`
`7
`Inventors; {figg-flsmvg 530‘; Sin Magma 9A
`lgrégéisczrg: ($13)” 23"" an
`S
`(73, Assignee: Genentech, Inc., South San Francisco.
`CA (US)
`_
`.
`_
`_
`8:113:52soeiggncgzglfinifilsfetfifigrflg
`08 C 1540)) by 0 days J
`‘
`‘
`Appl. No: 11/182,908
`'
`Flled:
`
`(75
`
`_
`( '
`
`(21
`
`(22
`
`p
`Nome
`
`Jul' 15’ 2005
`
`7.371,379 B2
`2001/0014326 A1
`200E0001587 A1
`2003/0147884 A1
`2003/0170234 A1
`2003/0202972 A1
`2004/0037823 A9
`2004/0037824 A1
`2004/0106161 A1
`2004/0258685 A1
`2005/0002928 A1
`2005/0208043 A1
`2005/0238640 A1
`2005/0244417 A1
`
`5/2008 Baughman et al.
`/2001 Andya et al.
`1/2002 Erickson et al,
`8/2003 Paton et 31.
`9/2003 Hellmann
`10/2003 Andya et 9114
`/2004 Paton et al.
`2/2004 Baughman et al
`6/2004 Bosseninaier et al.
`12/2004 Brunetta et a1.
`1/2005 Hellmann
`9/2005 Adams ct n11
`10/2005 Sliwkovvski
`11/2005 Ashkenazi et al.
`
`2006/0165702 A1
`2006/0188509 A1
`2006/0193854 A1
`2006/0198843 A1
`2006/0204505 A1
`
`7/2006 Allison et a.
`8/2006 Derynck etal.
`8/2006 Adams et a1.
`9/2006 Adams et a1.
`9/2006 Sliwkowski et al.
`
`Continued
`
`(
`)
`
`
`FOREIGN PAl 3N1 DOCUMJNl S
`’3
`’7
`1308455 A7
`5/7003
`
`EP
`
`.
`(Continued)
`
`OTHER PUBLICATIONS
`,
`.
`.
`.
`.
`.
`Agus et al., “Clinical Activity in a Phase 1 Trial of HERZ—Targeted
`rhuMAb 2C4(pe1tuzumab) 1n Pat1ents With Advanced SOlld Mahg-
`.
`,, 810
`t d tth 2003 ASCOAnn 1M t'
`[1111315125083 1 es Pres“ e a
`e
`‘
`“a
`66 mg) PP'
`)'
`_
`('
`
`(Continued)
`/
`
`Primary ExamineriLaura B Goddard
`(74) Attorney, Agent, or Firm7Wendy M. Lee
`
`(57)
`
`ABSTRACT
`
`O
`
`USOO7560111B2
`
`(12 Unlted States Patent
`(10) Patent N0.:
`US 7,560,11 1 B2
`
`Kao et al.
`(45) Date of Patent:
`Jul. 14, 2009
`
`(54‘ HERZ ANTIBODY CONJPOSITION
`
`(65,
`
`Prior Publication Data
`
`US 2006/0018899 A1
`
`Jan’ 26’ 2006
`
`2006/0013819 A1"‘
`2006/0034840 A1
`2006/0034842 A1
`
`1/2006 Kelsey .................... 424/155.1
`/2006 Agus
`2/2006 Adams et 211.
`
`Related U.S. Application Data
`.
`,
`.
`.
`.
`530218321211 application No. 60/590,202. filed 011 Jul.
`’
`.
`
`(60)
`
`2006/0073143 A1
`2006/0083739 A1
`2006/0088523 A1
`2006/0121044 A1
`
`47/2006 Adams et al.
`4/2006 Sliwkowski
`4/2006 Andya etal.
`6/2006 Aniler et al.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 39/395
`(2006.01)
`C07K 16/00
`(2006.01)
`C07K 16/30
`(52) US. Cl.
`.............. 424/138.1; 424/1431; 530/3888;
`530/388.85; 530/3897
`(58) Field of Classification Search ............... 530/3877
`See application file for complete search history.
`References Cited
`I
`,
`.
`.
`U S P \TENT DOCUMENTS
`
`(56)
`
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`
`424/143 1
`
`A composition comprising a main species HER2 antibody
`that binds to domain 11 ofHFRZ, and an amino acid sequence
`variant thereof comprising an amino-tenninal leader exten-
`sion is disclosed. Pharmaceutical formulations comprising
`the composition. and therapeutic uses for the composition are
`also dISCIOSCd‘
`
`12 Claims, 23 Drawing Sheets
`
`Pfizer v. Genentech
`|PR2017-01488
`Genentech Exhibit 2043
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2043
`
`

`

`US 7,560,111 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`2006/0210561 A1
`2006/0216285 A1
`2006/0228745 A1
`2006/0275305 A1
`2006/0275306 A1
`2007/0009976 A1
`2007/0020261 A1
`2007/0026001 A1
`2007/0037228 A1
`2007/0077243 A1
`2007/0166753 A1
`2007/0184055 A1
`2007/0202516 A1
`2007/0224203 A1
`2007/0269429 A1
`2007/0292419 A1
`2008/0038271 A1
`2008/0050373 A1
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`
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`5/2008 Friess et al.
`5/2008 Fendly et al.
`5/2008 Mass
`7/2008 Ashkenazi et al.
`
`FOREIGN PATENT DOCUMENTS
`
`W0
`W0
`W0
`W0
`W0
`W0
`
`WO 94/00136
`WO 94/22478
`WO 98/17797 A1
`WO 00/69460 A1
`WO 01/00238 A1
`W0 03/087131 A2
`
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`
`* cited by examiner
`
`

`

`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 1 of 23
`
`US 7,560,111 B2
`
`>>OO>MOHDOAmmqwflZBmqwfidmAZGO>>OUGOWAmmAZQQmEmmmdmdmAMEQEUBU>OB
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`

`

`US. Patent
`
`Jul. 14, 2009
`
`Sheet 2 0123
`
`US 7,560,111 B2
`
`VARIABLE LIGHT
`
`10
`
`20
`
`30
`
`40
`
`DTVMTQSHKIMSTSVGDRVSITC [KASQDVSIGVA] WYQQRP
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`EDFATYYC [QQYNSLPWT] FGQGTKVEIK (SEQ ID NO:5)
`
`FIG._2A
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`VARIABLE HEAVY
`
`10
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`****** *** ****
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`
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`
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`ELRSLTFEDTAVYYCAR [NLGPSFYFDY] WGQGTTLTVSS (SEQ ID NO:2)
`iii
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`QMNSLRAEDTAVYYCAR [GRVGYSLYDY] WGQGTLVTVSS
`
`(SEQ ID NO:6)
`
`FIG._ZB
`
`

`

`US. Patent
`
`Jul. 14, 2009
`
`Sheet 3 0123
`
`US 7,560,111 B2
`
`Amino Acid Sequence for Pertuzumab Light Chain
`
`1
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPS
`
`70
`
`80
`
`90
`
`100
`
`110
`
`120
`
`RFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRTVAAPSVFIFPP
`
`130
`
`140
`
`150
`
`160
`
`170
`
`180
`
`SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
`
`190
`
`200
`
`210
`
`LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
`
`FIG 3A
`
`Amino Acid Sequence for Pertuzumab Heavy Chain
`
`60
`50
`4o,
`30
`20
`10
`1
`I
`I
`I
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`EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIY
`
`7O
`
`80
`
`90
`
`100
`
`110
`
`120
`
`I
`I
`|
`I
`I
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`|
`I
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`I
`I
`I
`NQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSA
`
`180
`170
`160
`150
`140
`130
`|
`|
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`|
`I
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`STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
`
`240
`230
`220
`210
`200
`190
`I
`I
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`LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
`
`250
`260
`270
`280
`290
`300
`|||III||I||*|
`SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
`
`310
`
`320
`
`330
`
`340
`
`350
`
`360
`
`TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
`
`370
`
`380
`
`390
`
`400
`
`410
`
`420
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`
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`
`FIG._3B
`
`

`

`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 4 of 23
`
`US 7,560,111 B2
`
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`

`

`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 5 of 23
`
`US 7,560,111 B2
`
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`

`US. Patent
`
`Jul. 14, 2009
`
`Sheet 6 0123
`
`US 7,560,111 B2
`
`
`Unbound Complex
`
`EGFR
`
`EGFR-EGF
`
`FIG._5
`
`
`
`
`
`Ligand-activatedEGFRHeterodlmerlzeswithHER2204BindsattheHeterodlmerlcBlndlngSlte
`
`
`
`
`
`

`

`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 7 of 23
`
`US 7,560,111 B2
`
`5:23:05
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`
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`

`

`US. Patent
`
`Jul. 14, 2009
`
`Sheet 8 0123
`
`US 7,560,111 B2
`
`Trastuzumab
`
`Herceptin
`
`Pertuzumab
`
`Omnitarg
`
`
`
`- Binds in IV near JM.
`
`- Binds in H at dimerization interface
`
`- Protects against receptor shedding
`
`- Does not prevent receptor shedding
`
`- Moderately affects receptor down-
`modulation
`
`- Moderately affects receptor down-
`modulation
`
`. Slight effect on HER2’s role as a
`coreceptor
`
`0 Major effect on HERZ’s role as a
`coreceptor
`
`\——_Y_____J
`FIG._ 7
`
`

`

`U.S. Patent
`
`4,
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`

`

`US. Patent
`
`Jul. 14, 2009
`
`Sheet 12 0123
`
`US 7,560,111 B2
`
`Cation Exchange Chromatography Analysis of Native Pertuzumab
`50
`
`Absorbance
`at 280 nm
`(mAU)
`
`40
`
`30
`
`20
`
`10
`
`FIG._ 9A
`
`400 L332"?
`
`Lot $9802A
`
`Reference
`
`1 8
`
`20
`
`22
`
`24
`
`26
`
`28
`
`30
`
`Time (min)
`
`Material
`Material
`
`Cation Exchange Chromatography Analysis of CPB-Digested Pertuzumab
`50
`
`4O
`
`30
`
`Absorbance
`at 280 nm
`
`(mAU)
`
`20
`
`10
`
`400 L Scale
`RU“
`
`Lot 89802A
`
`Reference
`
`FIG. _ QB
`
`Time (min)
`
`

`

`US. Patent
`
`Jul. 14, 2009
`
`Sheet 13 0123
`
`US 7,560,111 B2
`
`Size Exclusion Chromatographic Analysis of Pertuzumab
`
`Absorbance
`
`at 280 nm
`
`(mAU)
`
`400 L Scale Run 1
`
`i
`
`Lot $9802A
`
`Reference
`Material
`
`FIG._ 10 5
`
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`
`15
`
`nmmm)
`
`20
`
`25
`
`

`

`US. Patent
`
`Jul. 14, 2009
`
`Sheet 14 0123
`
`US 7,560,111 B2
`
`CE-SDS-LIF Analysis of Reduced Pertuzumab
`
`300
`
`250
`
`200
`
`Relative
`
`Intensity
`
`150
`
`100
`
`50
`
`0
`
`FIG._ 11A
`
`250
`
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`
`100
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`
`Lot $9802A
`
`Reference Material
`
`
`Reference Material
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Migration Time (min)
`
`CE-SDS-LIF Analysis of Intact Pertuzumab
`
`400 L Scale Run 1
`
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`FIG.- 11B 5
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`7
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`9
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`11
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`Migration Time (min)
`
`13
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`15
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`

`

`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 15 of 23
`
`US 7,560,111 B2
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`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 16 of 23
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`US 7,560,111 B2
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`US. Patent
`
`Jul. 14, 2009
`
`Sheet 17 0123
`
`US 7,560,111 B2
`
`CE Analysis of N-linked Oligosaccharides Released from Pertuzumab
`
`Overlaid Traces: Aligned
`
`RFU
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`40
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`35
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`30
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`20
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`15
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`2.7
`
`2.8
`2.9
`3.0
`Time (min)
`
`3.1
`
`3.2
`
`3.3
`
`
`10000
`
`Positive Mode MALDl-TOF Mass Spectra of Released
`50000 Neutral Oligosaccharides Released from Pertuzumab
`
`40000
`
`30000
`
`20000
`
`Relative
`
`Intensity
`
`400 L Scale Run 1
`
`Lot 89802A
`
`1200
`
`1400
`
`1600
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`1800
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`2000
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`FIG._ 15
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`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 18 of 23
`
`US 7,560,111 B2
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`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 19 of 23
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`US 7,560,111 B2
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`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 20 of 23
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`US 7,560,111 B2
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`U.S. Patent
`
`Jul. 14, 2009
`
`Sheet 21 0f 23
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`US 7,560,111 B2
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