`
`(12) United States Patent
`US 7,060,269 B1
`(10) Patent No.:
`Baca et al.
`(45) Date of Patent:
`Jun. 13, 2006
`
`(54) AN 'l‘l—VEGF ANTIBODIES
`
`(75)
`
`Inventors: Manuel Baca, Foster City, CA (US);
`James A. Wells, Burlingame, CA (US);
`Leonard G. Presta, San Francisco, CA
`(US); Henry B. Lowman, El Granada,
`CA (US); Yvonne Man-yee Chen, San
`Mateo, CA (US)
`
`(73) Assignee: Genentech, Inc., South San Francisco,
`CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 697 days.
`
`(21) Appl. No.: 09/723,752
`
`(22)
`
`Filed:
`
`Nov. 27, 2000
`
`Related U.S. Application Data
`
`(62) Division of application No. 08/908,469, filed on Aug.
`6, 1997, now Pat. No. 6,884,879.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 39/395
`(52) U.S. Cl.
`...............................
`424/133.1; 424/156.1;
`530/387.3; 530/388.85
`(58) Field of Classification Search ............. 424/130.1,
`424/133.1,135.1,141.1,155.1,156.1; 530/387.1,
`530/387.3, 388.1, 388.24, 388.8, 388.85
`See application file for complete search history.
`
`(56)
`
`References Cited
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`Primary ExamineriLarry R. Helms
`(74) Attorney, Agent, or Firm7Steven X. Cui; Genentech,
`Inc.
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`OTHER PUBLICATIONS
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`ABSTRACT
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`Humanized and variant anti-VEGF antibodies and various
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`
`strong binding affinities for VEGF; inhibit VEGF-induced
`proliferation of endothelial cells in vitro; and inhibit tumor
`growth in vivo.
`
`57(20):4593—4599 (Oct. 15, 1997).
`
`2 Claims, 16 Drawing Sheets
`
`Regeneron Exhibit 1023.001
`
`
`
`US 7,060,269 B1
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`Page 2
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`* cited by examiner
`
`Regeneron Exhibit 1023.003
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 1 of 16
`
`US 7,060,269 B1
`
`Variable Heavy
`
`A4.6.l
`
`EIQLVQSGPELKQPGETVRISCKASQXIEIEXQMNWVKQAPGKGLKWMG
`*
`f
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`1
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`
`Regeneron Exhibit 1023.004
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 2 of 16
`
`US 7,060,269 B1
`
`
`
`Regeneron Exhibit 1023.005
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 3 of 16
`
`US 7,060,269 B1
`
`n.om>on.0w>n<22E+n_0m>:0:uGm>n<zse+u.0w>IO:
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`Regeneron Exhibit 1023.006
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 4 of 16
`
`US 7,060,269 B1
`
`Tumor Weight (gm)
`
`Control MAb (5)
`
`rhuMAb VEGF (5)
`
`muMAb VEGF (0.5)
`
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`
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`
`Fig. 4
`
`Regeneron Exhibit 1023.007
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 5 of 16
`
`US 7,060,269 B1
`
`Fig. 5A
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`Regeneron Exhibit 1023.008
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 6 of 16
`
`US 7,060,269 B1
`
`
`
`Regeneron Exhibit 1023.009
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 7 of 16
`
`US 7,060,269 B1
`
`
`
`Transform E. coli
`
`+ M13KO7 helper phage
`
`
`
`Fig. 1
`
`Regeneron Exhibit 1023.010
`
`
`
`U.S. Patent
`
`Jun.13,2006
`
`Sheet8 0f16
`
`US 7,060,269 B1
`
`0048800408
`0400484480
`8004440088
`4448440440
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`Regeneron Exhi
`
`it 1023.011
`
`
`
`U.S. Patent
`
`Jun.13,2006
`
`Sheet9 0f16
`
`US 7,060,269 B1
`
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`
`Regeneron Exhi
`
`it 1023.012
`
`
`
`
`U.S. Patent
`
`Jun. 13, 2006
`
`Sheet 10 of 16
`
`US 7,060,269 B1
`
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`
`down
`
`Regeneron Exhi
`
`it 1023.013
`
`
`
`U.S. Patent
`
`Jun.13,2006
`
`Sheetll 0f16
`
`US 7,060,269 B1
`
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`Noon
`
`HOOv
`
`HOHv
`
`Hch
`
`Honv
`
`Hovv
`
`Homv
`
`Howv
`
`Hone
`
`Hcov
`
`Home
`
`HOOm
`
`8800000800
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`HOHn
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`Homm
`
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`
`Hovm
`
`0080000004
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`uuauouuoua,
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`
`damn
`
`00
`
`.wfim
`
`Regeneron Exhi
`
`it 1023.014
`
`
`
`U.S. Patent
`
`Jun.13,2006
`
`Sheet12 0f16
`
`US 7,060,269 B1
`
`
`
`
`
`080400040444000800804440844440
`
`4800804404
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`
`doom
`
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`
`HOhm
`
`
`
`84448008804484484880
`