US007070959B1
`
`(12) United States Patent
`Papadopoulos et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,070,959 B1
`*Jul. 4, 2006
`
`(54)
`
`(75)
`
`(73)
`
`MODIFIED CHMERC POLYPEPTDES
`WITH IMPROVED PHARMACOKINETIC
`PROPERTIES
`
`Inventors: Nicholas J. Papadopoulos,
`Lagrangeville, NY (US); Samuel Davis,
`New York, NY (US); George D.
`Yancopoulos, Yorktown Heights, NY
`(US)
`Assignee: Regeneron Pharmaceuticals, Inc.,
`Tarrytown, NY (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is Subject to a terminal dis
`claimer.
`
`(21)
`(22)
`(86)
`
`Appl. No.:
`PCT Filed:
`
`10/009,852
`May 23, 2000
`
`PCT No.:
`
`PCT/USOO/14142
`
`S 371 (c)(1),
`(2), (4) Date: Dec. 6, 2001
`
`(87)
`
`PCT Pub. No.: WOOO/75319
`
`PCT Pub. Date: Dec. 14, 2000
`Related U.S. Application Data
`Provisional application No. 60/138,133, filed on Jun.
`8, 1999.
`
`Int. C.
`(2006.01)
`CI2N 5/62
`(2006.01)
`CI2N 15/63
`(2006.01)
`C7H 2L/04
`(2006.01)
`C07K 6/00
`(2006.01)
`C07K I4/00
`U.S. Cl. ................... 435/69.7:435/70.1; 435/71.1;
`435/320.1; 435/325; 435/252.3: 530/387.3;
`530/350,536/23.4
`Field of Classification Search ............... 435/69.7,
`435/320.1, 70.1, 71.1; 530/387.3
`See application file for complete search history.
`
`References Cited
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(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
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`
`WO97/.44453
`WO98, 13071
`WO99/03996
`
`11, 1997
`4f1998
`1, 1999
`
`OTHER PUBLICATIONS
`Herley et al. (1999), Biochem. Biophys. Res. Comm. 262:
`731-738.*
`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 interac
`tions: definitions of consensus sites in glycosaminoglycan
`binding proteins”, 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
`pharmacokinetics via chemical modification, Quart J. Nucl
`Med (1998) 42:242-249.
`Jensen-Pippo, K.E., et al., “Enteral bioavailability of human
`granulocyte 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 88:767
`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 carinoma and melanoma’, (1995) Can
`cer 76(4): 687-694.
`
`(Continued)
`Primary Examiner Lorraine Spector
`Assistant Examiner—Jon M Lockard
`(74) Attorney, Agent, or Firm Valeta Gregg, Esq.
`
`ABSTRACT
`(57)
`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.
`
`15 Claims, 55 Drawing Sheets
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 1
`
`Joining Petitioner: Apotex
`
`

`

`US 7,070,959 B1
`Page 2
`
`OTHER PUBLICATIONS
`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.
`Holash, J., et al. (2002) PNAS, vol. 99, No. 17, pp. 11393
`11398.
`Heidaran, M.A., (1990) The Journal of Biological Chemis
`try, vol. 265, No. 31, Issue of Nov. 5, pp. 18741-18744.
`
`Cunningham, S.A. et al., (1997) Biochemical and Biophysi
`cal Research Communications, vol. 231, pp. 596-599.
`Fuh, G. et al. (1998) The Journal of Biological Chemistry,
`vol. 273, No. 18, Issue of May 1, pp. 11197-11204.
`Wiesmann, C. et al. (1997) Cell, vol. 91, pp. 695-704.
`Barleon, B. et al. (1997) The Journal of Biological Chem
`istry, vol. 272, No. 16, pp. 10382-10388.
`Davis-Smyth, T. et al. (1998) The Journal of Biological
`Chemistry, vol. 273, No. 6, pp. 3216-3222.
`* cited by examiner
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 1 of 55
`
`US 7,070,959 B1
`
`Fig.1.
`
`1 2 3 4 5 6 7 8 9
`
`O
`
`
`
`
`
`O4
`
`0.3
`
`0.
`
`0.00
`
`FiC.2.
`
`O
`
`OO
`
`0.01
`
`0.1
`
`1
`ug/ml
`-- rTIE-2-Fo
`...a...... acetylated Flt-1 (1-3)-Fo
`----O--- unmodified Flt-1 (1-3)-Fo
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 3
`
`Joining Petitioner: Apotex
`
`

`

`Jul. 4, 2006
`
`Sheet 2 of 55
`
`US 7,070,959 B1
`
`
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 4
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 3 of 55
`
`US 7,070,959 B1
`US 7,070,959 B1
`
`
`
`
`
`0.4
`
`ug/ml
`
`0.01
`
`
`
`Fig.4.
`
`
`
`
`
`—A—unmodifiedFit-1(1-3)-Fe
`
`
`
`
`
`—a—acetylatedFit-1(1-3)-Fe—@—pegylatedFit-1(1-3)-Fe
`
` 0.001
`
`
`10
`
`1
`
`S
`Misuag jeondo
`
`0.01
`
`0.001
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`Joining Petitioner: Apotex
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 4 of 55
`
`US 7,070,959 B1
`
`
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 6
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet S of 55
`
`US 7,070,959 B1
`
`Fig.6A.
`
`1 2 3 4 5 6 7 8 9 O
`
`Fig.6B.
`
`
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 7
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 6 of 55
`
`US 7,070,959 B1
`
`
`
`Fig.7.
`
`-H rTIE-2-FC
`a
`y s As {X....... unmodified Flt-1 (1-3)-Fo
`----O---. acetylated Flt-1 (1-3)-Fo (10X)
`-----A----- acetylated Flt-1 (1-3)-FO (20X)
`-------. acetylated Flt-1 (1-3)-Fo (30X)
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 8
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 7 of 55
`
`US 7,070,959 B1
`
`Fig.8.
`
`0.5 g/ml
`
`1.0 g/ml
`
`5.0 g/ml
`
`
`
`:
`480HH
`
`380
`
`180
`
`80
`
`-20
`
`VEGF
`0.2 ug/ml
`Unmodified
`Fit-1 (1-3)
`-FC
`Acetylated
`Fit-1 (1-3)
`
`XXX
`OO
`--Degree of step-acetylation of Flt-1 (1-3)-Fo protein -->
`-
`-
`-
`-
`-
`-
`-
`H
`--
`-
`-
`
`--
`
`-
`
`+
`
`-
`
`-
`
`-
`
`p
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`is
`
`-
`
`a
`
`-
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 9
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 8 Of 55
`
`US 7,070,959 B1
`
`
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 10
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 9 of 55
`
`US 7,070,959 B1
`
`Fig.10A.
`
`10
`
`2O
`
`30
`
`40
`60
`k
`A.
`k
`t
`t
`ATG GTC AGC TAC TGG GAC ACC GGG GTC CTG CTG TGC GCG CTG CTC AGC TGT CTG CTT, CTC
`TAC CAG TCG ATG ACC CTG TGG CCXC 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 Lleu Leud
`
`50
`
`TO
`80
`90
`20
`s
`r
`t
`r
`1.
`s
`t
`ACA GGA TCT AGT TO A GGT TCA AAA TTA AAA GAT CCT GAA CTG AGT, TTA AAA GGC ACC CAG
`TGT CCT AGA TCA AGT CCA AGT TTT AAT TT CTA GGA CT GAC TCA AAt TTT CCG TGG GTC
`Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pre Glu Leu Ser Leu Lys Gly. Thr Glind
`
`OO
`
`10
`
`130
`
`140
`
`150
`
`70
`80
`s
`y
`t
`t
`r
`CAC ANC AG CAA, GCA GeC CAG ACA CTG CAT CTC CAA TGC AGG GGG GAA GOA GCC CAT AAA
`GTG TAG TAC GT CGT CCG GC IG GAC GTA GAG (GTT ACG TCC CCC CT CGT CGG GTA TTT
`His Ile Met Glin Ala Gly Glin Thr Leu. His Leu Gin Cys Arg Gly Glu Ala Ala. His Lys2
`
`50
`
`200
`
`20
`
`190
`*
`IGG TCT TTG CCT GAA ATG GG AGT AAG GAA AGC GAA AG CTG AGC ATA ACT AAA CT GCC
`ACC AGA AAC GGA CTT AC CAC TCA TTC CTT TCG CT TCC GAC TCG TAT TGA TTT AGA CGG
`Trp Ser Leu Pro Glu Met Val Ser Lys Glu Ser Glu Arg Feu. Ser Ile Thr Lys Ser Alad
`
`220
`
`230
`
`240
`
`250
`
`260
`
`270
`
`300
`1.
`t
`s
`GT GGA AGA AA GGC AAA CAA C GC GT ACT TTA ACC TGAAC ACA GCT CAA GCA AAC
`ACA CCT. EOT TTA. CCG TT GT AAG ACG TCA TGA AAT TGG AAC TG TGT CGA GT CGT TTG
`Cys Gly Arg Asn Gly Lys Glin Phe Cys Ser Thr Lieu. Thr Leu. Asn Thr Ala Glin Ala Asn->
`
`280
`
`29O.
`
`320
`
`30
`33
`350
`360
`A.
`r
`s
`y
`r
`t
`t
`CAC ACT GGC TTC TAC AGC AGC AAA TAT. CTA GCT, GTA CCT ACT CA AAG AAG AAG GAA ACA
`GTG TGA, CCG AAG AIG TCG ACG TT. AA GA CGA CAT GGA GA AG TC TTC TTC CIT TGT
`His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val Pro Thr Ser Lys Lys Lys Giu. Thr>
`
`340
`
`370
`
`38O
`
`390
`
`410
`420
`'
`s
`s
`GAA TCT, GCA AC. TATATA Ti Ali AG GAT ACA GGT AGA CC TVC GTA GAG ATG TAC AGT
`CT AGA CGT TAG ATA Air AAA AA FCA CTA G CCA TCT GGA AAG CAT CC TAC AG CA
`Glu Ser Ala Ile Tyr Ilie Phe Ile Ser Asp Thr Gly Arg Pro Phe Wall Glu Met Tyr Ser2
`
`400
`
`430
`440
`460
`470
`y
`r
`r
`t
`r
`r
`GAA ATC CCC GAA. A. AA CAC ATG ACT GAA GGA AGG GAG CYC GC A CCC GC CeG GT
`CTT TAG GGG CTT. AA A GTG TAC GA CTT CCT TCC CTC GAG CAG TAA GGG ACG GCC CAA
`Glu le Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
`
`ABO
`
`450
`
`490
`r
`
`t
`
`500
`
`51
`sk
`
`1A
`
`520
`s
`
`r
`
`Air
`
`530
`
`S40
`t
`
`r
`
`ACG TCA CCT AAC ATC ACT GTT ACT TTA. AAA AAG TTT CCA CTT GAC ACT TTG ATC CCT GAT
`IGC AGT GGA TTG TAG TGA CAA TGA AAT TTTTTC 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 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 11
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 10 Of 55
`
`US 7,070,959 B1
`
`Fig.10B.
`
`550
`
`560
`
`570
`580
`g
`Af
`t
`y
`y
`r
`GGA AAA CGC ATA ATC TGG GAC AGT AGA AAG GGC TTC ATC ATA TCA AAT GCA ACG TAC AAA
`CCTTTT GCG TAT TAG ACC CTG TCA TCT, TC CCG AAG TAG TAT AGT TA CGT TGC AIG TTT
`Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys2
`
`590
`
`600
`
`520
`
`630
`
`60
`r
`t
`GAA ATA GGG CTT. CTG ACC GT GAA GCA ACA GTC AAT GGG CAT TTG AT AAG ACA AAC TAT
`CT TAT CCC GAA GAC TGG ACA CTT, CG, TGT CAG TTA. CCC GTA AAC ATA TNC TGT TTG ATA
`Glu Ile Gly Leu Leu. Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyrd
`
`640
`
`650
`
`660
`
`580
`
`690
`
`670
`700
`710
`s
`r
`k
`e
`t
`CTC ACA CAT CGA CAA ACC AAT ACA ATC AIA GAT GTC CAA ATA AGC ACA CCA CGC CCA GTO
`GAG TGT GTA GCT GTT TGG TTA GT TAG A CTA CAG (GTT TAT TCG TGT. GGT GCG GGT CAG
`Leu Thr His Arg Glin Thr Asn. Thr Ile Ile Asp Val Glin Ile Ser Thr Pro Arg Pro Vald
`
`720
`
`730
`
`750
`
`740
`760
`t
`t
`s
`r
`t
`r
`AAA TTA CT AGA GGC CAT AC CTT, GTC CCAA TG ACT GCT ACC ACT CCC TTGAAC ACG
`TTT AAT GAA TCT CCG GTA TGA GAA CAG GAG TA ACA TGA CGA TGG. TGA. GGG AACTTG TGC
`Lys Lieu. Leu. Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr Pro Leu ASn Thr
`
`770
`
`780
`
`790
`
`800
`
`80
`
`840
`y
`k
`t
`AGA GTT CAA AG ACC TGG AGT AC CCT GA GAA AAA AAT AAG AGA GCT TOC GTA AGG CGA
`TCT CAA GTT TAC TGG ACC TCA ATG GGA CTA CAT TIT TTA TTC TCT, CGA AGG CAT ICC GCT
`Arg Val Glin Met Thr Trp Ser Tyr Pro Asp Glu Lys Asn Lys Arg Ala Ser Val Arg Arg>
`
`820
`
`830
`
`85C
`
`870
`
`850
`880
`890
`y
`t
`y
`*
`t
`CGA ATT GAC CAA AGC AA CC CAT GCC AAC AA TC TAC AGT, GTT CET ACT AT GAC AAA
`GCT TAA CTG GTTTCG TTA AGG GTA CGG TTG AT AAG ATG TCA CAA GAA TGA TAA CTG TTT
`Arg Ile Asp Glin Ser Asn. Ser His Ala Asn. Ilie Phe Tyr Ser Val Leu. Thir Ile Asp Lys2
`
`900
`
`90
`
`920
`
`930
`940
`r
`t
`t
`f
`y
`AG CAG AAC AAA GAC AAA GGA CT TAT ACT GT CG GTA AGG AGT GGA CCA TCA TTC AAA
`TAC GTC TTG.
`T. CTG TT CC GAA AA GA ACA GCA CA TCC TCA CCT GGT AGT AAG TT
`Met Gin Asn. Lys Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys
`
`950
`
`960
`
`970
`
`98O
`000
`100
`1020
`t
`r
`At
`i
`t
`TCT GTT AAC ACC TCA GG CA, ATA TA, GAT. AAA GCA GGC CCG GGC GAG CCC AAA TCT TGT
`AGA CAA TTG TGG AGT CAC GTA TAT ATA CTA TT CGT CCG GGC CCG CTC GGG TTT AGA ACA
`Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Gly Pro Gly Glu Pro Lys Ser Cys>
`
`990
`
`1030
`
`0.40
`
`1.050
`
`r
`
`1060
`e
`
`1070
`
`1080
`
`GAC AAA ACT CAC ACA TGC CCA CCG TGC CCA GCA CCT GAA CTC CTG GGG GGA CCG CA 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 val>
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 12
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`Jul. 4, 2006
`Fig.10C.
`
`Sheet 11 Of 55
`
`US 7,070,959 B1
`
`1090
`100
`1120
`1140
`k
`k
`y
`yk
`A.
`k
`TTC CTC TTC CCC CCA AAA CCC AAG GAC ACC CTC ATG ATC TCC CGG ACC CCT GAG GIC ACA
`AAG GAG AAG GGG GGT TT GGG TC CTG TGG GAG TAC TAG AGG GCC TGG GGA CTC CAG TGT
`Phe Leu Phe Pro Pro Llys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr)
`
`130
`
`10
`
`160
`
`150
`1170
`t
`r
`t
`t
`t
`TGC GTG GIG GIG GAC GTG AGC CAC GAA GAC CCT GAG GTC AAG TTC AAC TGG TAC GTG GAC
`ACG CAC CAC CAC CTG CAC TCG GTG. CTT CG GGA CTC CAG TC AAG TAG ACC ATG CAC CTG
`Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Wall Lys Phe Asn Trp Tyr Val Asp>
`
`180
`
`190
`
`1200
`
`1210
`1220
`1240
`y
`1.
`4.
`tr
`r
`k
`GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG GAG GAG CAG TAC AAC AGC ACG TAC
`CCG CAC CTC CAC GTA ITA CGG TC TGT, TTC GGC GCC CTC CTC GTC ATG TTG TCG TGC ATG
`Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Glin Tyr Asn Ser Thr Tyr2
`
`2SO
`
`1260
`
`230
`
`1270
`
`280
`3OO
`1310
`1320
`s
`k
`t
`t
`t
`CGT GTG GTC AGC GTC CIC ACC GC CTG CAC CAG GAC GG CTG AAT GGC AAG GAG TAC AAG
`GCA CAC CAG TCG CAG GAG GG CAG GAC GTG GTC CTG ACC GAC TA CCG TTC CTC AG TTC
`Arg Val Vai Ser Vali Leu Thr Val ieu. His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys2
`
`1290
`
`330
`1340
`1360
`1380
`t
`t
`r
`s
`ye
`TGC AAG GTC TCC AAC AAA GCC CTC CCA GCC CCC ATC GAG AAA ACC ATC TCC AAA GCC AAA
`ACG TTC CAG AGG TTG TTT CGG GAG GGT CGG GGG TAG CTC TTT TGG TAG AGG TTT CGG TTT
`Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys2
`
`1370
`
`350
`
`1390
`
`400
`
`140
`1420
`1430
`r
`t
`k
`t
`t
`GGG CAG CCC CGA GAA CCA CAG GTG TAC ACC CTG CCC CCA TCC CGG GAT GAG CTG ACC AAG
`CCC GTC GGG GCT. CTT GGT GTC CAC AG GG GAC GGG GG AGG GCC CTA CTC GAC TGG TC
`Gly Glin Pro Arg Giu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Lieu. Thr Lys2
`
`1440
`
`1450
`1460
`1470
`1480
`1490
`1500
`k
`r
`t
`e
`y
`t
`g
`t
`r
`AAC CAG GC AGC CTG ACC TGC CTG GTC AAA GGC TTC TAT CCC AGC GAC ATC GCC GTG GAG
`G GIC CAG TCG GAC TGG ACG GAC CAG TT CCG AAG ATA GGG TCG CTG TAG CGG CAC CTC
`Asn Glin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu2.
`
`510
`
`520
`t
`r
`TGG GAG AGC AAT GGG CAG CCG GAG AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC
`ACC CTC TCG TTA CCC GTC GGC CTC TG TOG AG TC TGG GC GGA. GGG CAC GAC CTG AGG
`Trp Glu Ser Asn Gly Glin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Wai Leu Asp Ser
`
`530
`
`1540
`
`1550
`
`560
`
`1S70
`t
`
`A.
`
`k
`
`58O
`
`1590
`
`600
`A.
`
`1610
`
`1620
`r
`
`r
`
`GAC GGC ICC TTC TTC CTC TAC AGC AAG CTC ACC GTG GAC AAG AGC AGG TGG CAG CAG GGG
`CTG CCG AGG AAG AAG GAG ATG TCG TTC GAG TGG CAC CTG TTC TCG TCC ACC GTC GTC Coc
`Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu. Thr Val Asp Lys Ser Arg Trp Gin Gin Gly>
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 13
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 12 of 55
`
`US 7,070,959 B1
`
`Fig.1OD.
`
`630
`
`1640
`
`1650
`
`1660
`
`1670
`
`1680
`
`r
`ir
`r
`AAC GTC TTC TCA TGC TCC GTG AIG CAT GAG GCT. CTG CAC AAC CAC TAC ACG CAG AAG AGC
`TTG CAG AAG AGT ACG. AGG CAC TAC GTA CTC CXGA (GAC GTG T G GTG ATG TGC GTC TC ECG
`Asn Wall Phe Ser Cys Ser Wal Met His Giu Ala Leu. His Asn His Tyr Thr Glin Lys Ser>
`
`700
`
`1690
`r
`s
`CC TCC CG TCT CCG GGT AAA TGA
`GAG AGG GAC AGA GGC CCA
`ACT
`Leu Ser Leu Ser Pro Gly Lys * * *>
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 14
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 13 of 55
`
`US 7,070,959 B1
`US 7,070,959 B1
`
`geet
`
`ujewop
`
`surewop
`
`SSBUlyJEIN|PAoeIU|
`
`SBURIGWSLUSUBI)
`
`
`Bulpuiqpuebysejnjeoes1xy
`
`NZNQ9NSNbNENe
`
`“LEBig
`
`
`
`
`
`
`
`
`
`
`
`tSEL¥66926
`
`08/
`OBZ
`
`
`
`ztg\6S40GZ289«OSG:Ge)GEC}ONpiceOUILUY
`
`‘eeLeenbiun
`
`SNUILUIE}-9
`
`
`
`ad$SyidS}b-HASN9
`
`*E-HsNG
`
`
`
`+78SWSSy7S8§b-4ldsNE
`
`*7S$$s$sL-HASNZ
`
`L-HASNP
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 15
`Joining Petitioner: Apotex
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 15
`
`Joining Petitioner: Apotex
`
`
`
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 14 of 55
`
`US 7,070,959 B1
`
`
`
`s
`
`s
`
`c
`
`S.
`
`S
`
`S
`
`Sp
`
`See as as cases des ed
`C C C C C C C C C C C.
`Low cici - c. cici f is
`A9|LudolpAH
`
`O. O. O. C. O. O.
`C C C C C C C C C C C.
`Lort cro Q - O CN C2 it up
`AloudolpAH
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 16
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 15 of 55
`
`US 7,070,959 B1
`
`Fig.13A.
`
`r
`t
`ATG GTC AGC TAC TGG GAC ACC GGG GTC CTG CTG TGC GCG CING CIC AGC GT CTG CTT CTC
`TAC CAG TCG ATG ACC CTG TGG CCC CAG GAC GAC ACG CGC GAC GAG TCG ACA GAC GAA GAG
`Met Wal Ser Tyr Trip Asp Thr Gly Val Lieu. Leu. CyS Ala Leu Leu Ser Cys Lieu. Leu Lieu>
`
`70
`
`80
`90
`100
`110
`s
`t
`r
`k
`r
`e
`ACA GGA TCF AGT TXA GGT TCA AAA TTA AAA GA CCT GAA CG AG TA AAA GGC ACC CAG
`TGT CCT AGA TCA AGT CCA AGT TT AAT TT CTA GGA CTT GAC TNA AA TT CCG GG GTC
`Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro Giu. Leu Ser Leu Lys Gly. Thr Gln2
`
`120
`
`140
`
`130
`60
`17O
`180
`r
`t
`t
`k
`s
`y
`CAC ATC ATG CAA GCA GGC CAG ACA CTG CAT CTC CAA TGC AGG GGG GAA GCA GCC CAT AAA
`GTG TAG AC GT CGT CCG GC EST GAC GTA AG GT ACG TCC CCC. CTT, CGT CGG GAT
`His Ile Met Glin Ala Gly Glin Thr Leu. His Leu Gln Cys Arg Gly Glu Ala Ala His Eys>
`
`50
`
`190
`
`200
`
`20
`
`220
`240
`k
`t
`TGG TCT TIG CCT GAA ATG GTG AGT AAG GAA AGC GAA AGG CTG AGC ATA AC AAA TCT, GCC
`ACC AGA AAC GGA CT TAC CAC ICA TTC CT, TCG CTT. TCC GAC CG TAT GATT AGA CGG
`Trp Ser Leu Pro Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr Lys Ser Alia>
`
`230
`
`2SO
`
`270
`
`2SO
`290
`300
`A.
`t
`f
`t
`TGT (GGA AGA AAT GGC AAA CAA TTC GC AG ACT TTA ACC TTG AAC ACA GCT CAA GCA AAC
`ACA CCT TOT TA CCG TTT GTT AAG ACG TCA TGA AAT TGG AACTTG GF CGA GTT CGT TTG
`CyS Gly Arg Asn. Gly Lys Glin Phe Cys Ser Thr Leu Thr I.eu. Asn. Thr Ala Glin Ala Asn->
`
`280
`
`30
`
`320
`
`330
`360
`A.
`r
`r
`y
`t
`CAC ACT GGC. TC TAC AGC TGC AAA TAT CTA GCT GTA CCT ACT TCA AAG AAG AAG GAA ACA
`{GTG GA CCG AAG ATG TCG ACG T ATA GAT CGA CAT GGA TGA AG
`TC TTC TTC CTTGT
`His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Wal Pro Thr Ser Lys Lys Lys Glu Thrx
`
`340
`
`350
`
`38O
`
`370
`390
`40
`*
`r
`i
`y
`s
`k
`GAA TCT, GCA ATC TATATA TT ATI AGF GAT ACA GGT AGA CCTTC GTA GAG ATG TAC AGT
`CTT AGA CGT TAG ATA TAT AAA TAA CA CTA GT CCA TCT GGA AAG CAT CTC TAC ATG TCA
`Glu Ser Ala Ile Tyr Ile Phe Ile Ser Asp Thr Gly Arg Pro Phe Wall Glu Met Tyr Ser>
`
`400
`
`420
`
`430
`
`450
`
`440
`460
`r
`sk
`s
`k
`g
`st
`se
`GAA ATC CCC GAA ATT ATA CAC ATG ACT GAA GGA AGG GAG CTC GTC AT CCC TNGC CGG GTT
`CTT AG GGG CTT TAA TAT GTG TAC GA CTT CCT TCC CTC GAG CAG TAA GGG ACG GCC CAA
`Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu. Leu waii Ile Pro Cys Arg wal
`
`470
`
`480
`
`490
`
`SO
`
`510
`t
`
`520
`Af
`
`e
`
`S30
`
`54D
`
`r
`
`f
`
`ACG TCA CCT AAC ATC ACT GTT ACT TTA AAA AAG TTT CCA CT GAC ACT TG AIC CCT GAT
`IGC AGT GGA TFG TAG TGA CAA TGA AAT TTTTTC 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 Lea Ile Pro Asp>
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 17
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 16 of 55
`
`US 7,070,959 B1
`
`Fig.13B.
`
`550
`
`560
`
`570
`
`S80
`
`590
`
`600
`
`t
`
`GGA AAA CGC ATA ATC
`AGT
`GG GAC
`CCT TTT GCG TAT TAG
`ACC CG
`Gly Lys Arg Ile Ile
`Trp Asp
`See
`
`GGC TTC ATC ATA TCA AAT GCA ACG TAC AAA
`CCG AAG TAG TAT AGT, TTA, CGT TGC AIG TTT
`Gay Phe Ile Ile Ser Asn Ala Thr Tyr LysX
`Lys
`
`610
`
`620
`
`630
`
`640
`A.
`t
`TAT. AAG ACA AAC TA
`GAA ATA GGG CT CTG
`GGG CAT TTG
`ACA GC AA
`GAA
`ACC TGT
`CTT TAT CCC GAA GAC
`ATA TTC TGT TTGAA
`CCC GTA AAC
`CGT
`GG ACA
`CAG TA
`CTT
`Tyr Lys Thr Asn Tyre
`Glu Ilie Gly Lieu. Leu
`Gly. His Leu
`Thr Cys
`Val Asn
`Ala
`Glu
`
`650
`
`660
`
`670
`
`690
`
`700
`WA
`
`710
`
`720
`
`CIC ACA CAT CGA CAA ACC AAT
`GAG TGT GTA GCT GTT TGG TTA
`Let Thr His Arg Glin Thr Asn
`
`ACA CCA CGC CCA GC
`AGC
`CAA AA
`AC
`GA GC
`AA
`TGT GGT GCG GG CAG
`TCG
`GT TAT
`CA CAG
`AT
`TAG
`Thr Pro Arg Pro Val
`Asp Wall
`Glin le
`Cie
`Ile
`Set
`
`730
`
`740
`
`r
`y
`AAA TTA CTTAGA GGC
`CAT ACT
`TTT AAT GAA TCT COG
`GA GA
`Lys Let Leu Arg Gly
`His Thr
`Lell
`
`750
`
`780
`760
`T
`A.
`ACT CCC TG AAC ACG
`ACC
`ACT GCT
`AA GT
`CTC
`GA. GGG AAC TNG TGC
`GA CGA
`CAG
`GAG
`TA ACA
`ASE Cys
`The pro Leu. As thr>
`Thr Ala
`T
`Wall
`Leul
`
`770
`y
`
`800
`
`790
`y
`AGA GTT CAA ATG ACC TGG AGT
`TAC
`NCT CAA GT TAC GG ACC TCA
`AG
`Arg Val Glin Met Thr Trip Ser
`
`810
`s
`
`820
`y
`
`y
`
`830
`
`840
`y
`
`A.
`AGC AAT TCC CAT GCC AAC
`GAC CAA
`GAT GAA All
`TCG TA AGG GTA CGG TTG
`CTG GTT
`CA CT AA
`Asp Glin
`Ser Asn. Ser His Ala Asn)
`Asp Glu Ile
`
`850
`
`860
`
`900
`890
`870
`t
`t
`y
`k
`t
`AT ACT
`GAC AAA (GGA CT
`ATA TTC TAC AGT, GT CET ACT
`AAC AAA
`AAA AG CAG
`A GAC
`CTG. T. CCT GAA AA TGA
`AT AAG ATG TCA CAA GAA TGA
`ITG TTT
`TTT TAC GTC
`AA CTG
`Asp Lys Gly Leu Tyr Thr>
`Lys Met Glin
`ASn Lys
`Ile Phe Tyr Ser Val Leu Thr
`Ile Asp
`
`880
`r
`
`920
`
`930
`
`910
`w
`t
`A.
`A.
`TGT CGT GTA AGG AG GGA CCA
`TCA GTG CAT ATA TAT GAT
`AAA TCT, GT AAC ACC
`TCA TTC
`AG CAC GTA TATATA CTA
`ACA GCA CAT TCC TCA CCT GGT
`TTT AGA CAA T G TGG
`AG AAG
`Ser Val His Ile Tyr Asp
`Cys Arg Wa Arg Ser Gly Pro
`Lys Ser Val Asn. Thr
`Ser Phe
`
`940
`
`950
`
`960
`
`980
`
`990
`
`970
`k
`k
`AAA GCA GGC CCG GGC GAG CCC
`AAA TCT TG GAC AAA ACT CAC ACA TGC CCA CCG GC CCA
`TTT CGT CCG GGC CCG CTC GGG
`TT AGA ACA CTG TTT GA. GG TGT ACG GGT GGC ACG (GGT
`Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
`Lys Ala Gly Pro Gly Glu Pro
`
`OCO
`y
`
`y
`
`100
`
`20
`
`1030
`
`lO50
`
`1060
`
`1040
`Ar
`A.
`r
`k
`1.
`r
`GCA CCT GAA CTC CG GGG GGA
`CCG TCA GTC TTC CTC TTC CCC CCA AAA CCC AAG GAC ACC
`GGC AGT CAG AAG GAG AAG GGGGGTTTT GGGTTC CTG TGG
`CGT GGA CTI GAG GAC CCC CCT
`Ala Pro Glu Leu Leu Gly Gly
`Pro Ser Val Phe Leu Phe Pro Pro Llys Pro Lys Asp Thr2
`
`O80
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 18
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 17 Of 55
`
`US 7,070,959 B1
`
`Fig.13C.
`
`OO
`
`10
`
`1090
`s
`t
`t
`CTC ATG ATC CC CGG ACC CCT GAG GIC ACA IGC GTG. GTG GTG GAC GTG AGC CAC GAA GAC
`GAG TAC TAG AGG GCC TGG GGA CTC CAG TGT ACG CAC CAC CAC CTG CAC CG GTG CTT. CTG
`Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp>
`
`20
`
`130
`
`40
`
`1150
`
`1160
`
`110
`
`2OO
`r
`CCT GAG GEC AAG TC AAC TGG AC GTG GAC GGC GTG GAG GTG CAT AAF GCC AAG ACA AAG
`GGA CTC CAG TC AAG TG ACC ATG CAC CTG CCG CAC CTC CAC GTA TA CGG TTC TGT TTC
`Pro Glu Wall Lys Phe ASn Trp Tyr Val Asp Gly Val Glu Val His Asn Alia Lys Thr Lys)
`
`18O
`
`190
`
`1220
`
`23 O
`
`1210
`r
`k
`CCG CGG GAG GAG CAG TAC AAC AGC ACG TAC CGT GG GC AGC GC CIC ACC GTC CG CAC
`GGC GCC CTC CTC GTC AG G TCG GC AIG GCA CAC CAG TCG CAG GAG GG CAG GAC GTG
`Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Wai Leu Thr Val Leu. His>
`
`1240
`
`1250
`
`1260
`
`270
`
`280
`
`29O.
`
`130
`130
`y
`e
`t
`CAG GAC TGG CTG AA GGC AAG GAG AC AAG GC AAG GC. TCC AAC AAA GCC CTC CCA GCC
`GTC CTG ACC GAC TTA CCG TC CFC AG TC ACG TO CAG AGG TTG TTT CGG GAG GGT CGG
`Glin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Llys Wal Ser Asn Lys Ala Leu Pro Ala)
`
`1320
`
`33O
`
`340
`
`350
`
`360
`
`te
`
`t
`
`s
`
`t
`
`370
`t
`
`380
`
`CCC ATC GAG AAA ACC ATC. TCC AAA GCC AAA GGG CAG CCC CGA GAA CCA CAG GIG TAC ACC
`GGG TAG CTC TT TGG TAG AGG TT, CGG TTT CCC GTC GGG GCT. CTT GGT GTC CAC AIG GIG
`Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Glin Pro Arg Glu Pro Glin Wall Tyr Ehr)
`
`400
`
`40
`
`420
`
`390
`r
`t
`CTG CCC CCA CC CGG GAT GAG CG ACC AAG AAC CAG GC AGC CG ACC GC CTG GC AAA
`GAC GGG GGET AGG GCC CTA CTC GAC TGG TC TTG GTC CAG TCG GAC TGG ACG GAC CAG TTT
`Leu Pro Pro Ser Arg Asp Glu Leu Thir Lys Asn Glin Val Ser Leu Thr Cys Lieu Wall Lys
`
`30
`
`440
`
`450
`
`460
`se
`g
`GGC TTC TAF CCC AGC GAC ATC GCC GTG GAG GG GAG AGC AA. GGG CAG CCG GAG AAC AAC
`CCG AAG ATA GGG TCG CTG TAG CGG CAC CTC ACC CTC TCG TTA CCC GTC GGC CTC TTG TG
`Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Giu Ser Asn Gly Gin Pro Glu Asn. Asn->
`
`4TO
`
`1480
`
`490
`
`SOO
`
`1SO
`520
`540
`1550
`s
`y
`s
`t
`TAC AAG ACC ACG CC CCC GTG CG GAC TCC GAC GGC FCC TTC TTC CTC TAC AGC AAG CC
`ATG TC TGG GC GGA. GGG CAC GAC CG AGG CTG CCG AGG AAG AAG GAG ATG TCG TC GAG
`Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu)
`
`1550
`
`S3 O
`
`1570
`
`160
`590
`580
`ye
`*
`y
`t
`t
`ACC GTG GAC AAG AGC AGG TGG CAG CAG GGG AAC GTC TTC TCA TGC TCC GTG ATG CAF GAG
`TGG CAC CTG TTC TCG TCC ACC GTC GC CCC TG CAG AAG AGT ACG. AGG CAC TAC GTA CTC
`Thr Val Asp Llys Ser Arg Trp Glin Glin Gly Asn Val Phe Ser Cys Ser Val Met His Glux
`
`1600
`
`620
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 19
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 18 Of 55
`
`US 7,070,959 B1
`
`Fig.13D.
`
`640
`
`1650
`
`630
`1570
`t
`e
`GCT CG CAC AAC CAC AC ACG CAG AAG AGC CTC CC CTG TCT CCG GG AAA GA
`CGA GAC GTG TTG GTG AG GC GTC TTC TCG GAG AGG GAC AGA. GGC CCA TTT ACT
`Ala Leu. His Asn His Tyr Thr Glin Lys Ser Leu Ser Leu Ser Pro Gly Lys * * * >
`
`660
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 20
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 19 of 55
`
`US 7,070,959 B1
`
`Fig.14A.
`
`r
`t
`s
`t
`t
`s
`ATG GTC AGC TAC TGG GAC ACC GGG GTC CTG CTG TGC GCG CTG CTC AGC TGT CTG CTT, CTC
`TAC CAG TCG AG ACC CNG GG CCC CAG GAC GAC ACG CGC GAC GAG TCG ACA GAC GAA GAG
`Met Val Ser Tyr Trp Asp Thr Gly Wall Leu Lieu. Cys Ala Lieu. Let Ser Cys Leu Leu. Leux
`
`70
`
`80
`k
`r
`ar
`ACA GGA TCT AGT TCC GGA GGT AGA CCT TTC GTA GAG ATG TAC AGT GAA AC CCC GAA. A
`TGT CCT AGA TCA AGG CCT CCA TCT GGA AAG CAT CTC TAC AG CA CTT TAG GGG CT TAA
`Thr Gly Ser Ser Ser Gly Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ilex
`
`90
`
`100
`
`10
`
`120
`
`30
`140
`50
`15)
`t
`e
`k
`y
`t
`ATA CAC ATG ACT GAA GGA AGG GAG CTC GTC. A CCC GC CGG GT ACG TCA CCT. AAC ANC
`TAT GTG TAC TGA CTT CCT, TCC CTC GAG CAG TAA GGG ACG GCC CAA TGC AGT GGA TTG TAG
`Ile His Met Thr Glu Giy Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ilex
`
`170
`
`18C
`
`190
`
`200
`230
`240
`r
`t
`r
`s
`t
`r
`i
`ACT GTT ACT TA AAA AAG TT CCA CTT GAC ACTTG ATC CCT GAT GGA AAA CGC ATA ATC
`TGA CAA TGA AAT TTT TIC AAA GGT CAA CTG TGA AAC TAG GGA CTA CCTT. GCG AT TAG
`Thr Wall Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu le Pro Asp Gly Lys Arg Ile Ilex
`
`210
`
`22)
`
`250
`
`260
`
`270
`300
`r
`r
`r
`re
`*
`r
`GG GAC AGT AGA AAG GGC TTC ATC ATA TCA AAT, GCA ACG TAC AAA GAA ATA GGG CTT CG
`ACC CTG TCA TCT, TTC CCG AAG TAG TAT AGT, TTA CGT TGC ATG TTT CTT TAT CCC GAA GAC
`Trp Asp Ser Arg Lys Gly Phe Ile Ie Ser Asn Ala Thr Tyr Lys Giu Ile Gly Lieu. Leux
`
`280
`
`290
`
`310
`
`320
`
`330
`
`340
`
`3SO
`
`360
`
`r
`t
`ACC TGT GAA GCA ACA GTC AA. GGG CAT TTG TAT AAG ACA AAC TAT CTC. ACA CAT CGA CAA
`GG ACA CTT, CGT GT CAG TA CCC GTA AAC ATA
`C G T S ATA GAG GT GTA GCT GT
`Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn. Tyr Lieu. Thr His Arg Glind
`
`380
`
`390
`
`370
`400
`40
`t
`y
`r
`k
`r
`ACC AAT ACA ATC AA GAT GTC CAA ATA AGC ACA CCA CGC CCA GTC AAA TTA CT AGA. GGC
`TGG TTA TGT TAG TAT. CTA CAG GTT TAT TCG TGT GGT GOG GGT CAG TTT AAT GAA TCT CCG
`ihr Asn. Thir Ile Ile Asp Wall Glin Ile Ser Thr Pro Arg Pro Val lys Leu Leu Arg Gly>
`
`420
`
`430
`
`440
`
`450
`
`460
`
`470
`
`480
`
`CAT ACT CT, GC CTC AAT GT ACT GCT ACC ACT CCC TG AAC ACG. AGA GTT CAA ATG ACC
`GTA TGA GAA CAG GAG TA ACA TGA CGA TGG. TGA GGG AAC TG GC TCT CAA GT TAC GG
`His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr Pro Leu. Asn Thr Arg Val Glin Met Third
`
`A90
`rt
`
`r
`
`t
`
`500
`r
`
`50
`
`520
`
`r
`
`t
`
`S30
`t
`
`540
`r
`
`r
`
`TGG AGT TAC CCT GAT GAA ATT GAC CAA AGC AAT TCC CAT GCC AAC ATA TTC TAC AGT, GTI
`ACC TCA ATG GGA CTA CTT TAA CTG GET TCG TTA AGG GTA CGG TFG TAT. AAG ATG TCA CAA
`Trp Ser Tyr Pro Asp Glu Ilie Asp Gin Ser Asn Ser His Ala Asn Ile Phe Tyr Ser Vald
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 21
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 20 Of 55
`
`US 7,070,959 B1
`
`Fig.14B.
`
`S
`
`58)
`s
`s
`k
`CTT ACT A GAC AAA ATG CAG AAC AAA GAC AAA GGA CTT TAT ACT GT CGT GTA AGG AGT
`GAA TGA TAA CTG TTT TAC GTC TG TTT CEG TTT CC GAA ATA GA ACA GCA CAT ICC TCA
`Asp Lys Gly Leu Tyr Thr
`Cys Arg Wall Arg Serd
`Leu Thir Ile Asp Lys Met Glin Asn Lys
`
`STO
`
`S90
`
`5
`
`SO
`
`63
`
`640
`
`650
`
`560
`
`g
`s
`w
`GGA CCA TCA TC AAA TCT GT AAC ACC
`CA GTG CAT AA TAT GA
`AAA GCA GGC CCG GGC
`CCT GGT AGT AAG TTT AGA CAA TG TGG.
`TTT CGT CCG GGC CCG
`AG CAC GTA TA, ATA CTA
`Giy Pro Ser Phe Lys Ser Val Asn. Thr Ser Val His Ile Tyr Asp Lys Ala Gly Pro Gly>
`
`670
`
`580
`
`590
`
`700
`
`70
`
`720
`
`e
`s
`GAG CCC AAA C GT GAC AAA ACT CAC
`ACA GC CCA CCG GC CCA
`GCA CCT GAA CC CTG
`CIC GGG T AGA ACA CTG TTT TGA GTG GT ACG GG GGC ACG GGT CGT. GGA CT GAG GAC
`Glu Pro Lys Ser Cys Asp Llys Thr His
`Thr Cys Pro Pro Cys Pro
`Ala Pro Gu Lieu. Leux
`
`30
`
`40
`
`750
`s
`CIC ANG ATC. TCC CGG
`
`GGG GGA CCG TCA GTC TTC CTC TTC CCC CCA AAA CCC AAG GAC
`
`CCC CCT GGC AG CAG AAG GAG AAG GGG GG T GGG TTC CTG
`GAG TAC AG AGG GCC
`Thr Leu Met Ile Ser Arge
`Pro Llys Pro Lys Asp
`Gly Giy Pro Ser Wall. Phe Leu Phe Pro
`
`760
`
`770
`
`780
`
`790
`
`8O
`
`SOO
`t
`ACC CCT GAG GTC ACA GC GTG GIG
`CC GAG G.C. AAG XC
`GG GAC GG AGC CAC GAA
`GAC
`GGA CTC CAG TTC AAG
`GG GGA CTC CAG GT ACG CAC CAC
`CAC CTG CAC TCG GIG CT
`CTG
`Asp Pro Glu Val Lys Phex
`Val Asp Val Ser His Giu
`Thr Pro Glu Val Thr Cys Val Val
`
`83
`
`840
`
`85
`
`870
`
`360
`s
`CCG CGG GAG GAG CAG
`CAF AAT GCC AAG ACA
`AAC TGG TAC GTG GAC GGC GG GAG
`GGC GCC CTC CTC GTC
`TTG ACC ATG CAC CTG CCG CAC CTC
`GA TA CGG TC TGT
`CAC
`Lys Pro Arg Glu Gu Gln)
`Asn Trp Tyr Val Asp Gly Val Glu
`His Asn Alia Lys Thr
`Wall
`
`890
`
`900
`
`90
`
`920
`r
`y
`GTC CIC ACC GTC CTG
`CAC CAG GAC TGG CG AA
`TAC AAC AGC ACG TAC CGT GTG GC
`AGC
`GG GC CG ACC GAC A
`CAG GAG TGG CAG GAC
`AIG TTG TCG TGC ATG GCA CAC CAG
`His Glin Asp Trp Leu Asn)
`Tyr Asn. Ser Thr Tyr Arg Val Val
`Wai Lieu. The Walt Lieu
`Sea
`
`930
`
`940
`
`950
`
`96.O.
`
`970
`
`98O
`
`GGC AAG GAG TAC AAG GC AAG GC
`CCG TC CTC ATG TIC ACG TC CAG
`Gly Lys Glu Tyr Lys Cys Llys Val
`
`OOO
`
`100
`
`O20
`
`990
`s
`GCC CCC AC GAG AAA ACC
`AAC AAA GCC CTC CCA
`CGG GGG TAG CTC TT TGG
`G TTT CGG GAG (GGT
`ASn Lys Ala Leu Pro
`Ala Pro Ile Glu Lys Third
`
`O3C
`
`1040
`
`OSO
`
`1070
`
`1080
`
`ATC TCC AAA GCC AAA GGG CAG CCC CGA GAA CCA CAG GTG TAC
`
`ACC CTG CCC CCA TCC CGG
`TGG GAC GGG GGT AGG GCC
`TAG AGG T CGG TT CCC GTC cagg
`GCT. CT GG GTC CAC AG
`Ile Ser Lys Ala Lys Gly Glin Pro
`Arg Glu Pro Glin Val Tyr
`Thr Leu Pro Pro Ser Arg>
`
`Mylan Exhibit 1023
`Mylan v. Regeneron, IPR2021-00880
`Page 22
`
`Joining Petitioner: Apotex
`
`

`

`U.S. Patent
`
`Jul. 4, 2006
`
`Sheet 21 of 55
`
`US 7,070,959 B1
`
`Fig.14C.
`
`109)
`
`10
`e
`
`20
`100
`sk
`k
`:
`iA
`ACC TGC CTG GTC AAA. GGC. TC. At CCC AGC
`AAG AAC CAG
`GTC AGC (CG
`CG ACC
`GAT GAG
`GG ACG GAC CAG TT CCG AAG ATA GGG TCG
`GAC GG
`TTC TTG GTC
`CTA CTC
`CAG CG GAC
`Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser2
`Lys ASn Glin
`Asp Glu
`Wall Ser Leu
`eu Thr
`
`1130
`
`1140
`
`1150
`
`60
`
`180
`200
`O
`t
`t
`k
`r
`r
`t
`CAG CCG GAG AAC AAC AC AAG ACC ACG CCT
`AGC AA. GGG
`GAG TGG GAG
`GCC GTG
`GAC ATC
`GTC GGC CTC TTG TTG AEG TC TGG TGC GGA
`CGG CAC
`TCG TTA CCC
`CTG TAG
`CTC ACC CTC
`Gln Pro Glu Asn ASn Tyr Lys Thr Thr Prox
`Asp Ile
`Glu Trp Glu
`Ser Asn Gy
`Ala Val
`
`190
`
`1210
`
`1220
`y
`
`y
`
`1250
`250
`t
`rt
`t
`y
`st
`CTC TAC AGC AAG CTC ACC GTG GAC AAG ACC
`CTG GAC
`TCC TTC TTC
`TCC GAC GGC
`CCC GTG
`AGG CTG CCG AGG AAG AAG GAG ATG TCG TTC GAG GG CAC CTG CCG
`GAC CG
`GGG CAC
`Pro Wall Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Lieu. Thr Val Asp Llys Ser
`
`1230
`
`1240
`
`270
`
`1290
`
`280
`1300
`t
`r
`st
`t
`AGG TGG CAG CAG GGG AAC GC TTC TCA TGC TCC GTG ATG CAT GAG GCT. CTG CAC AAC CAC
`TCC ACC GTC GTC CCC TTG CAG AAG AGT AC