US008343737B2
`
`(12) United States Patent
`Papadopoulos et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,343,737 B2
`*Jan. 1, 2013
`
`(54) CELL CULTURE COMPOSITIONS CAPABLE
`OF PRODUCING A VEGF-BINDING FUSION
`POLYPEPTIDE
`
`(75) Inventors: Nicholas J. Papadopoulos,
`Lagrangeville, NY (US); Samuel Davis,
`New York, NY (US); George D.
`Yancopoulos, Yorktown Heights, NY
`(Us)
`
`(73) Assignee: Regeneron Pharmaceuticals, Inc.,
`Tarrytown, NY (U S)
`
`( * ) 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) Appl.No.: 13/106,910
`
`(22) Filed:
`
`May 13, 2011
`
`(65)
`
`Prior Publication Data
`
`US 2012/0064621A1
`
`Mar. 15, 2012
`
`Related US. Application Data
`
`(60) Continuation of application No. 12/334,927, ?led on
`Dec. 15, 2008, now Pat. No. 7,964,377, which is a
`continuation of application No. 12/ 102,648, ?led on
`Apr. 14, 2008, now Pat. No. 7,524,499, which is a
`division 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/USOO/ 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)
`C12N 5/10
`(2006.01)
`C12N 5/16
`(2006.01)
`C12N15/62
`(2006.01)
`C12N15/63
`(2006.01)
`C07H 21/04
`(52) US. Cl. ............... .. 435/69.7; 435/252.3; 435/320.1;
`435/325; 435/358; 536/23.4
`(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 al.
`6,011,003 A
`1/2000 Charnock-Jones et al.
`6,100,071 A
`8/2000 Davis-Smyth et a1.
`6,833,349 B2 12/2004 Xia et al.
`6,897,294 B2
`5/2005 Davis-Smyth et a1.
`7,070,959 B1
`7/2006 Papadopoulos et al.
`7,087,411 B2
`8/2006 Daly et al.
`7,279,159 B2 10/2007 Daly et al.
`7,303,746 B2 12/2007 Wiegand et al.
`7,303,747 B2 12/2007 Wiegand et al.
`
`7,306,799 B2 12/2007 Wiegand et a1.
`7,374,757 B2
`5/2008 Papadopoulos et a1.
`7,374,758 B2
`5/2008 Papadopoulos et a1.
`7,396,664 B2
`7/2008 Daly et al.
`7,399,612 B2
`7/2008 Daly et al.
`7,521,049 B2
`4/2009 Wiegand et a1.
`7,524,499 B2
`4/2009 Papadopoulos et a1.
`7,635,474 B2 12/2009 Daly et al.
`7,704,500 B2
`4/2010 Papadopoulos et a1.
`2004/0265309 A1
`12/2004 Kendall et al.
`8/2005 Wiegand et a1.
`2005/0175610 A1
`11/2005 Wiegand et a1.
`2005/0260203 A1
`2005/0281822 A1
`12/2005 Cedarbaum et al.
`12/2005 Davis-Smyth et al.
`2005/0281831 A1
`2006/0210566 A1
`9/2006 Holash et al.
`2007/0037748 A1
`2/2007 Stahl et al.
`3/2009 Papadopoulos et a1.
`2009/0081217 A1
`6/2009 Papadopoulos et a1.
`2009/0155899 A1
`9/2009 Davis-Smyth et al.
`2009/0234103 A1
`2010/0087632 A1
`4/2010 Daly et al.
`2010/0221782 A1
`9/2010 Papadopoulos et a1.
`
`W0
`W0
`W0
`W0
`W0
`
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`Yang et al. (1995), The use of polyethylene glycol-modi?ed
`interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic
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`. Cancer 76:687-694.
`Davis-Smyth et a1. (1996), The second immunogiobulin-like domain
`of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding
`and may initiate .
`.
`. EMBO J. 15:4919-4927.
`
`(Continued)
`
`Primary Examiner * Christine J Saoud
`Assistant Examiner * Jon M Lockard
`(74) Attorney, Agent, or Firm * Frank R. Cottingham
`
`ABSTRACT
`(57)
`The present invention provides cell culture compositions
`capable of producing fusion polypeptides that bind vascular
`endothelial growth factor (V EGF). The cell culture compo
`sitions of the invention comprise cells which contain an
`expression vector comprising a nucleic acid molecule encod
`ing a fusion polypeptide that binds VEGF. The fusion
`polypeptides may comprise a VEGF receptor component
`having an immunoglobulin-like (Ig) domain 2 of a ?rstVEGF
`receptor, an Ig domain 3 of a second VEGF receptor, and a
`multimeriZing component.
`
`12 Claims, 55 Drawing Sheets
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`

`

`US 8,343,737 B2
`Page 2
`
`OTHER PUBLICATIONS
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`receptor for vascular endothelial cell growth factor, Biochem
`Biophys Res Commun 187: 1579-1586.
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`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.
`Kendall et al. (1993), Inhibition of vascular endothelial cell growth
`factor activity by an endogenously encoded soluble receptor, Proc.
`Natl. Acad. Sci. USA 90:10705-10709.
`Kendall et al. (1996), Identi?cation of a natural soluble form of the
`vascular endothelial growth factor receptor, FLT-1, and its .
`.
`.
`Biochem Biophys Res Commun 226:324-328.
`Autiero et al. (2003), Role of PIGF in the intra~ and intermolecular
`cross talk between the VEGF receptors Fltl and Flkl, Nature Medi
`cine 9:936-943.
`Mahdadevan et al. (1995), Structural role of extracellular domain 1 of
`alpha-platelet-derived growth factor (PDGF) receptor for PDGF-AA
`and. . .J Biol. Chem. 270:27595-27600.
`Yu et a1, (1995), Differential requirement of a motif within the
`carboXyl-terminal domain of alpha-platelet-derived growth
`factor .
`.
`. J. Biol. Chem. 270:7033-7036.
`
`Tanaka et al. (1995). Characterization of the ligand binding domain
`of FLT- 1, .
`.
`. The 8th Annual Meeting of Japanese Molecular Biology,
`Nov. 21, 1995, Abstract 2P-227.
`Keyt et al. (1996), Identi?cation of vascular endothelial growth factor
`determinants for binding KDR and FLT-1 receptors; generation
`of. .
`. J. Biol. Chem. 271:5638-5646.
`Heidaran et al. (1990), Chimeric alpha- and beta-platelet derived
`growth factor (PDGF) receptors de?ne three immunoglobulin-like
`domains .
`.
`. J. Biol. Chem. 265: 18741-18744.
`Park et al. (1994), Placenta growth factor; potentiation of vascular
`endothelial growth factor bioactivity, in vitro and in vivo, and
`high .
`.
`. J. Biol. Chem. 269:25646-25654.
`Shibuya et al. (1990), Nucleotide sequence and expression of a novel
`human receptor-type tyrosine kinase gene (?t) closely related to the
`fms family, Oncogene 51519-524.
`Heidaran et al. (1995), Beta-PDGFR-IgG chimera demonstrates that
`human beta-PDGFR Ig-like domains 1 to 3 are suf?cient for high
`af?nity PDGF BB .
`.
`. FASEB Journal 9: 140-145.
`Yu et al. (1994), Structural coincidence of alpha-PDGFR pitopes
`binding to platelet-derived growth factor-AA and a potent neutraliz
`ing .
`.
`. J. Biol. Chem. 269:10668-10674.
`Herley et al. (1999), Characterization of the VEGF binding site on the
`Flt-1 receptor, Biochem Biophys Res Commun 262:731-738.
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 1 0155
`
`US 8,343,737 B2
`
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
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`US 8,343,737 B2
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`
`
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`US. Patent
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`Jan. 1, 2013
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`

`

`US. Patent
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`Jan. 1, 2013
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 5 0f55
`
`US 8,343,737 B2
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`

`

`US. Patent
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`Jan. 1, 2013
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 9
`
`
`
`
`
`

`

`US. Patent
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`Jan. 1, 2013
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 10
`
`

`

`U.S. Patent
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`Jan. 1, 2013
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 11
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 11
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
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`US 8,343,737 B2
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 12
`
`€
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 11 0155
`
`US 8,343,737 B2
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`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 13
`
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 12 0155
`
`US 8,343,737 B2
`
`Figii?
`
`Asn Va}. Pha gar Cys Se: Val Met His G111 Ala Len His Ran His was Th2: Gin Lys Sam»
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 14
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
`Sheet 13 of 55
`
`US 8,343,737 B2
`
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 15
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 15
`
`
`
`
`
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 14 0f55
`
`US 8,343,737 B2
`
`mm
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`mm
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`mm
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`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 16
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
`Sheet 15 of 55
`
`US 8,343,737 B2
`
`FIG.13A.
`
`+
`
`*
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`30
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`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 17
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 17
`
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 16 0f 55
`
`US 8,343,737 B2
`
`Pm
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`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 18
`
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 17 0155
`
`US 8,343,737 B2
`
`115-3
`116.0
`1H6
`116D
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`QCTGAGG’PCAAG'I‘ICPACWTAC E’IGGACGGCEGTGWGTGCATMTGCCARQACRZM
`QSFLC‘I‘CCAG'I'MAAGTi?ACCATGCAEC‘EGEC CACDTCFACGTAWAQEG’I‘ICTGTTIYZ
`Pm Glu val Lys Phe Asa ‘12:1: Ty): val Asp 61y val Gin Val His Asn Ale bys Th1." Lys.»
`
`L2H)
`12130
`12%
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`cmmaccmcma CCGWCWCATGMAQGTWCAGAGGTTGWI‘CGGGMGQ‘TCQ
`@111 has ‘up mu Asn @131 Lys G12. ‘9y: Lys we Lys Val sax‘ A521 Lys Ala Len 212:0 311m
`
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`QCCA‘DCGASAAAADCATC TCICMAQCMGGGCAGCLT CESAMCZCACAGG‘EG TACALC
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`11150
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`Ty‘: L-ys ‘r11: “S‘kv: gm Pro Val Lam Asp 5&5: Imp Gly 5e: Elma P‘xm Leu Tyr Ear Lye Lem
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 19
`
`

`

`US. Patent
`
`Jan. 1, 2013
`
`Sheet 18 0f55
`
`US 8,343,737 B2
`
`3.538
`i?
`
`‘11
`
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`Ala Len His Asa His T‘ .2:
`£31m Legs Sax Lem Ear Lem Sax: Pro (31y Lys "*3
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 20
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
`Sheet 19 of 55
`
`US 8,343,737 B2
`
`4G
`
`: GAC
`eu
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`Val
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`Cys arg
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`Val
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`Bra Asn Tle»
`
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`
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`
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`ATG
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`
`350
`
`AGS
`
`Sar
`
`450
`
`378
`
`380
`¥
`
`ACK
`BLEe]
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`
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`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 21
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
`Sheet 20 of 55
`
`US 8,343,737 B2
`
`S80
`*
`
`588
`Ly
`
`600
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`
`Fig. 146.
`
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`
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`2
`
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`
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`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 22
`
`FOG
`sar
`
`* T
`
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`Ser
`
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`Lys
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`
`Val
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`TET OGG
`lys Ala
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`Ser
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`
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`TTT
`bye
`
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`Gly
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`
`eee
`BGG
`Pro
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 22
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
`Sheet21 of 55
`
`US 8,343,737 B2
`
`Fig.14C.
`
`*
`
`1030
`*
`
`4100
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`®
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`OTA CPC GAC UNas (Pr TS GC CAG TOG GAT TGS ACG GAC CAS. Trl COG ARG ATA GG TOG
`2
`Asp Giu Leu Ther Lys Asn Gln Val Ser Leu Thy Cys Leu Val Lye Gly Phe Tyr bro Sears
`
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`
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`Acgd Dep Gln Gin Gly Aen Val Bhe Ser Cys Ser Val Met His Glu Ala leu His AsHie
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`ATG Tac GI PIC TOR Gas AGS GAC AGA Got CCA PPT ACT
`Tyr Thr Gln Lys Ser teu Ser Len Ser Bro Gly Lys ***>
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 23
`
`Mylan Exhibit 1161
`Mylan v. Regeneron, IPR2021-00881
`Page 23
`
`

`

`U.S. Patent
`
`Jan. 1, 2013
`
`Sheet 22 of 55
`
`US 8,343,737 B2
`
`§0
`*
`
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`Cre
`GAG
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`
`Fig. 15A.
`2b*
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`
`18
`x
`
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`Ser Tyr
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`Trp
`
`cH TOG CCC
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`. Met
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