`GTT
`Gin
`
`GAT
`CTA
`Asp
`
`GTC
`CAG
`Val
`
`CAA ATA
`GTT TAT
`Gin Ile
`
`ACA CCA
`TST GST
`Thr Pro
`
`eGc CCA GTC
`GCG GGT CAG
`Arg Pro Val>
`
`TCG
`Ser
`
`*
`
`730
`*
`
`AAA TTA CTT AGA
`TIT AAT GAA TCT
`ys Leu beu Arg
`
`*
`
`790
`*
`
`740
`*
`
`CAT ACT
`GTA TGA
`His Thr
`
`g00
`*
`
`750
`
`760
`*
`
`770
`
`*
`
`780
`*
`
`eTT GTC cre
`
`Leu Val Leu
`
`AAT
`TDA
`Asn
`
`TCT
`ACA
`Cys
`
`ACT GCT
`TGA CGA
`Thr Ala
`
`ACC
`
`AcT ccc
`TGA GGG
`Thr Pro
`
`TTG AAC ACG
`AaC TIG TGC
`Leu Asn Thr>
`
`810
`
`GAA
`
`TAC
`ATS
`
`820
`*
`
`830
`
`*
`
`840
`*
`
`AAT TCC
`TTA AGG
`Asn Ser
`
`AGA GTT CAA ATG
`TCT CAR GTT TAC
`Arg Val Gin Met
`
`*
`
`850
`*
`
`TGG AGT
`ACC TCA
`Trp Ser
`
`B60
`*
`
`Cot GAT
`GGA CTA
`Pro Asp
`
`ATT
`TRA
`Tle
`
`GAC CAA
`cits GTT
`Asp Gln
`
`Glu
`
`CAT GCC AAC
`GTA CGG PIS
`His Ala Asn>
`
`870
`
`880
`*
`
`ago
`
`*
`
`900
`*
`
`ATA TIC TAC AGT
`TAT AAG ATG TCA
`
`Tle Phe Tyr Ser
`
`GTT
`
`Val
`
`CTT acr
`GAA TGA
`Leu Thr
`
`ArT
`TAA
`Ile
`
`GAC AAA
`
`Asp Lys
`
`ANG
`TAC
`Met
`
`CAG
`GTC
`Gin
`
`AAC AAA
`TTS TIT
`Asn Lys
`
`CTG
`Asp
`
`AAA GGA
`TIT ccT
`Lys Gly
`
`CTT TAT aAcT
`GAA ATA TGA
`Leu Tyr Thr>
`
`*
`
`910
`*
`
`920
`*
`
`930
`
`940
`*
`
`950
`
`*
`
`960
`*
`
`TST CGT GTA AGG
`ACA GCA CAT TCC
`Cys Arg Val arg
`
`AGT
`TCA
`Ser
`
`GGA CCA
`ccT GoT
`Gly Pro
`
`AGT AAG TIT
`Ser Phe Lys
`
`Ser
`
`GTT
`CAA
`Val
`
`ARC ACC
`TTS TGG
`Asn Thr
`
`AGT
`Ser
`
`GTG CAT
`CAC GTA
`Val His
`
`ATA TAT GAT
`TAT ATA CTA
`Ile Tyr Asp>
`
`*
`
`970
`*
`
`980
`*
`
`6
`
`950
`*
`
`1000
`x
`
`1010
`
`1020
`*
`
`*
`
`ABA GCA GSC COG
`TIT CGT CCG GGC
`Lys Ala Gly Pro
`
`ccs
`Gly
`
`GAG ccc
`CTC GGG
`Glu Pro
`
`AAA TCT TOT
`AGA ACA
`Lys Ser Cys
`
`GAC
`
`Asp
`
`ASA
`TIT
`Lys
`
`ACT CAC
`TGA GTG
`Thr His
`
`ACA,
`Tat
`
`TGC CCA
`ACG GGT
`Cys Pro
`
`CCG TGC CCA
`GoC ACG GGT
`Pro Cys Pro>
`
`*
`
`1030
`*
`
`1040
`*
`
`1050
`*
`
`*
`
`1060
`*
`
`1070
`
`1080
`*
`
`*
`
`GCA CCT GAA crc
`CGT GGA CTT GAG
`Ala Pro Glu Leu
`
`GAC
`Leu
`
`GGG GGA
`ccc ccTr
`Gly Gly
`
`ccG TCA GTC
`GGC AGT CAG
`Pro Ser Val
`
`AAG
`Phe
`
`etc
`GAG
`Leu
`
`Tre coc
`AAG GGG
`Phe Pro
`
`CCA
`GoT
`Pra
`
`BAR CCC
`TTT GGG
`Lys Pro
`
`BAG GAC ACC
`TIC CTG TGG
`Lys Asp Thr>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 17
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 17
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet17 of 55
`
`US 8,029,791 B2
`
`Fig.13C.
`
`*
`
`1090
`*
`
`1100
`*
`
`1110
`*
`
`*
`
`*
`
`1120
`«=
`
`1130
`*
`
`1140
`*
`
`*
`
`OTC ATG ATC Tec
`GAG TAC TAG AGG
`Leu Met Ile Ser
`
`ccs
`Gece
`Arg
`
`Ace cct
`TSG GGA
`Thr Pro
`
`GAG
`cre
`Glu
`
`GTC ACA
`CAG TOT
`Val Thr
`
`TGC GIG GTG GTG
`ACG CAC CAC CAC
`
`Cys Val Val Val
`
`GAC
`CTS
`Asp
`
`GTS AGC CAC GAA GAC
`CAC TCG GTG CTT CiG
`Val Ser His Glu Asp>
`
`1150
`*
`
`*
`
`1160
`*
`
`1170
`*
`
`*
`
`*
`
`1180
`*
`
`1190
`*
`
`1200
`+
`
`*
`
`CCT GAG GTC AAG
`GGA CTC CaAG TIC
`Pro Glu Val Lys
`
`TIC
`AAG
`Phe
`
`AAC TGG
`TTG ACC
`Asn Trp
`
`TAC
`ATG
`
`GTG GAC
`CAC CTG
`Val Asp
`
`GGC GTG GAG GTG
`ceG cac CIC CAC
`Gly Val Glu Val
`
`CAT
`GTA
`His
`
`AAT GCC AAG ACA AAG
`TTA CGG TIC TET TIC
`Asn Ala Lys Thr Lys>
`
`©
`
`1210
`*
`
`1220
`*
`
`1236
`*
`
`*
`
`*
`
`1240
`*
`
`1250
`*
`
`1260
`*
`
`*
`
`CCG CGG GAG GAG
`Goo Gee cM cre
`
`Pro Arg Glu Glu
`
`CAG
`Gr
`Gln
`
`TAC AAC
`ATG TIG
`Tyr Asn
`
`AGC
`
`Ser
`
`ACG TAC
`TGC ATG
`Thre Tyr
`
`CGT GTG GTC AGC
`GCA CAC CAG TCG
`Arg Val Val Ser
`
`otc
`
`Val
`
`crc Acc Git CTG Cac
`GAG TGG CAG GAC GTG
`Leu Thr Val Leu His>
`
`1270
`*
`
`*
`
`1280
`*
`
`1290
`*
`
`*
`
`*
`
`1300
`*
`
`1310
`*
`
`1320
`*
`
`*
`
`CAG GAC TGG CTG
`GTC CTG ACC GAC
`Gln Asp Trp Leu
`
`AAT
`TTA
`Asn
`
`GGC AAG
`cee Tre
`Gly Lys
`
`GAG
`etc
`Glu
`
`TAC AAG
`ATG TTC
`Tyx Lys
`
`TGC AAG GTC TCC
`ACG TTC CAG AGG
`
`Cys Lys Val Ser
`
`AAC
`
`Asn
`
`AAB GCC CNC CCA GSC
`[TTT CGG GAG GGT CGG
`Lys Ala Leu Pro Ala>
`
`1350
`*
`
`*
`
`*
`
`1360
`*
`
`1370
`*
`
`1380
`*
`
`*
`
`*
`
`1330
`*
`
`1340
`*
`
`*
`
`CCC ATC GAG AAA ACC
`GGG TAG CT TTT TSG
`
`Pro Ile Glu Lys Thr
`
`ATC TCC
`TAG AGG
`Ile Ser
`
`GCC AAA GGG CAG CCC CGA
`CGG TIT
`ccc GTC GGG GCT
`Gly Glin Pro Arg
`
`Ala Lys
`
`Lys
`
`*
`
`1390
`*
`
`1400
`*
`
`1410
`*
`
`*
`
`1420
`*
`
`*
`
`CCA CAG GIG TAC ACC
`GGT GTC CAC ATG TGG
`Pro Gln Val Tyr Thr>
`
`1430
`*
`
`1440
`*
`
`*
`
`CTG ccc CCA TCC
`GAC GGG GGT AGG
`Leu Pro Pro Ser
`
`CGS
`gcc
`Arg
`
`GAT GAG
`CTA CTC
`Asp Glu
`
`egg
`Gac
`Leu
`
`ACC AAG
`766 TIC
`Tir Lys
`
`AAC CAG GTC AGC
`TIG GTC CAG TCG
`Asn Gln Val Ser
`
`GAC
`Leu
`
`Acc TGC CIG GTC AAA
`TGG ACG GAC CAG TIT
`
`Thr Cys Lev Val Lys>
`
`*
`
`1450
`*
`
`1460
`*
`
`1470
`*
`
`*
`
`*
`
`1480
`*
`
`1490
`*
`
`1500
`*
`
`¥
`
`GGC TIC TAT CCC
`CCG AAG ATA GGG
`
`Gly Phe Tyr Pro
`
`acc
`
`Ser
`
`GAC ATC
`CTG TAG
`Asp Ile
`
`Gcc
`CGG
`Ala
`
`GTG GAG
`Cac cic
`Val Glu
`
`TSG GAG AGC AAT
`ACC CTC TCG TTA
`Trp Glu Ser Asn
`
`ccc
`Gly
`
`CAG CCG GAG AAC AAC
`GTC aac CT TH MG
`Gln Pro Glu Asn Asn>
`
`1510
`*
`
`*
`
`1520
`*
`
`1530
`*
`
`*
`
`*
`
`1540
`*
`
`1550*
`
`1560
`*
`
`*
`
`TAC AAG ACC ACG
`ATG TTC TOG TG
`
`Tyr Lys Thr Thr
`
`ccr
`GGA
`Pro
`
`cece GTG
`GGG CAC
`Pro Val
`
`CTG
`GAC
`Leu
`
`Gac TCC
`CTG AGG
`Asp Ser
`
`Gac Goc Tee TIC
`CTS CCG AGG AAG
`Asp Gly Ser Phe
`
`CTC TAC AGC AAG CIC
`GAG ATG TCG TIC GAG
`Leu Tyr Ser Lys Leu>
`
`AAG
`Phe
`
`*
`
`1570
`*
`
`1580
`*
`
`1590
`*
`
`*
`
`1600
`*
`
`*
`
`1610
`*
`
`1620
`*
`
`¥*
`
`ACC GTG GAC AAG
`TGG CAC CTG Tre
`Thr Val Asp Lys
`
`AGC
`
`Ser
`
`AGG TSG
`Tee acc
`Arg Trp
`
`CAG
`GTe
`Gin
`
`CAG GGG
`ere cce
`Gin Gly
`
`ABC GTC TIC TCA
`TTS CAG AAG AGT
`Asn Val Phe Ser
`
`Tcc GTG ATG CAT GAG
`AGG CAC TAC GTA CTC
`Ser Val Met His Glu>
`
`ACG
`Cys
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 18
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 18
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet18 of 55
`
`US 8,029,791 B2
`
`Fig.13D.
`
`1630
`*
`
`*
`
`1640
`*
`
`x
`
`1650
`*
`
`*
`
`1660
`x
`
`*
`
`*
`
`1670
`*
`
`GCT CT CAC AAC CAC TAC ACG CAG AAG AGC CTC TCO CNG TCT CCG GGT AAA TGA
`CGA GAC GTG TIG GTG ATG TGC GTC TH TG GAG AGG GAC AGA GGC CCA TYT ActT
`Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys ‘***>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 19
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 19
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 19 of 55
`
`US 8,029,791 B2
`
`Fig. 14A.
`
`&
`
`*
`
`*
`
`*
`
`30
`
`40
`*
`
`50
`*
`
`*
`
`60
`*
`
`ATG GTC AGC TAC
`TAC CAG TCG ATG
`Met Val Ser Tyr
`
`TSG
`ACC
`Trp
`
`Gac acc
`eCmG TGG
`Asp Thr
`
`GGG
`cce
`Gly
`
`GTc
`
`Val
`
`CTs
`Gac
`Leu
`
`ciTG TEC
`GBC ACG
`Leu Cys
`
`GOs CIG
`cGc GAC
`Ala Leu
`
`ere
`GAG
`Leu
`
`AGC TST
`TOG ACA
`Ser Cys
`
`Clic ctr cre
`GAC GAA GAG
`Leu Leu Leu>
`
`*
`
`70
`*
`
`80
`*
`
`ACA GGA TCT AGT
`TST CCT AGA TCA
`Thr Gly Ser Ser
`
`TCC
`AGG
`Ser
`
`GGA GGT
`ccT CCA
`Gly Gly
`
`AGA
`TCT
`Arg
`
`cc?
`GGA
`Pro
`
`*
`
`130
`*
`
`140
`
`90
`
`Phe
`
`150
`
`*
`
`100
`*
`
`110
`*
`
`120
`*
`
`*
`
`GTA GAG
`CAT CTC
`Val Glu
`
`ATG TAC
`TAC ATG
`Met Tyr
`
`AGT
`
`Ser
`
`GAA ATC
`CTT TAG
`Glu Tle
`
`ccc GAA ATT
`GGG CTT TAA
`Pro Glu Ile>
`
`Lf
`
`160
`*
`
`170
`*
`
`180
`*
`
`*
`
`ATA CAC ATG ACT
`TAT GTG TAC TGA
`Ile His Met Thr
`
`erT
`Glu
`
`GGA AGG
`cer rec
`Gly Arg
`
`eT
`Glu
`
`ere
`
`GTc
`
`Leu
`
`val
`
`ATT CCC
`TAA GGG
`Tle Pro
`
`TGC CGS
`ACG GCC
`Cys Arg
`
`ott
`
`Val
`
`ACG TCA
`"GC AGT
`Thr Ser
`
`CCT AAC ATC
`GGA TTG TAG
`Pro Asn Ile>
`
`*
`
`190
`*
`
`200
`
`ACT GTT ACT TTA
`TGA CAA TGA AAT
`Thr Val Thr Leu
`
`AAG TTT
`TTC ABA
`Lys Phe
`
`cca
`GcT
`Pro
`
`CTT
`
`Leu
`
`210
`
`GAC
`cTG
`Asp
`
`270
`
`220
`*
`
`230
`*
`
`240
`*
`
`*
`
`ACT TTG
`TGA AAC
`Thr Leu
`
`ATC cect
`TAG GGA
`Tle Bro
`
`GAT
`CTA
`ASP
`
`GGA AAA
`cer TTT
`Gly Lys
`
`CGC ATA ATC
`GCG TAT TAG
`Arg Ile Ile>
`
`280
`*
`
`250
`*
`
`300
`*
`
`*
`
`*
`
`250
`*
`
`TGG GAC AGT AGA
`ACC CIG TCA TCT
`frp Asp Ser Arg
`
`*
`
`310
`*
`
`260
`*
`
`Goe TIC
`CCG AAG
`
`Gly Phe
`
`320
`*
`
`ATC
`TAG
`Tie
`
`ATA
`TAT
`Tle
`
`TCA
`AGT
`Ser
`
`BAT GCA
`TTA CGT
`Asn Ala
`
`ACG TAC
`TGC ATG
`Thr Tyr
`
`GAA ATA
`cr? TAT
`Glu Ile
`
`GGG CTT CTS
`ccc GAA GAC
`Gly Leu Leu>
`
`330
`
`340
`*
`
`350
`*
`
`360
`*
`
`*
`
`ACC TGT GAA GCA
`TGG ACA CTT CGT
`Thr Cys Glu Ala
`
`GTC AAT
`CAG TTA
`Val Asn
`
`TST
`Thr
`
`cece
`Gly
`
`GTA
`His
`
`aac
`Leu
`
`TAT AAG
`ATA TTC
`Tyr Lys
`
`ACA AAT
`TOT TTG
`Thr Asn
`
`*
`
`370
`*
`
`380
`*
`
`390
`
`*
`
`400
`*
`
`cre ACA
`GAG TGT
`Leu Thr
`
`CAT CGA CAA
`GTA GCT GIT
`His Arg Gln>
`
`410
`*
`
`*
`
`420
`*
`
`ACC AAT ACA ATC
`TGG TTA ToT TAG
`Thr Asn Thr Ile
`
`ATA
`TAT
`Ile
`
`GAT GTC
`CTA CAG
`Asp Val
`
`ATA
`TAT
`Tle
`
`AGC
`TCG
`Ser
`
`ACA CCA
`TGT GGT
`Pro
`
`CGC CCA
`GCG GoT
`Arg Pro
`
`Git
`Glin
`
`CAG
`Val
`
`BAA TTA
`TTT AAT
`Lys Leu
`
`CTT AGA GGC
`GAA ToT CCG
`Leu Arg Gly>
`
`*
`
`430
`*
`
`440
`*
`
`CAT ACT CTT GTC
`GTA TGA GAA CAG
`His Thr Leu Val
`
`ere
`
`Leu
`
`AAT TCT
`TTA ACA
`Asn Cys
`
`450
`
`460
`*
`
`470
`*
`
`«
`
`480
`*
`
`oT
`CGA
`Ala
`
`ACC
`
`acT cce
`
`Thr
`
`Thr Pro
`
`ACG
`
`[TG AAC
`AAC TTS
`Leu Asn
`
`AGE GTT
`TCT CAA
`Arg Val
`
`CAA ATG ACC
`GTT TAC TGG
`Gin Met Thr>
`
`*
`
`490
`*
`
`500
`*
`
`510
`
`520
`*
`
`530
`*
`
`540
`*
`
`*
`
`TGG AGT TAC CCT
`ACC TCA ATG GGA
`Trop Ser Tyr Pro
`
`GAT
`CTA
`Asp
`
`GAA ATT
`CTT TAA
`Glu Ile
`
`GAC
`Cte
`Asp
`
`CRA
`oTT
`Gln
`
`AG
`TCG
`Ser
`
`AAT TCC
`TTA AGG
`Asn Ser
`
`CAT GCC
`GTA CGG
`His Ala
`
`AAC
`
`Asn
`
`ATA TIC
`TAT AAG
`Tle Phe
`
`TAC AGT GTT
`ATG TCA CAA
`Tyr Ser Val>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 20
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 20
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 20 of 55
`
`US 8,029,791 B2
`
`Fig.14B.
`
`*
`
`550
`*
`
`ecTT ACT ATT GAC
`GAA TGA TAA CTG
`Leu Thr Ile Asp
`
`560
`*
`
`*
`
`ATG CAG
`TAC GT¢c
`Met Gln
`
`AAC ABA
`TTS TIT
`Asn Lys
`
`*
`
`610
`*
`
`620
`*
`
`GGA CCA TCA TIt
`CCT GGT AGT AAG
`Gly Pro Ser Phe
`
`TOT GTT
`AGA CAA
`Ser Val Asn
`
`*
`
`670
`*
`
`680
`*
`
`GAG CCC AAA TCT
`Cie GGG TIT AGA
`
`Glu Pro Lys Ser
`
`GAC AAA
`CTG TTT
`Asp Lys
`
`ACA
`Cys
`
`*
`
`730
`*
`
`740
`“€
`
`GGG GGA CCG TCA
`ccc COT GSC AGT
`
`Gly Gly Pro Ser
`
`GTC
`
`Val
`
`'TC crc
`AAG GAG
`Phe Leu
`
`*
`
`790
`*
`
`800
`*
`
`ACT CAC
`
`His
`
`ece
`
`Phe Pro
`
`GTS
`
`570
`*
`
`GAC
`jevie)
`Asp
`
`630
`*
`
`TCA
`AGT
`Ser
`
`690
`
`ACA
`TST
`
`750
`
`CCA
`GST
`Bro
`
`810
`
`580
`*
`
`$90
`
`GGA
`cer
`Lys Gly
`
`evr TAT
`GAA ATA
`Leu Tyr
`
`ACT
`
`TST CGT
`ACA GCA
`Cys Arg
`
`GTA AGG
`CAT TCC
`Val Arg
`
`600
`
`AGT
`TCA
`Ser>
`
`640
`*
`
`650
`*
`
`*
`
`GTS
`CAS
`Val
`
`CAT
`GTA
`His
`
`ATA ‘TAT
`TAT ATA
`
`GAT
`CTA
`
`AAA GCA
`Tr? CGT
`
`Tle Tyr
`
`Asp
`
`Lys Ala
`
`Géc CCG
`CCG GGC
`Gly Pro
`
`GGc
`Ces
`Gly>
`
`700
`*
`
`710
`*
`
`720
`
`TGC
`ACG
`Cys
`
`CCA
`GGT
`Pro
`
`ccG TC
`GGC ACG
`Pro Cys
`
`CCA
`GST
`Pro
`
`GCA CCT
`CGT GGA
`Ala Pro
`
`GAA CTC
`CTT GAG
`Glu Leu
`
`crs
`GAC
`Leu>
`
`760
`*
`
`770
`*
`
`780
`
`ece
`
`Lys Pro
`
`acc
`
`AAS GAC
`TTC Cis
`Lys Asp
`
`OTC ATG
`GAG TAC
`Leu Met
`
`Ate tcc
`TAG AGG
`Tle Ser
`
`cae
`Gee
`Arg>
`
`820
`*
`
`830
`*
`
`840
`
`GTS
`CAC
`Val
`
`AGC
`TOS
`Ser
`
`CAC GAA
`GTG CTT
`His Glu
`
`Gac
`evs
`Asp
`
`CCT GAG
`GGA CTC
`Pro Glu
`
`GTC AAG
`CAG TTC
`Val Lys
`
`TTC
`AAG
`Phe>
`
`880
`*
`
`890
`*
`
`£00
`*
`
`*
`
`cee CcGG
`Goce GcCc
`Pro arg
`
`GAG GAG
`ere crc
`Glu Glu
`
`CAG
`Gtc
`Gln>
`
`950
`*
`
`960
`*
`
`*
`
`ACC CCT GAG GTC
`TSG GGA CIC CAG
`Thr Pro Glu Val
`
`TGC GIG
`ACG CAC
`Cys Val
`
`GTG
`Cac
`Val
`
`Val
`
`*
`
`850
`*
`
`B60
`*
`
`Cts
`Asp
`
`870
`
`AAC TGG TAC GIG
`TTG ACC ATG CAC
`Asn Trp Tyr Val
`
`GAC
`Cts
`ASD
`
`GGC GTG
`cece CAC
`
`Gly val
`
`GAG
`ere
`Glu
`
`GTG
`CAC
`val
`
`cat
`GTA
`Eis
`
`BAT
`[TA
`Asn
`
`Gee
`
`Ala
`
`AAG ACA
`[Tc TST
`Lys Thr
`
`*
`
`$10
`*
`
`920
`*
`
`$30
`
`940
`*
`
`TAC AAC AGC ACG
`ATG TTG TCG Toe
`Tyr Asn Ser Thr
`
`TAC
`ATG
`
`CGT GTG
`GCA CAC
`Arg Val
`
`ote
`CAG
`Val
`
`GTc
`CAG
`Val
`
`ere
`GAG
`Leu
`
`ace
`
`Thre
`
`GTC ctG
`CAG GAC
`Val Leu
`
`GTG
`His
`
`CAG GAC
`GT¢ cise
`Gln Asp
`
`TGG CTG AAT
`ACC GAC TTA
`Trp Leu Asn>
`
`980
`*«
`
`1000
`*
`
`L010
`*
`
`1920
`*
`
`*
`
`AAG
`TTC
`Lys
`
`TGC AAG
`ACG TIC
`Cys Lys
`
`GTe
`CAG
`Val
`
`TCC
`AGG
`Ser
`
`ece
`CGG
`Lys Ala
`
`eTc CCA
`GAG GGT
`Leu Pro
`
`ccc
`CGS
`Ala
`
`ccc ATC
`GGG TAG
`Pro Ile
`
`GAG AAA ACC
`eT TYT TSS
`Glu Lys Thr>
`
`* T
`
`AC
`ATG
`Tyr
`
`970
`
`*
`
`GGC AAG GAG
`cee TTC crc
`Gly Lys Glu
`
`*
`
`1030
`*
`
`1040
`*
`
`1050
`
`1060
`*
`
`1070
`*
`
`1080
`*
`
`*
`
`ATC TCC AAA GCC
`TAG AGG TIT COG
`Tle Ser Lys Ala
`
`BAR
`TTT
`Lys
`
`GGG CAG
`coe GTc
`Gly Gin
`
`ccc CGA
`GcT
`Pro Arg
`
`GAA
`CTT
`Glu
`
`CCA
`GoT
`Pro
`
`CAG
`GTC
`Gin
`
`GTG TAC
`CAC ATG
`Val Tyr
`
`ACC
`
`Thr
`
`eTsg cece
`GaC GGG
`Leu Pro
`
`CCA TCC CGG
`GGT AGG GCC
`Pro Ser Arg>
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 21 of 55
`
`US 8,029,791 B2
`
`Fig.14C.
`
`1090
`*
`
`1100
`*
`
`1110
`*
`
`*
`
`1120
`*
`
`GAT
`CTA
`
`GAG
`eTc
`Glu
`
`ctG acc
`GAC TGG
`Leu Thr
`
`AAG
`TIC
`Lys
`
`AAC CAG
`TG GTC
`Asn Gin
`
`Gt
`CAG
`Val
`
`AGC CTG
`TCG GAC
`Ser Leu
`
`ACC
`TSG
`Thr
`
`CTG GTC
`GAC CAG
`Leu Val
`
`ACG
`cys
`
`1150
`*
`
`1160
`*
`
`1170
`*
`
`*
`
`1180
`*
`
`ATC
`TAG
`Tle
`
`GCC GTG
`CGG CAC
`Ala Val
`
`GAG
`er
`Glu
`
`TGG GAG
`Ace cre
`Trp Glu
`
`AGC
`TCS
`Ser
`
`AAT GGG
`TTA CCC
`Asn Gly
`
`CAG
`GTC
`Glin
`
`CCG
`
`Pro
`
`GAG AAC
`ere TG
`Glu Asn
`
`1130
`
`1140
`*
`
`*
`
`Got TIC
`CCG AAG
`Gly Phe
`
`TAT CCC AGC
`ATA GGG TCG
`Tyr Pro Ser>
`
`1190
`
`1200
`*
`
`*
`
`TAC AAG
`ATG TIC
`Tyr Lys
`
`ACC ACG CCT
`TGG TGC GGA
`Thr Thr Pro>
`
`1210
`*
`
`1220
`*
`
`1230
`*
`
`*
`
`1240
`*
`
`1250
`
`1260
`*
`
`*
`
`ecc
`
`GTS
`
`Pro
`
`Val
`
`CTS GAC
`GAC CTG
`Leu Asp
`
`Tce
`AGG
`Ser
`
`GAC GGC
`CTG CCG
`
`Asp Gly
`
`Tce
`AGG
`Ser
`
`Tre TIC
`AAG AAG
`Phe Phe
`
`cTe TAC
`GAG ATG
`Leu Tyr
`
`AGC AAG
`TCG TTC
`Ser Lys
`
`em
`GAG
`Leu
`
`ACC GTG
`TGG CAC
`Thr Val
`
`GAC AAG AGC
`cig TIC TCG
`Asp Lys Ser>
`
`1310
`
`1320
`*
`
`*
`
`GCT CTG
`CGA GAC
`Ala Leu
`
`CAC AAC CAC
`GTG TIG Gic
`His Asn His>
`
`rnG.
`ere
`Glu
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 22
`
`1300
`
`* C
`
`AT
`GTA
`His
`
`1270
`*
`
`1280
`*
`
`AGG
`
`Arg
`
`acc
`trp
`
`CAG CAG
`GTC GTC
`Gln Gin
`
`GGG
`cece
`Gly
`
`AAC GTC
`TTG CAG
`Asn Val
`
`TIC
`AAG
`Phe
`
`1330
`*
`
`1340
`*
`
`1290
`*
`
`*
`
`TCA TGC
`AGT ACG
`Ser Cys
`
`1350
`*
`
`*
`
`Tec
`AGG
`Ser
`
`GTG
`CAC
`Val
`
`ATG
`TAC
`Met
`
`*
`
`TAC
`ATG
`
`ACG CAG AAG
`TSC GTC TIC
`Thr Gin Lys
`
`AGC
`TCG
`Ser
`
`etc ToC
`GAG AGG
`Leu Ser
`
`Chg
`GAC
`Leu
`
`TCT CCG
`AGA GGC
`Ser Pro
`
`GGT AAA
`ccA TIT
`Gly Lys
`
`act
`wey
`
`Mylan Exhibit 1159
`Mylan v. Regeneron, IPR2021-00881
`Page 22
`
`

`

`U.S. Patent
`
`Oct. 4, 2011
`
`Sheet 22 of 55
`
`US 8,029,791 B2
`
`Fig.15A.
`
`10
`*
`
`*
`
`20
`*
`
`30
`
`40
`
`50
`*
`
`*
`
`ATG
`TAC
`Met
`
`CAG
`Val
`
`AGC TAC
`TCG ATG
`Ser Tyr