(12)
`
`United States Patent
`Papadopouloset al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,647,842 B2
`*Feb. 11, 2014
`
`US008647842B2
`
`
`
`7,087,411 B2
`8/2006 Daly et al.
`rarae Bo ee ie, cal al
`4
`4
`iegand etal.
`7,303,747 B2
`12/2007 Wiegand etal.
`7.306.799 B2
`12/2007 Wiegandetal.
`7,374,757 B2
`5/2008
`Papadopouloset al.
`7,374,758 B2
`5/2008
`Papadopoulosetal.
`7,396,664 B2
`7/2008 Dalyet al.
`7,399,612 B2
`7/2008 Daly et al.
`7,521,049 B2
`4/2009 Wiegandetal.
`7,524,499 B2
`4/2009
`Papadopoulosetal.
`7,635,474 B2
`12/2009 Dalyet al.
`7,704,500 B2
`4/2010
`Papadopoulosetal.
`2004/0265309 Al
`12/2004 Kandelef al.
`
`2005/0175610 Al
`shoeooetgeo ‘i
`5
`;
`2005/0281831 Al
`2006/0210566 Al
`2007/0037748 Al
`2009/0081217 Al
`2009/0155899 Al
`2009/0234103 Al
`2010/0087632 Al
`2010/0221782 Al
`
`(75)
`
`(54) METHODS FOR PRODUCING A FUSION
`PROTEIN CAPABLE OF BINDING VEGF
`.
`:
`;
`Inventors: Nicholas J. Papadopoulos,
`Lagrangeville, NY (US): SamuelDavis,
`NewYork, NY (US); George D.
`Yancopoulos, Yorktown Heights, NY
`(US)
`:
`:
`
`.
`.
`(73) Assignee: Regeneron Pharmaceuticals, Inc..
`Tarrytown, NY (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`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) Appl. No.: 13/439,889
`:
`(22)
`Filed:
`Apr. 5, 2012
`
`(65)
`
`Prior Publication Data
`US 2013/0149744 Al
`Jun. 13, 2013
`
`8/2005 Wiegandetal.
`Iy“008 eageand et a I
`dataef a
`12/2005 Davis-Smyth ctal.
`9/2006 Holash etal.
`2/2007 Stahlet al.
`3/2009 Papadopoulos etal.
`6/2009
`Papadopoulosetal.
`9/2009 Davis-Smythet al.
`4/2010 Dalyet al.
`9/2010
`Papadopoulosetal.
`
`POREIGN PATENT DOCUMENTS
`WO 94/21679
`9/1994
`WO 97/44453
`11/1997
`wo oydao‘
`999
`WO00/75319
`12/2000
`
`wo
`WO
`wo
`wo
`
`Related U.S. Application Data
`(60) Continuation of application No. 12/885,185, filed on
`Sep. 17,2010, now abandoned, whichis a continuation
`of application No. 12/715,128, filed on Mar. 1, 2010,
`now Pat. No. 8,084,234, which is a continuation of
`Chunget al. (2008), Treatment of malignant ascites, Current Treat-
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`ment Options in Oncology 9:215-233.
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`Wells et al. (1990), Additivity of mutational effects in proteins, Bio-
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`
`OTHER PUBLICATIONS
`
`(60) Provisional application No. 60/138,133, filed on Jun.
`8, 1999.
`
`(Continued)
`
`
`
`(51) Primary Examiner—Christine J SaoudInt. Cl.
`
`
`
`65006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`aoNy;’
`CION 15/462
`CI2N 15/63
`CO7H 21/04
`(52) US. CL.
`USPC weseseseseceenees 435/69.7; 435/252.3; 435/320.1,
`435/325; 435/358; 536/23.4
`(58) Field of Classification Search
`;
`None
`See applicationfile for complete searchhistory.
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`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`5,712,380 A
`6,011,003 A
`6,100,071 A
`6,833,349 B2
`6,897,294 B2
`7,070,959 Bl
`
`1/1998 Kendall etal.
`1/2000 Charnock-Joneset al.
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`12/2004 Xiaetal.
`5/2005 Davis-Smythet al.
`7/2006 Papadopouloset al.
`
`AssistantExaminer — Jon M Lockard
`(74) Attorney, Agent, or Firm — Frank R. Cottingham
`
`(57)
`
`ABSTRACT
`
`invention provides methods for producing a
`The present
`fusion protein capable of binding vascular endothelial cell
`
`growth factor (VEGF). The methods of the invention com-
`prise growing recombinant cells in suspension culture,
`wherein the recombinantcells contain an expression vector
`comprising a nucleic acid molecule encoding a fusion protein
`that binds VEGF, and isolating the fusion protein from the
`suspension culture. The fusion proteinmay comprise a VEGF
`receptor component having an immunoglobulin-like (Ig)
`domain 2 ofa first VEGF receptor, an Ig domain 3 ofa second
`VEGFreceptor, and a multimerizing component.
`
`
`
`14 Claims, 55 Drawing Sheets
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`

`

`US 8,647,842 B2
`
`Page 2
`
`(56)
`
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`the European Patent Office in EP Appl. No.
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`05023819.5 on Ocl. 9, 2009, on behalf of Applicant Genentech,Inc.
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`in U.S. Appl. No.
`
`
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 1 of 55
`
`US 8,647,842 B2
`
`Fig.1.
`123 45 67 8
`
`9
`
`10
`
`jd
`
`
`
`0.01
`
`0.1
`
`1
`
`10
`
`100
`
`ug/ml
`——{}—rTIE-2-Fe
`moAe acetylated Fit-1(1-3)-Fe
`----©--- unmodified Fit-1(1-3)-Fe
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 2 of 55
`
`US 8,647,842 B2
`
`HSVM-LIVS
`
`HSVM-LIVS
`
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`
`+
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`-O4-(€-b)bd
`
`94-c-SL
`
`uleday
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 3 of 55
`
`US 8,647,842 B2
`
`—
`
`—
`S
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`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 4 of 55
`
`US 8,647,842 B2
`
`&bene
`wo
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`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 5 of 55
`
`US 8,647,842 B2
`
`Fig.6A.
`
`123 45 67 8
`
`9
`
`10
`
`
`Fig.6B.
`
`11
`
`12 13 14 15 1617 1819 20
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 6 of 55
`
`US 8,647,842 B2
`
`
`
`
`
`—{}— 'TIE-2-Fe
`serene Ove unmodified Fit-1(1-3)-Fe
`----Cy--- acetylated Fit-1(1-3)-Fe (10X)
`oanwen/y----- acetylated Fit-1(1-3)-Fe (20X)
`---{f--- acetylated Fit-1(1-3)-Fe (30X)
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 8
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 8
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 7 of 55
`
`US 8,647,842 B2
`
`Fig.8.
`
`
`0.5 ug/ml
`
`1.0 pg/ml
`
`5.0 pg/ml
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`
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`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 8 of 55
`
`US 8,647,842 B2
`
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`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`
`
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 9 of 55
`
`US 8,647,842 B2
`
`Fig.10A.
`20*”
`GAC ACC
`oTG TSG
`Asp Thr
`
`ece
`Gly
`
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`Trp
`
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`
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`
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`
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`
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`
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`
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`
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`
`250
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`
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`
`370
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`
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`
`490
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`Gly
`
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`
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`
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`
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`
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`
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`
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`
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`Ala Asn>
`
`260*
`AAA CAA
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`Lys Gla
`
`320
`*
`
`AAG
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`
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`
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`Tyr
`
`Acc TGC
`TCG ACG
`Ser Cys
`
`Lys
`
`TAT
`ATA
`tyr
`
`CTA
`GAT
`Leu
`
`ocT
`CGA
`Ala
`
`CAT
`Val
`
`350
`*
`BAG AAG
`TTC TTC
`Lys Lys
`
`TCA
`
`Ser
`
`Lys
`
`ATG
`TAC
`Met
`
`ACG
`Cys
`
`Tyr Ser>
`
`480
`*
`*
`CCGG GTT
`GCC CAA
`Arg Val>
`
`380
`*
`ATA TIT
`TAT ABA
`Tle Phe
`
`440*
`ATA CAC
`TAT GTG
`Tle His
`
`TAT
`ATA
`Tyr
`
`ATT
`TAA
`Ile
`
`ATT
`TAA
`Tle
`
`AGT
`
`Ser
`
`ACT
`
`ATG
`TAC
`Met
`
`390
`
`GAT
`CTA
`Asp
`
`450
`
`GAA
`crt
`Blu
`
`510
`
`400
`
`ACA
`TOT
`
`oot
`CCA
`Gly
`
`AGA CCT
`TCT GGA
`Arg Pro
`
`TIC
`BAG
`Phe
`
`460*
`GAG CTC
`CTC GAG
`Glu Leu
`
`*
`AGG
`rc¢
`Arg
`
`GTC
`
`Val
`
`cer
`Giy
`
`410&
`GTA GAG
`CAT CTC
`Val Glu
`
`470
`*
`AYY CCC
`TAA GGG
`Tle Pro
`
`ATC
`TAG
`Tle
`
`ACT
`
`Thr
`
`PAT
`Leu
`
`AAG
`TEC
`Lys
`
`Lys
`
`¥e
`TTT
`ABA
`Phe
`
`520
`*.
`CcA CTT
`GGT GAA
`Pro Leu
`
`530*
`ACT TTG
`TGA AAC
`Thr Leu
`
`ATC
`TAG
`Tle
`
`540
`ve
`*
`ccT GAT
`GGA CTA
`Pro Asp>
`
`GAC
`CTG
`Asp
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 11
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 11
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 10 of 55
`
`US 8,647,842 B2
`
`550
`560
`580
`
`.7 i
`*
`ACG
`TAC
`TCA
`CGC ATA
`TGG GAC
`AGT
`AGA
`AVC ATA
`TGC
`ATG
`AGT
`TAG TAT
`G TAT
`ACC CTG
`Thr
`sex
`Tle Tle
`Trp Asp
`Arg Ile
`
`Ser
`
`Arg
`
`Lys>
`
`Fig.10B.
`
`ect
`Gly
`
`ATC
`TAG
`Ile
`
`610
`*
`
`ATA
`TAT
`Ile
`
`Gas CTT
`CCC GAA
`Gly Leu
`
`CTS
`GAC
`Leu
`
`670
`*
`
`640
`
`GAA
`CTT
`Glu
`
`GCA
`CoT
`Ala
`
`GTC
`CAG
`Val
`
`GGG CAT
`cece GTA
`Gly His
`
`TTS
`AAC
`Leu
`
`TAT AAG
`ATA TIC
`Tyr Lys
`
`ACA
`ToT
`
`AAC
`TIS
`Asn
`
`700
`Ed
`
`710
`*
`
`ATA
`Tyx>
`
`720
`
`ACA
`ToT
`Thr
`
`CAT CGA
`GTA GCT
`His Arg
`
`CAA
`GTT
`Gin
`
`ACC AAT
`TG6G TTA
`Thr Asn
`
`ACA
`(GT
`Thr
`
`ATC
`TAG
`Tle
`
`GAT
`CTA
`ASP
`
`CAA ATA
`GTT TAT
`Gin Ile
`
`CAG
`Val
`
`730
`*
`
`740
`
`TTA
`AAT
`Leu
`
`CTT AGA
`GAA TCT
`Leu Arg
`
`Got
`CCG
`Gly
`
`CAT ACT
`GTA TGA
`His Thr
`
`etrT
`GAA
`Leu
`
`Lys
`
`GAG
`Leu
`
`TTA
`Asn
`
`TeT
`ACA
`Cys
`
`790
`*
`CAA ATG
`GTT TAC
`Gln Met
`
`GTT
`CAA
`Val
`
`ACC
`TGS
`Thr
`
`800
`os
`
`810
`
`GAT
`CTA
`Asp
`
`TAC
`ATG
`Tyr
`
`Pro
`
`crr
`Glu
`
`TTT
`Lys
`
`760*
`AcT GT
`TGA CGA
`Thr Ala
`
`820
`*
`AAT AAG
`TTA TTC
`Asn Lys
`
`TCT
`Arg
`
`ACA CCA
`{GT GGT
`Thr Pro
`
`ccc
`GCG
`Arg
`
`CCAer&
`Pro
`
`GTC
`CAG
`Val>
`
`770*
`ACT CCC
`TGA GGG
`Thr Pro
`
`830
`*
`GCT TCC
`CGA AGG
`Ala Ser
`
`780
`
`TIG
`ABC
`Leu
`
`AAC
`
`ACG
`
`Asn
`
`Thr>
`
`840
`
`GTA
`Cat
`val
`
`AGG
`TCC
`Arg
`
`GcT
`Arg>
`
`TGG AGT
`ACC TCA
`Trp Ser
`
`860
`*
`
`850
`*
`
`ATT
`TAA
`Tle
`
`GAC CAA
`cite GTt
`Asp Gin
`
`AGC
`TOG
`Ser
`
`AAT TCC
`TTA AGG
`Asn Ser
`
`CAT
`GTA
`His
`
`870
`
`880
`*
`
`890
`*
`
`AAC
`
`Asn.
`
`ATA
`TAT
`Tle
`
`TIC
`AAG
`Phe
`
`TAC AGT
`ATG TCA
`Tyx Ser
`
`GoTTt
`CAA
`Val
`
`ceTvTt ACT
`GAA TGA
`Leu Thr
`
`ATT
`TAA
`Ile
`
`910
`*
`
`920
`*
`
`ATG
`TAC
`Met
`
`CAG
`eT¢
`Gln
`
`AAC AAA
`TTG TTT
`Asn Lys
`
`GAC
`cic
`Asp
`
`BAA GGA
`TTT CCT
`Lys Gly
`
`GRA
`Leu
`
`930
`
`TAT
`ATA
`
`ACT
`TGA
`
`ACA
`Cys
`
`950
`*
`
`AGT
`TCA
`Ser
`
`GGA CCA
`CCT GGT
`Gly Pre
`
`TCA
`AGT
`Ser
`
`AAG
`Phe
`
`900
`
`Lys>
`
`960
`*
`
`BARA
`TTT
`Lys>
`
`940
`*
`GTA AGG
`cAT Tee
`Val Arg
`
`1000
`*
`GGC CCG
`cee Gcc
`Gly Pro
`
`1060
`*
`
`Goce
`ccs
`Gly
`
`1020*
`TGT
`CT
`AGA ACA
`Ser
`cys>
`
`* T
`
`1980*
`*
`TCA GTC
`AGT CAG
`Ser Val>
`
`1010
`*
`GAG CCC
`cre GGG
`Glu Pro
`
`1070
`%
`GGG GGA
`cee CccT
`Gly Gly
`
`AAA
`[TT
`Lys
`
`cos
`oe
`Pro
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`$70
`*
`AAC ACC
`TTS TSG
`Asn Thr
`
`1030*
`ACT CAC
`TGA GIG
`The His
`
`TCT
`AGA
`ser
`
`CAA
`val
`
`ABA
`
`Lys
`
`980
`*
`
`990
`
`TCA
`AGT
`Ser
`
`GTG CAT
`CAC GTA
`Val His
`
`ATA
`TAT
`Tle
`
`TAT
`ATA
`Tyr
`
`CAT
`CTA
`Asp
`
`ABA
`TTT
`Lys
`
`GCA
`cot
`Ala
`
`1050
`
`1040*
`TGC CCA
`ACG GOT
`Cys Pro
`
`ACA
`TST
`
`ccG
`occ
`
`TGC
`ACG
`Cys
`
`CCA
`GGT
`Pro
`
`GCA
`cer
`Ala
`
`ccT
`GGA
`Pro
`
`GAA CTC
`CMP GAG
`Glu Leu
`
`CG
`GAS
`Leu
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 11 of 55
`
`US 8,647,842 B2
`
`Fig.10C.
`
`1090
`*
`
`1100
`*
`
`CTC
`GAG
`Leu
`
`TTC cce
`AAG GGG
`Phe Pro
`
`CCA
`GGT
`Pro
`
`AAG
`Phe
`
`AAA CCC
`TTT GGG
`Lys Pro
`
`1110
`*
`
`*
`
`GAC ACC
`CTG TGS
`
`AAG
`
`Lys
`
`Asp Thr
`
`1120
`*
`
`1130
`*
`
`1140
`*
`
`*
`
`crc
`GAG
`Lew
`
`ATG
`TAC
`Met
`
`ATC TCC
`TAG AGG
`Tle Ser
`
`CGG
`ecc
`Arg
`
`acc ccT
`TGG GGA
`Thr Pro
`
`GAG
`eT
`Glu
`
`GTc ACA
`CAG TOT
`Val Thr>
`
`1150
`*
`
`1160
`*
`
`TGC
`ACG
`cys
`
`GTG
`CAC
`Val
`
`GTG GIG
`CAC CAC
`Val val
`
`GAC
`Cte
`ASD
`
`GTG AGC
`caACc TCG
`Val Ser
`
`CAC
`GTS
`His
`
`1176
`*
`
`*
`
`GAA GAC
`cTT cic
`Glu Asp
`
`1186
`*
`
`1190
`*
`
`ect
`GGA
`Pro
`
`GAG
`ere
`Glu
`
`GTC AAG
`CAG TTC
`Val Lys
`
`TAC
`ATG
`
`BAC TGG
`TTS acc
`Asn Trp
`
`SAG
`Phe
`
`1200
`*
`
`*
`
`GTG GAC
`CAC CTG
`Val Asp>
`
`1220
`*
`
`1240
`*
`
`1250
`*
`
`1260
`*
`
`*
`
`1210
`*
`
`1230
`*
`
`*
`
`oTG
`Cac
`Val
`
`GAG GTG
`eTe CAC
`Glu Val
`
`CAT
`GTA
`His
`
`AAT GCC
`TTA CGG
`Asn Ala
`
`AAG
`
`Lys
`
`ACA AAG
`TST TIC
`Thr Lys
`
`ccs
`
`Pro
`
`CGG
`Gcc
`arg
`
`GAG GAG
`etc cTc
`Glu Glu
`
`CAG
`otc
`Glin
`
`TAC AAC
`ATG TITG
`Tyr Asn
`
`AGC
`
`ser
`
`ACG TAC
`TGC ATG
`Thr Tyr>
`
`ccG
`Gly
`
`127¢
`*
`
`1280
`*
`
`1290
`*
`
`ke
`
`1300
`*
`
`1310
`*
`
`1320
`*
`
`*
`
`GTG
`CAC
`Val
`
`GTc AGC
`CAG TCG
`Val Ser
`
`GTC
`CAG
`Val
`
`cgTc Acc
`GAG TGG
`Leu Thr
`
`GTC
`
`Val
`
`CTG CAC
`GAC GTG
`Leu His
`
`CAG
`
`Gin
`
`GAC
`cTG
`Asp
`
`TGG cTG
`ACC GAC
`{Trp Leu
`
`AAT
`TTA
`Asn.
`
`GGC AAG
`ccG TIC
`Gly Lys
`
`GAG
`em
`Glu
`
`TAC AAG
`ATG TIC
`Tyr Lys>
`
`1330
`*
`
`1340
`*
`
`1350
`*
`
`*
`
`1360
`*
`
`1370
`*
`
`1380
`*
`
`*
`
`AAG
`
`cece
`
`GAG AAA
`cTtc TTT
`
`ACC
`
`ACG
`Cys
`
`Lys
`
`eve TCC
`CAG AGG
`Val Ser
`
`AAC
`TT
`Asn
`
`AAA GCC
`TIT CGG
`Lys Ala
`
`cre
`GAG
`Leu
`
`CCA GCC
`GGT CGG
`Pro Ala
`
`ATC
`TAG
`Ile
`
`Pro
`
`Glu Lys
`
`Thr
`
`atc TCC
`TAG AGG
`Ile Ser
`
`AAA
`TIT
`Lys
`
`GCC ABA
`CcGG TTT
`Ala Lys>
`
`1390
`*
`
`1400
`e
`
`ccc
`Gly
`
`GTC
`Gin
`
`COC CGA
`GGG GCT
`Pro Arg
`
`GAA
`CTT
`Glu
`
`CCA CAG
`GGT GTC
`Pro Gln
`
`GTG
`CAC
`Val
`
`1450
`*
`
`1460
`*
`
`CAG
`GTC
`Gln
`
`GTC AGC
`CAG TCG
`Val Ser
`
`CTG
`GAC
`Leu
`
`CTG
`GAC
`Leu
`
`1410
`*
`
`*.
`
`TAC ACC
`ATG TGG
`Tyr Thr
`
`1470
`*
`
`*
`
`1420
`*
`
`1430
`x
`
`1440
`*
`
`*
`
`cece
`
`Pro
`
`CCA TCC
`GGT AGG
`Pro Ser
`
`GAC
`Leu
`
`GAT GAG
`CTA CTC
`
`Asp Glu
`
`CcTG
`GAC
`Leu
`
`ACC BAG
`TSG TIC
`Thr Lys>
`
`1480
`*
`
`1490
`*
`
`GAC ATC
`CTIG TAG
`
`1500
`k
`
`*
`
`6ce
`CoG
`Ala
`
`GTG GAG
`CAC CIC
`Val Glu>
`
`AGC
`
`Ser
`
`ccG
`
`AAG
`Phe
`
`ACC Tac
`TGG ACG
`Thr Cys
`
`1520
`*
`
`Gic AAA
`CAG TIT
`Val Lys
`
`1530
`*
`
`*
`
`Gly
`
`TAT CCC
`ATA GGG
`Tyx Pro
`
`1540
`*
`
`Asp Ile
`
`1550
`*
`
`1510
`*
`
`GAG
`eT
`Glu
`
`AGC AAT
`TG TTA
`Ser Asn
`
`GGG
`ece
`Gly
`
`ACC
`Trp
`
`CAG CCG
`GTC GGC
`Gin Pro
`
`GAG
`cTc
`Glu
`
`AAC AAC
`TTG TTG
`Asn Asn
`
`TAC
`ATG
`Tyr
`
`BAG
`
`Lys
`
`ACC ACG
`TOG Toc
`Thr Thr
`
`cer
`
`Pro
`
`cee GTG
`GGG CAC
`Pro Val
`
`CTG
`GAC
`Leu
`
`1570
`*
`
`1580
`*
`
`1590
`*
`
`*
`
`*
`
`1600
`*
`
`1610
`*
`
`1560
`*
`
`*
`
`GAC Tec
`CTG AGG
`Asp Ser>
`
`1620
`*
`
`*
`
`GAC
`CTG
`
`GGC
`cCcG
`Gly
`
`Tec TTC
`AGG AAG
`Ser Phe
`
`AAG
`Phe
`
`ecTc TAC
`GAG ATG
`Leu Tyr
`
`AGC
`TCG
`Ser
`
`BAG CTC
`TTC GAG
`Lys Leu
`
`ACC
`
`Thro
`
`GTG
`CAC
`Val
`
`GAC AAG
`
`Asp Lys
`
`AGC
`TCG
`Ser
`
`AGG TGG
`TCC ACC
`Arg Trp
`
`CAG
`ote
`Gln
`
`CAG GGG
`GTC CCC
`Gln Gly>
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 13
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 13
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 12 of 55
`
`US 8,647,842 B2
`
`Fig.1 0D.
`
`*
`
`1630
`*
`
`+.
`
`1640
`*
`
`1650
`*
`
`*
`
`*
`
`1660
`t
`
`*
`
`1670
`*
`
`1680
`*
`
`*
`
`AAC GTC TIC TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC ACG CAG AAG AGC
`TG CAG AAG AGT ACG AGG CAC TAC GTA CTC CGA GAC GIG TYG GTG ATG TGC GTC TIC TCG
`Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser>
`
`*
`
`1690
`*
`
`*
`
`1700
`*
`
`cTc TCC CTG TCT CCG GGT AAA TGA
`GAG AGG GAC AGA GGC CCA TTT ACT
`Leu Ser Leu Ser Pro Gly Lys ***>
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 13 of 55
`
`US 8,647,842 B2
`
`
`
`
`
`
`
`SSeuryJe/N|jSoesujBulpuiqpuebyeynyjecenxy
`
`“EL61
`
`SUBIQUISWWSUEL]
`
`
`
`urewopsurewop
`
`NZNONGNevNENe
`
`oes
`
`‘eeLeanbiun
`
`SNUIWU9)-9
`
`SsSs
`
`
`
`Zig\6S40G/189LONploeoulwy
`
`ssidS}basNZ
` SyidS}b-HASNEidS|b-HASNP
`
`
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 15
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 15
`
`
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet14 of 55
`
`US 8,647,842 B2
`
`
`
`
`
` 100
`
` 80
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Fig.12A.
`
`
`
`Fig.12B.
`
`60
`
`40
`
`
`
` 20
`
`
`
`Ayoi!ydoipAH
`
`AyoutydospAy
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 16
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 16
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 15 of 55
`
`US 8,647,842 B2
`
`Fig.13A.
`
`10
`*
`AGC TAC
`TOG ATG
`Ser Tyr
`
`+
`
`TGG
`Acc
`Trp
`
`GAC ACC
`CTG TSG
`Asp Thr
`
`GGG
`ece
`Gly
`
`ATG
`TAC
`Met
`
`GTC
`CAG
`Val
`
`30
`
`40
`*
`
`50
`
`ct
`GAC
`Leu
`
`CcTG
`GAC
`Leu
`
`TGC
`ACG
`Cys
`
`GCG CTG
`CGC GAC
`Ale Leu
`
`ete
`GAG
`Leu
`
`AGC TCT
`TCG ACA
`Ser Cys
`
`CTS
`GAC
`Leu
`
`70
`*
`
`ACA
`TST
`Thr
`
`GGA
`cert
`Gly
`
`TCT AGT
`AGA TCA
`Ser Ser
`
`TCA
`AGT
`Ser
`
`130
`*
`
`80*”
`GGT TCA
`CCA AGT
`Gly Ser
`
`140
`
`90
`
`TET
`Lys
`
`AAT
`Leu
`
`TTT
`Lys
`
`GAT
`CTA
`ASp
`
`cer
`GGA
`Pro
`
`Ag
`TAG
`Tle
`
`ATG CAA
`TAC GTT
`Met Gln
`
`GCA
`cGcT
`Ala
`
`GGC CAG
`cee GTC
`Gly Gin
`
`ACA
`TCT
`Thr
`
`cts
`GAC
`Leu
`
`GTG
`His
`
`ALC
`Trp
`
`AGA
`Ser
`
`190
`*
`TTS CcT
`AAC GGA
`Leu Pro
`
`250
`*
`
`200
`*
`
`GAA
`cTr
`Glu
`
`ATG GTG
`TAC CAC
`Met Val
`
`AGT
`
`AAG
`
`Ser
`
`Lys
`
`150
`
`CAT
`GTA
`His
`
`210
`
`CTT
`Glu
`
`270
`
`cre
`GAG
`Leu
`
`CAA
`ott
`Gln
`
`AGC
`
`Ser
`
`GAA
`cTt
`Glu
`
`100*
`GAA CTG
`cTT GAC
`Glu Leu
`
`160
`*
`TGC AGG
`ACG TCC
`Cys Arg
`
`220*
`AGG CTG
`TCC GAC
`Arg Leu
`
`280
`*
`
`1160
`*
`TTA AAA
`AAT TTT
`Leu Lys
`
`GGc
`ccc
`Gly
`
`AGT
`
`Ser
`
`170
`*«
`
`GGG
`ccc
`Gly
`
`GAA GCA
`crTrr CGT
`Glu Ala
`
`6ce
`CGG
`Ala
`
`GTA
`His
`
`230
`x
`ATA ACT
`TAT TGA
`Ile Thr
`
`296
`*
`
`ABA
`TTT
`Lys
`
`AGA
`Ser
`
`AGC
`TCG
`Ser
`
`ABC
`TTS
`Asn
`
`GGA
`ccT
`Gly
`
`AGA AAT
`TCT TTA
`Arg Asn
`
`cea
`cece
`Gly
`
`310*
`Gee Tre
`ccs AAG
`Gly Phe
`
`370
`*
`GCA ATC
`CGT TAG
`Ala Ile
`
`430
`*
`CCC GAA
`GGG CTT
`Pro Glu
`
`490
`¥
`CCT AAC
`GGA TTG
`Pro Asn
`
`TAC
`ATG
`Tyr
`
`TAT
`ATA
`Tyr
`
`ATT
`TAA
`Ile
`
`ATC
`TAG
`Tle
`
`cac
`
`His
`
`AGA
`Ser
`
`ATC
`TAG
`Ile
`
`ACG
`TSC
`
`TCA
`AGT
`Ser
`
`260*
`AAA CAA
`TTT GTT
`Lys Glin
`
`320*
`AGC TGC
`TCG ACG
`Ser Cys
`
`380
`*
`ATA TTT
`TAT AAA
`Ile Phe
`
`440
`*
`ATA CAC
`TAT GTG
`Ile His
`
`500*
`ACT GTT
`TGA CAA
`Thr val
`
`TTC
`AAG
`Phe
`
`ACG
`Cys
`
`AGT
`TCA
`Ser
`
`AacT
`TGA
`Tho
`
`TTA
`AAT
`Leu
`
`ACC TTIG
`TGG AAC
`Thr Leu
`
`ACA GCT
`TGT CGA
`Thr Ala
`
`CAA
`GTT
`Gln
`
`GCA
`CGT
`Ala
`
`TAT
`ATA
`Tyx
`
`TTT
`Lys
`
`330
`
`cTzA
`GAT
`Leu
`
`350
`
`340
`*
`
`cet
`
`Ala
`
`GTA
`CAT
`Val
`
`CccT ACT
`GGA TGA
`Pro Thr
`
`TCA
`AGT
`Ser
`
`356
`*
`PAG AAG
`TEC TIC
`Lys Lys
`
`410
`
`DAG
`
`Lys
`
`ATT
`TAA
`ile
`
`AGT
`
`Ser
`
`GAT
`CTA
`Asp
`
`ACA
`TGT
`
`GGT
`CCA
`Gly
`
`ATG
`TAC
`Met
`
`ACT
`TGA
`Tor
`
`GGA
`ccT
`Gly
`
`ACT
`TGA
`The
`
`TTA
`AAT
`Leu
`
`AAG
`TIC
`Lys
`
`TrT
`
`Phe
`
`400
`*
`AGA CCT
`TCT GGA
`Arg Pro
`
`460
`*
`GAG CTC
`CTC GAG
`Glu Leu
`
`520
`&
`cca cTt
`GGT GAA
`Pro Leu
`
`TTC
`AAG
`Phe
`
`GTA GAG
`CAT CTC
`Val Glu
`
`ATG
`TAC
`Met
`
`Tyr
`
`47 2
`*
`
`420
`
`AGT
`TCA
`Ser>
`
`480
`
`GTC
`CAG
`Val
`
`ATT CCC
`TAA GGG
`Tle Pro
`
`TEC
`ACG
`Cys
`
`CGG
`gcc
`Arg
`
`GTT
`CAA
`Val>
`
`530oa
`ACT TTG
`TGA AAC
`Thr Leu
`
`GAC
`CTG
`ASP
`
`540
`
`ATC
`TAG
`Tle
`
`cer
`GGA
`Pro
`
`GAT
`CTA
`Asp>
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 17
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 17
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 16 of 55
`
`US 8,647,842 B2
`
`GGA
`cer
`Gly
`
`CGC ATA
`GcG TAT
`Arg Ile
`
`TTY
`Lys
`
`GAA
`CTT
`Glu
`
`ATA
`TAT
`Tle
`
`ACA
`TST
`
`TTA
`AAT
`Lew
`
`Fig.13B.
`560*
`TSG GAC
`ACC CTG
`Trp Asp
`
`AGT
`TCA
`ser
`
`AGA
`ToT
`Arg
`
`ATC
`TAG
`Tle
`
`580*
`ATC ATA
`TAG TAT
`Ile Tle
`
`TCA
`AGT
`Ser
`
`590
`&
`AAT GCA
`TTA CGT
`Asn Ala
`
`Go
`CCG
`Giy
`
`AAG
`Phe
`
`ACG
`TecomT
`
`TAC
`ATG
`Tyr
`
`ACA
`
`AAC
`
`Thr
`
`Asn
`
`600
`
`AAA
`
`Lys>
`
`660
`
`TAT
`ATA
`
`720
`
`CCA
`Got
`Pro
`
`STC
`CAG
`Val>
`
`GOG
`arg
`
`780
`
`TIG
`AAC
`Leu
`
`AAC
`
`ACG
`
`Asn
`
`Thr>
`
`840
`
`BAC
`
`620
`*
`acc TGT
`TGS ACA
`Thr Cys
`680x
`ACC AAT
`TOG TTA
`Thr Asn
`
`740*
`CAT ACT
`GTA TGA
`His Thre
`
`eTG
`GAC
`Leu
`
`CRA
`GTT
`Gin
`
`ccG
`Gly
`
`GCA
`cer
`Ala
`
`OTC
`CAG
`Val
`
`DAT
`TTA
`Asn
`
`690
`
`ATA
`TAT
`Tle
`
`730
`
`ere
`GAG
`Leu
`
`B10
`
`ACA
`ToT
`Thr
`
`ATC
`TAG
`Tle
`
`CTT
`GAA
`Leu
`
`oTc
`CAG
`Val
`
`ecr
`
`GAT
`CTA
`Asp
`
`GTC
`CAG
`val
`
`AAT
`TTA
`
`TST
`ACA
`Cys
`
`640*
`G&G CAT
`ccc GTA
`Gly His
`706*
`CAA ATA
`GTT TAT
`Gin Tle
`
`160«
`ACT GCT
`TGA CGA
`Thr Ala
`
`650*
`TAT AAG
`ATA THX
`Tyr Lys
`710*
`ACA CCA
`TGT GoT
`Thr Pro
`
`770os
`ACT ccc
`TGA GGG
`Thr Pro
`
`BBC
`Leu
`
`AGC
`TCG
`Ser
`
`ACT
`
`Thr
`
`AGC
`
`ATT
`TAA
`Ile
`
`CTT
`Glu
`
`820“
`GAC CAA
`cTG GTT
`Asp Gin
`
`880
`
`830
`*
`AAT TCC
`TTA AGG
`Asn Ser
`
`Ser
`
`CAT
`GTA
`His
`
`Goce
`CGG
`Ala
`
`Asn>
`
`900
`
`CTT
`GAA
`Leu
`
`TAT
`ATA
`Tyr
`
`ACT
`TGA
`Thr>
`
`ATA.
`TAT
`Tle
`
`TAT
`ATA
`Tyr
`
`S60*
`GAT
`CTA
`Asp>
`1620*
`CccG
`oC
`cca
`GGT
`ACG
`GGC
`Pro Cys Pro>
`1080*
`*
`AAG GAC ACC
`TTC
`TGG
`cTG
`Thr>
`Lys
`Asp
`
`* T
`
`ATG
`TAC
`Met
`
`CAG
`GTC
`Gln
`
`ASC AAA
`TTS TTT
`Asn Lys
`
`GAC
`Cts
`Asp
`
`940*
`AAC ACC
`TIG TSG
`Asn Thr
`
`1000
`*
`BET CAC
`TGA GTG
`Thr His
`
`1060*
`TTC ccc
`AAG GGG
`Phe Pro
`
`Act
`Ser
`
`ACA
`ToT
`Thr
`
`cca
`Got
`Pro
`
`TCT
`AGA
`Ser
`
`GTT
`CAA
`Val
`
`cic
`ASP
`
`TTC
`AAG
`Phe
`
`GAG
`Leu
`
`890*
`ABA GGA
`TTT Cot
`Lys Gly
`
`950
`*
`GIG CAT
`CAC GTA
`Val His
`
`1010*
`TGC CCA
`ACG GGT
`Cys Pro
`1076*
`BAA CCC
`TIT GGG
`Lys Pro
`
`GAT
`CTA
`Asp
`
`870
`
`Lys
`930*
`AAA
`TTT
`Lys
`990*
`TCT
`ACA
`Cys
`1056*
`STC
`CAG
`Val
`
`TAC
`ANG
`
`Pro
`
`GAC
`CTs
`Asp
`
`TCA
`AGT
`Ser
`
`AAG
`Phe
`
`7 T
`
`CT
`AGA
`Ser
`
`* T
`
`CA
`AGT
`Ser
`
`AAA
`TIT
`Lys
`
`CCG
`GG6Cc
`Pro
`
`BOG*
`TGS AGT
`ACC TCA
`Trp Ser
`
`860
`*
`CTT AcT
`GAA TGA
`Leu Thr
`
`920*
`GGA CCA
`ccT GGT
`Gly Pro
`980*
`GAG ccc
`cTc GGG
`Glu Pro
`
`1040*
`G6G GGA
`cere cCcrT
`Gly Gly
`
`ACC
`
`Thr
`
`GTT
`CAA
`Val
`
`AGT
`
`Ser
`
`eee
`CCG
`Gly
`
`CTS
`GAC
`Leu
`
`610
`cf
`GGG CTT
`CCC GAA
`Gly Leu
`670*
`CAT CGA
`GTA GCT
`His Arg
`730*
`CTT AGA
`GAA TCT
`Leu Arg
`730*
`CAA ATG
`GTT TAC
`Gin Met
`
`oTT
`
`val
`
`850
`*
`TAC AGT
`ATG TCA
`Tyr Ser
`910*
`GTA AGG
`CAT TCC
`Val arg
`970*
`Goce CCG
`cee Got
`Gly Pro
`1030a
`GAA CTC
`CTT GAG
`Glu Leu
`
`ATA
`TAT
`Tle
`
`AAG
`Phe
`
`TGT
`ACA
`Cys
`
`CGT
`GCA
`Arg
`
`GCA.
`Cct
`Ala
`
`TIT
`Lys
`
`SCA
`CGT
`Ala
`
`cer
`GGA
`Pro
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 18
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 18
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 17 of 55
`
`US 8,647,842 B2
`
`Fig.13C.
`
`1090
`*
`
`1160
`*
`
`1110
`x
`
`*
`
`ere
`GAG
`Leu
`
`ATG
`TAC
`Met
`
`ATC TCC
`TAG AGG
`Tle Ser
`
`CGG
`Gec
`Arg
`
`ace ccr
`TGG GGA
`Thr Pro
`
`GAG
`ere
`Glu
`
`GTC ACA
`CAG TOT
`Val Thr
`
`ACG
`cys
`
`CcT
`
`Pro
`
`GAG
`ere
`Glu
`
`115¢
`*
`GTC AAG
`CAG TTC
`val Lys
`
`1210
`*
`
`TIC
`BAG
`Phe
`
`1160
`*
`AAC TGG
`TTG ACC
`Asn Trp
`
`1220
`*
`
`TAC
`ATG
`
`1170
`*
`*
`GTG GAC
`CAC CTG
`Val Asp
`
`1230
`*
`
`*
`
`cca
`Gly
`
`CAC
`Val
`
`ccG
`
`Pro
`
`cea
`Gcc
`Arg
`
`GAG GAG
`ere crc
`Glu Glu
`
`CAG
`GTC
`Gin
`
`TAC AAC
`ATG TTG
`‘yr Asn
`
`AGC
`
`Ser
`
`ACG TAC
`TGC ATG
`Thr Tyr
`
`GTG
`CAC
`Val
`
`Arg
`
`12706
`*
`
`1280
`*
`
`1290
`*
`
`*
`
`GAC
`CTG
`Asp
`
`TGS CTG
`ACC GAC
`Trp Leu
`
`BAT
`TTA
`Asn
`
`GGC AAG
`ccG TTC
`Gly Lys
`
`GAG
`eT
`Glu
`
`TAC AAG
`ATG TTC
`Tyr Lys
`
`ACG
`cys
`
`Gin
`
`1350
`*
`
`+
`
`1120
`*
`
`11306
`*
`
`1140
`*
`
`*
`
`GIG GTG
`CAC CAC
`Val Val
`
`GAC
`CTs
`Asp
`
`GIG AGC
`CAC TCG
`Val Ser
`
`Cac
`GTG
`His
`
`GAA GAC
`CTT CTG
`Glu Asp>
`
`1180*
`GAG GTG
`erc CAC
`Glu Val
`
`1240
`*”
`
`GTC AGC
`
`Val Ser
`
`1300*
`GT¢ TCC
`CAG AGG
`Val Ser
`
`1360
`*
`
`1190
`*
`
`1200
`+
`
`+
`
`CAT
`GTA
`His
`
`AAT GCC
`TTA CGG
`Asn Ala
`
`DAG
`TT
`Lys
`
`ACA AAG
`TGT TIC
`Thr Lys>
`
`1250
`*
`CTC BCC
`GAG TSG
`Leu Thr
`
`GTe
`CAG
`Val
`
`1266
`*
`
`*
`
`ote
`CAG
`Val
`
`CPG CAC
`GAC GTG
`Leu His>
`
`1310
`*
`
`1320
`*
`
`*
`
`ABA GCC
`TTT CGG
`Lys Ala
`
`CTC
`GAG
`Leu
`
`CCA GCC
`GGT CGG
`Pro Ala>
`
`TTS
`Asn
`
`1370
`*
`
`cece
`Gly
`
`GTC
`Glo
`
`cece CGA
`GGG GCT
`Pro Arg
`
`GAA
`eTT
`Glu
`
`CCA CAG
`GGT GTC
`Pro Gln
`
`STG
`CAC
`Val
`
`1420
`*
`
`1430
`*
`
`1380
`x
`.
`TAC ACC
`ATG TGG
`Tyr Thr>
`
`1440
`*
`
`*&
`
`AAC
`
`Asn
`
`CAG
`oT
`Gln
`
`GTC AGC
`CAG TCG
`Val Ser
`
`cts
`GAC
`Leu
`
`Acc TGC
`TGG ACG
`Thr Cys
`
`eTs
`GAC
`Leu
`
`GTC AAA
`CAG TIT
`Val Lys>
`
`1480
`*
`
`1490
`*
`
`1500
`*
`
`*
`
`GCC BAA
`cae TTT
`Ala Lys
`
`1410
`*
`*
`ACC AAG
`TGG TIC
`Thr Lys
`
`1470
`*
`
`*
`
`C GIG GAG
`cac cTc
`CGG
`Ala
`Val Glu
`
`ACC
`Trp
`
`GAG
`Cte
`Glu
`
`AGC AAT
`TCG TTA
`Ser Asn
`
`ece
`Gly
`
`CAG CCG
`GTC Goce
`Gin Pro
`
`GAG
`crc
`Glu
`
`BAC AAC
`TTS TIG
`Asn Asn>
`
`ece
`CoG
`Pra
`
`ATC
`TAG
`Tle
`
`1330*
`GAG AAA
`crc TTT
`Glu Lys
`
`1390
`¥*
`
`1340*
`ATC TCC
`TAG AGG
`Tie Ser
`
`ACC
`TSG
`Thr
`
`Lys
`
`1400
`*
`
`ece
`
`Pre
`
`CCA TCC
`GGT AGG
`Pro Ser
`
`OGG
`
`arg
`
`GAT GAG
`CTA CIC
`Asp Glu
`
`CTG
`GAC
`Leu
`
`CCG
`Gly
`
`TAC
`ATG
`Tyx
`
`AGC
`
`Ser
`
`1460*
`GAC ATC
`CTG TAG
`Asp Ile
`
`1520
`*e
`
`cer
`
`Pro
`
`Cece GTG
`GGG CAC
`Pro Val
`
`CTG
`GAC
`Leu
`
`1580
`*
`
`1530
`*
`*
`Gac TCC
`CTG AGG
`Asp Ser
`
`1590
`*
`
`*
`
`1540
`*
`
`1550
`*
`
`GAC
`
`ASP
`
`ccs
`Gly
`
`Tec TTC
`AGG AAG
`Ser Fhe
`
`AAG
`Phe
`
`etc TAC
`GAG ATG
`Leu Tyr
`
`AGC
`TCG
`Ser
`
`1560
`*
`*
`AAG CTC
`TIC GAG
`Lys Leu>
`
`4620
`*
`
`*
`
`1600
`*
`TTC TCA
`AAG AGT
`Phe Ser
`
`TGC
`ACG
`Cys
`
`1610
`*
`TCC GTG
`AGG CAC
`Ser Val
`
`ATS
`TAC
`Met
`
`CAT GAG
`GTA CTC
`His Glu>
`
`ACC
`
`Thr
`
`CAC
`Val
`
`AGC
`TCG
`Ser
`
`AGG TGG
`Tce ACC
`Axg Trp
`
`CAG
`oT
`Gln
`
`CAG GGG
`GTC ccc
`Gln Gly
`
`BAC
`TTG
`Asn
`
`GTC
`CAG
`Val
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 19
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 19
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet18 of 55
`
`US 8,647,842 B2
`
`Fig.13D.
`
`*
`
`1630
`*
`
`*
`
`1640
`*
`
`1650
`*
`
`*
`
`*
`
`1660
`*
`
`*
`
`1670
`*
`
`GCT CTIG CAC AAC CAC TAC ACG CAG AAG AGC CTC TCC CTG TCT CCG GGT AAA TGA
`CGA GAC GIG TTG GTG ATG TGC GTC TIC TCG GAG AGG GAC AGA GGC CCA TTT ACT
`Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys ***>
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 20
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 20
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 19 of 55
`
`US 8,647,842 B2
`
`Fig.14A.
`
`a7
`
`*
`
`*”
`
`*
`
`40
`
`56
`*
`
`60
`
`ATG
`TAC
`Met
`
`GTC
`CAG
`Val
`
`AGC TAC
`TCG ATG
`Ser Tyr
`
`TGG
`ACC
`Trp
`
`GAC ACC
`CIG TSG
`Asp Thr
`
`GGG
`cece
`Gly
`
`Gre
`CAG
`Val
`
`CTG
`GAC
`Lew
`
`CTG
`GAC
`Leu
`
`ACG
`Cys
`
`GCG CTG
`CGl GAC
`Ala Leu
`
`crc
`GAG
`Leu
`
`AGC TOT
`TCG ACA
`Ser Cys
`
`CTG
`GAC
`Leu
`
`cTT
`GAA
`Leu
`
`cTc
`GAG
`Leu>
`
`70
`”
`
`80
`”
`
`ACA
`
`The
`
`GGA
`cer
`Gly
`
`TCT ACT
`AGA TCA
`Ser Ser
`
`TCC
`AGG
`Ser
`
`SGA GCT
`cot CCA
`Gly Gly
`
`ACA
`TCT
`Arg
`
`cer
`GGA
`Pro
`
`TTC
`AAG
`Phe
`
`GTA
`CAT
`Val
`
`100
`*
`
`110
`*”
`
`120
`
`ATG TAC
`TAC ATG
`i Met Tyr
`
`AST
`TCA
`Ser
`
`GAA ATC
`CTT TAS
`Glu Tle
`
`ece
`GGG
`Pro
`
`GAA
`CTT
`Glu
`
`ATT
`TAA
`Tle>
`
`140
`
`159
`
`180
`
`130
`*
`
`160
`*
`
`170
`*«
`
`ATA
`TAT
`Tle
`
`CAC
`GTG
`His
`
`ATG ACT
`TAC TGA
`Met. Thr
`
`GAA
`CTT
`Glu
`
`GGA AGG
`cr TCC
`Gly Arg
`
`GAG
`cTc
`Glu
`
`ere
`GAG
`Leu
`
`oTc
`CAG
`Val
`
`ATT
`TAA
`Ile
`
`cece
`
`Pro
`
`TGC CGG
`ACG GCC
`Cys Arg
`
`ACG TCA
`TGC AGT
`Thr Ser
`
`Cet
`
`AAC
`
`Pro
`
`Asn
`
`ATC
`TAG
`ile>
`
`240
`
`190
`*
`
`200
`*
`
`ACT
`
`Thr
`
`GTT
`CAA
`Val
`
`ACT TTA
`TGA AAT
`Thr Leu
`
`AAA
`
`Lys
`
`AAG TTT
`TTC AAA
`Lys Phe
`
`CCA
`GGT
`bro
`
`cTT
`
`Leu
`
`260
`*
`
`210
`
`GAC
`CTG
`Asp
`
`270
`
`220
`*
`
`230
`*
`
`ACT
`TGA
`
`ATC ccT
`TAG GGA
`Tle Pro
`
`AAC
`Leu
`
`GGA ABA
`cer TTT
`Gly Lys
`
`eae
`
`Arg
`
`ATA
`TAT
`Ile
`
`ATC
`TAG
`Ile>
`
`286
`*
`
`290
`*
`
`300
`
`250
`*
`
`TGG
`acc
`Trp
`
`GAC
`CTG
`Asp
`
`AGT AGA
`TCA TCT
`Ser Arg
`
`AAG
`
`Lys
`
`Gec TTC
`CCG AAG
`Gly Phe
`
`ATC
`TAG
`Ile
`
`ATA
`TAT
`Ile
`
`AGT
`Ser
`
`TTA
`Asn
`
`GCA
`CGT
`Ala
`
`ACG TAC
`TGC ATG
`Thr Tyr
`
`AAA
`TTT
`Lys
`
`GAA ATA
`CTT TAT
`Glu Tle
`
`G&G
`ece
`Gly
`
`otY
`
`Leu
`
`cts
`GAC
`Leu>
`
`350
`
`310
`*
`
`ACC
`TSG
`
`TOT
`ACA
`Cys
`
`GRA GCA
`CTT cot
`Glu Ala
`
`ACA
`TOT
`Thr
`
`370
`*
`
`Acc
`
`320*
`GTC AAT
`CAG TTA
`Val Asn
`
`380
`*
`
`340
`
`350
`*
`
`GGG
`ccc
`Gly
`
`CAT
`GTA
`His
`
`TAT
`ATA
`Tyr
`
`BAG
`
`Lys
`
`ACA AAC
`TST TTG
`Thr Asn
`
`TAT
`ATA
`Tyr
`
`cTC ACA
`GAG TGT
`Lev Thr
`
`CAT
`GTA
`His
`
`CGA
`oct
`Arg
`
`CAA
`GTT
`Gln>
`
`400
`
`410
`*
`
`CAA
`GTT
`Gln
`
`ATA
`TAT
`Ile
`
`ACA
`TOT
`Thr
`
`CCA
`
`Pro
`
`oTc
`CAG
`Val
`
`eTT
`GAA
`Leu
`
`AAT
`TTA
`4sn
`
`ACA ATC
`TST TAG
`Thr Ile
`
`ATA
`TAT
`tle
`
`GAT GTC
`CTA CAG
`Asp Val
`
`Thr
`
`430
`*
`
`440
`+
`
`coc CCA.
`GCG GGT
`Arg Pro
`
`460
`*
`
`AAA TTA
`TTT AAT
`Lys Leu
`
`470
`*
`
`AGA
`TCT
`Arg
`
`CAT
`GTA
`His
`
`ACT
`TGA
`Thy
`
`CTT GTC
`GAA CAG
`Leu Val
`
`ere
`GAG
`Leu
`
`AAT TGT
`TTA ACA
`Asn Cys
`
`ACT
`TGA
`
`GCT
`CGA
`Ala
`
`ACT
`
`Thr
`
`cece
`SSG
`Pro
`
`TTG AAC
`AAC TTG
`Leu Asn
`
`ACG
`
`Thr
`
`AGA GTT
`TCT CAA
`Arg Val
`
`CAA
`GTT
`Gln
`
`ATG
`TAC
`Met.
`
`490
`a
`
`500
`*
`
`520
`*
`
`cd
`
`530
`*
`
`540
`
`T OG
`acc
`Trp
`
`AGT
`TCA
`Ser
`
`TAC CCT
`ATG GGA
`Tyr Pre
`
`GAT
`CTA
`Asp
`
`GAA ATT
`CTT TAA
`Glu Ile
`
`GAC
`CTG
`Asp
`
`CAA
`oTT
`Gln
`
`AAT
`TTA
`Asn
`
`Tce
`AGG
`Ser
`
`CAT GCC
`GTA CGG
`His Ala
`
`DAC
`TTG
`Asn
`
`ATA TIC
`TAT AAG
`Ile Phe
`
`TAC
`ATG
`Tyr
`
`AGT
`TCA
`Ser
`
`GIT
`CAA
`Val>
`
`Ser
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`
`Mylan Exhibit 1162
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`
`

`

`U.S. Patent
`
`Feb. 11, 2014
`
`Sheet 20 of 55
`
`US 8,647,842 B2
`
`Fig.14B.
`
`560
`”
`
`er?
`
`Leu
`
`ACT
`TGA
`Thr
`
`ADA
`
`Lys
`
`ATG CAG
`TAC GTC
`Met Gin
`
`AAC
`
`Asn
`
`TTT CTG
`Lys Asp
`
`ABA
`
`Lys
`
`GGA
`ccT
`Gly
`
`626
`*
`
`580k
`cTT TAT
`GAA ATA
`Leu Tyr
`
`640
`*
`
`§90
`*
`
`600
`
`ACT
`TGA
`Thr
`
`TGT CGT
`ACA GCA
`Cys Arg
`
`GTA
`CAT
`Val
`
`AGG AGT
`Tce TCA
`Arg Ser>
`
`650
`*
`
`660
`
`CCA
`GGT
`Pro
`
`TCA TIC
`AST AAG
`Ser Phe
`
`AAA
`TTT
`Lys
`
`TCT GiT
`AGA CAA
`Ser Val
`
`AAC
`TTS
`Asn
`
`ecT
`Gly
`
`ACC TCA
`
`Thr Ser
`
`CAT
`GTA
`His
`
`ATA TAT
`TAT ATA
`Tle Tyr
`
`GAT
`CTA
`Asp
`
`ABA GCA
`‘TT CGT
`Lys Ala
`
`GGCc
`cee
`Gly
`
`cee Goce
`Gat CCG
`Pre Gly>
`
`CAC
`Val
`
`670
`*
`ABA TCT
`TTT AGA
`Lys Ser
`
`TCT
`ACA
`cys
`
`680
`*
`GAC AAA
`cTG TTT
`Asp Lys
`
`ece
`
`Pro
`
`730
`*
`
`740
`*
`
`ACT
`