`
`
`
`
`
`
`PHIGENIX
`PHIGENIX
`Exhibit 1001
`Exhibit 1 00 1
`
`

`

`(12) Unlted States Patent
`(10) Patent No.:
`US 8,337,856 B2
`
`Bliittler et al.
`(45) Date of Patent:
`*Dec. 25, 2012
`
`USOO8337856B2
`
`.................. 536/235
`................ 424/1811
`
`................... 530/326
`
`............ 424/1301
`. 424/1431
`. 530/3873
`. 424/1381
`424/93,7
`.....
`.............. 435/691
`
`
`
`............. 424/1951
`
`................. 435/696
`
`............... 424/1431
`
`
`
`5,183,884 A
`5,208,020 A *
`5,217,713 A
`5,395,924 A
`5,416,064 A
`5,480,968 A
`5,514,554 A
`5,639,641 A
`5,648,237 A
`5,677,171 A
`5,679,648 A
`5,705,157 A
`5,725,856 A
`5,747,261 A
`5,772,997 A
`5,783,186 A
`5,821,337 A
`5,824,311 A
`5,837,234 A
`5,840,525 A
`5,877,305 A
`5,919,815 A
`5,968,517 A
`6,022,541 A
`6,054,297 A *
`6,333,410 B1
`6,436,931 B1
`6,441,163 B1
`6,531,131 B1
`6,627,196 B1
`233% E?
`,
`,
`6,914,130 B2
`6,949,245 B1*
`7,030,231 B1
`7,041,292 B1
`7,097,840 132
`7,122,636 B1
`7,214,776 132
`7,276,497 B2
`7 288 249 B2
`7,303,749 B1
`7:375:078 B2
`7,435,416 B2
`
`2/ 993 Kraus et a1.
`5/ 993 Chari et al.
`6/ 993 Iwasa et al.
`3/ 995 Blattleretal.
`5/ 995 Chariet al.
`1/ 996 Kraus et a1.
`5/ 996 1330115
`6/ 997 Pedersen et 31.
`7/ 997 Carter
`10/ 997 Hudziak et 3.1 .......... 435/24027
`10/ 997 McCaffrey et al.
`1/ 998 Greene
`3/ 998 Hudziak
`5/ 998 King et al.
`6/ 998 Hudziak et al.
`7/ 998 Arakawa et a1.
`10/ 998 Carter etal.
`10/ 998 Green et al.
`11/ 998 Gentile et al.
`11/ 998 Vandlen etal.
`3/ 999 Huston et al.
`7/ 999 Bradley et a1.
`10/ 999 Duncan et al,
`2/3000 Senger et 3L
`4/2000 Carter et al.
`12/2001 Chari et a1.
`8/2002 Charietal.
`8/2002 Chan et 31'
`3/2003 Gu etal.
`9/2003 Bqughman et al.
`1%882 $145011:th
`1.
`evaux e a.
`7/2005 Gao et a1.
`9/2005 Sliwkowski
`4/2006 Craik et al.
`5/2006 Sliwkowski
`8/2006 Erickson et 31.
`10/2006 Hseiet al.
`5/2007 Hseiet 81.
`10/2007 Charlet al.
`10/2007 Carter et al.
`12/3007 Chari et a1
`5/2008 Feng
`10/2008 Devaux et a1.
`(Continued)
`
`(54) METHODS OF TREATMENT USING
`ANTI-ERBB ANTIBODY-MAYTANSINOID
`
`CONJUGATES
`
`(75)
`
`Inventors: Walter Blattler, Brookline, MA (US);
`RaviV. J. Chari, Newton, MA (US)
`
`.
`~
`(73) ASSlgnee Immunogen9 Inc" Waltham, MA (Us)
`.
`*
`.
`.
`.
`.
`) Not1ce:
`Subject to any d1scla1mer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 15403) by 839 days.
`
`(
`
`This patent is subject to a terminal dis-
`claimer.
`
`.
`(21) APPLNO" 110493351
`.
`Flled:
`
`DeC- 3, 2007
`
`(22)
`
`(65)
`
`Prior Publication Data
`
`US 2008/0226659 A1
`
`Sep. 18, 2008
`
`Related U.S.Application Data
`
`(60) Division of application No. 11/488,545, filed on Jul.
`17, 2006, now Pat. No. 7,575,748, which is a
`.
`.
`.
`.
`cont1nuation of application No. 09/811,123, filed on
`Man 16, 2001,110W Pat N0~ 7,097,840
`.
`.
`.
`.
`Prov1s1onal application No. 60/238,327, filed on Oct.
`5, 2000, prov1s1onal application No. 60/189,844, filed
`011 Mar.
`16, 2000, provisional application No.
`60/327,563, filed on Jun. 23, 2000.
`
`(60)
`
`(51)
`
`Int“ Cl“
`(200601)
`A61K 39/00
`(52) US. Cl.
`.................................. 424/181.1; 530/387.1
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`FOREIGN PATENT DOCUMENTS
`
`(56)
`
`References Cited
`
`AU
`
`2003/259913
`
`8/2003
`
`U.S. PATENT DOCUMENTS
`3,896,111 A
`7/1975 Kupchan et a1.
`........ 260/239.3 T
`4,137,230 A
`l/l979 Hashimoto et al.
`..... 260/239.3 P
`4,151,042 A
`4/1979 ngashlde et 31' """"""" 195/96
`4,248,870 A
`2/l98l Mlyashlta et al.
`....... 424/248.54
`4,256,746 A
`3/1981 Miyashita et al.
`....... 424/248.54
`4,260,608 A
`4/l98l Miyashita et al.
`....... 424/248.54
`4,265,814 A
`5/1981 Hashimoto et 31.
`..... 260/2393 P
`.................
`4,294,757 A
`10/1981 Asai
`260/239.3 P
`
`4,307,016 A
`12/1981 Asai et al.
`260/239.3 P
`
`....... 424/248.54
`4,308,268 A
`l2/l98l Miyashita et al.
`4,308,269 A
`12/1981 Miyashita et al.
`....... 424/248.54
`4,309,428 A
`1/1982 Miyashita et al.
`....... 424/248.54
`4,313,946 A
`2/1982 Powell et al.
`............ 424/248.54
`4,315,929 A
`2/1982 Freedman et al.
`....... 424/248.54
`4,317,821 A
`3/1982 Miyashita et al.
`....... 424/248.54
`4,322,348 A
`3/1982 A531 et 31~
`~~~~~~~~~~~~~~~ 260/2393 P
`2,321,223 2
`1313:; 22:??? et al' """ 26023331313
`4:362:663 A
`12/1982 Kida et 31'. """""""""2'6'0/2393 P
`260/239.3 P
`4,364,866 A
`1 2/ 1982 Asai et 31,
`
`
`2/ 1983 Akimoto et a1.
`.
`. 424/24854
`4,371,533 A
`1/1984 Hashimoto et 31.
`...... 424/248.54
`4,424,219 A
`4,450,254 A
`5/1984 Isley et 31.
`4,968,603 A
`ll/l990 Slamon et al.
`.................... 435/6
`4,981,979 A
`1/1991 Sivam
`
`(commued)
`4
`,
`,
`V
`v
`,
`,
`OTHER PUBLILAT IONS
`Liu et 31. (Exp. Opin. Invest. Drugs vol. 6(2), pp. 169-172, 1997),
`It d
`IDS fil d] 1 6 2010 *
`Cl e on
`e
`u '
`’
`'
`
`-
`(commued)
`
`Primary Examiner 7 Laura B Goddard
`-
`- 7
`~
`.
`ASS’SmmExammer Mega Natarajan
`(74) After/16y, Agent, or Firm * Sthrue M1011, PLLC
`
`ABSTRACT
`(57)
`The application concerns methods of treatment using anti-
`ErbB receptor antibody-maytansinoid conjugates,
`and
`articles of manufacture suitable for use in such methods. In
`particular,
`the 1nventlon concerns ErbB receptor-d1rected
`cancer therapies, using anri-ErbB receptor antibody-may-
`tansinoid conjugates.
`
`8 Claims, 46 Drawing Sheets
`
`PHIGENIX
`
`Exhibit 1001-01
`
`

`

`US 8,337,856 B2
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`7,485,302 B2
`7,498,030 B2
`7,501,122 B2
`7,507,405 B2
`7,537,931 B2
`7,575,748 B1
`7,618,631 B2
`7,754,211 B2
`7,820,161 B1
`7,842,789 B2
`7,862,817 B2
`8,147,830 B2
`2002/0001587 A1
`2002/0004587 A1
`2003/0060612 A1
`2003/0086924 A1
`2003/0170235 A1
`2004/0013667 A1
`2004/0126807 A1
`2004/0235068 A1
`2004/0241174 A1
`2005/0133285 A1
`2005/0169933 A1
`2005/0238650 A1
`2005/0276812 A1
`2006/0025576 A1
`2006/0083739 A1
`2006/0216285 A1
`2007/0092940 A1
`2007/0104719 A1
`2007/0184055 A1
`2007/0269429 Al
`2007/0269446 A1
`2008/0050373 A1
`2008/0085283 A1
`2008/0114153 A1
`2008/0145374 A1
`2008/0166294 A1
`2008/0171040 A1
`2008/0171856 A1
`2008/0171865 A1
`2008/0226659 A1
`
`2008/0299120 A1
`2009/0041791 A1
`2009/0087432 A1
`2009/0202536 A1
`2010/0003252 A1
`2010/0136033 A1
`2011/0008250 A1
`2011/0008336 A1
`2011/0008337 A1
`2011/0008338 A1
`2011/0110852 A1
`2011/0129464 A1
`2012/0201818 A1
`
`2/2009 Adams et al.
`3/2009 Adams et a1.
`3/2009 Adams et al.
`3/2009 Hsei et al.
`5/2009 Adams etal.
`8/2009 Erickson et al.
`11/2009 Sliwkowski
`7/2010 Rosenblum et al.
`10/2010 Curd et a1.
`11/2010 Hsei et al.
`1/2011 Adams et al.
`4/2012 Hsei et al.
`1/2002 Erickson et al.
`1/2002 Miller et al.
`3/2003 Goddard et al.
`5/2003 Sliwkowski
`9/2003 Cohen
`1/2004 Kelsey et al.
`7/2004 Goddard et al.
`11/2004 Levinson
`12/2004 Amphlett et al.
`6/2005 Shimizu
`8/2005 Steeves et al.
`10/2005 Crowley et a1.
`12/2005 Ebens et al.
`2/2006 Miller et al.
`4/2006 Sliwkowski
`9/2006 Adams et al.
`4/2007 Eigenbrot et al.
`5/2007 Carter et al.
`8/2007 Sliwkowski
`I 1/2007 Kelsey et al.
`11/2007 de Sauvage et al.
`2/2008 Cohen
`4/2008 Levinson
`5/2008 Steeves et al.
`6/2008 Steeves et al.
`7/2008 de Sauvage et al.
`7/2008 Ebens et al.
`7/2008 Steeves et al.
`7/2008 Steeves et al.
`.
`9/2008 Erickson et al.
`.
`12/2008 Miller et al.
`2/2009 Feng
`4/2009 Sliwkowski
`8/2009 Ebens et al.
`1/2010 Grillo-Lopez et al.
`6/2010 Erickson et al.
`1/2011
`Curd et al.
`1/2011
`Curd et al.
`1/2011
`Curd et al.
`1/2011
`Curd et al.
`5/2011
`Miller et al.
`6/2011
`Adams et al.
`8/2012
`Curd et al.
`
`AU
`CA
`CR
`EP
`EP
`EP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`W0
`W0
`W0
`WO
`
`FOREIGN PATENT DOCUMENTS
`2003/247762
`1/2004
`2306183
`5/1999
`8207
`5/2011
`0 425 235 A2
`5/1991
`0 563 475 A1
`10/1993
`1 354 896 A1
`10/2003
`58-167592
`10/1983
`62-195387
`8/1987
`3161490 A
`7/1991
`2001-503760 A
`3/2001
`2002-541088
`12/2002
`2002-543093
`12/2002
`2003-503365
`1/2003
`2003203395
`1/2003
`2003501487 A
`1/2003
`2009528034
`9/2003
`89/06692
`7/1989
`WO 89/06692
`7/1989
`9306217 A1
`4/1993
`93/21319
`10/1993
`
`W0
`
`$8
`WO
`W0
`WO
`W0
`WO
`W0
`WO
`W0
`WO
`W0
`W0
`WO
`W0
`WO
`WO
`W0
`WO
`W0
`WO
`W0
`WO
`WO
`WO
`W0
`W0
`W0
`W0
`WO
`W0
`W0
`W0
`W0
`WO
`WO
`W0
`W0
`
`WO
`WO
`W0
`WO
`W0
`W0
`
`WO 93/21319
`
`WO 318882
`94/22478
`WO 94/22478
`96/16173
`WO 96/16173
`97/002“
`WO 97/00271
`97/04801
`WO 97/04801
`98/02463
`WO 97/02463
`WO 98/08506
`98/17797
`WO 98/17797
`9820020 A2
`99/31140
`WO 99/31140
`00/20579
`WO 00/20579
`00/69460
`WO 00/69460
`0076554 A1
`01/00238 A1
`01/00244 A2
`WO 01/00238 A1
`WO 01/00244 A2
`W0 0100245
`W0 0100594
`01/5730 A1
`WO 01/15730 A1
`0124673 A2
`W0 0124763
`WO 02/16429
`02057316 A1
`02098883 A1
`W0 03/000113
`W0 03/024392
`
`03057163 A2
`03068956 A1
`W0 03/070234
`03074081 A1
`WO 2004/005470
`WO 2004/016225
`
`10/1993
`
`333::
`10/1994
`10/1994
`5/1996
`5/1996
`“1997
`“1997
`2/1997
`2/1997
`1/1998
`1/1998
`3/1998
`4/1998
`4/1998
`5/1998
`6/1999
`6/1999
`4/2000
`4/2000
`“/2000
`“/2000
`12/2000
`“2001
`“2001
`“2001
`“2001
`“2001
`“2001
`3/2001
`3/2001
`4000‘
`4/2001
`2/2002
`7/2002
`12/2002
`1/2003
`3/2003
`
`7/2003
`8/2003
`8/2003
`9/2003
`1/2004
`2/2004
`
`OTHER PUBLICATIONS
`
`Erickson H.K. et al., “Antibody-Maytansinoid Conjugates are acti-
`vated in targeted cancer cells by Lysosomal degradation and Linker-
`Dependent Intracellular Processing”, Cancer Res. 66: (8), pp. 4426-
`4433, (2006).
`Xu, et al., Clinical Cancer Research, Abstract, 3(9): 1629-1634,
`1997.
`Chari, RVJ “Targeted delivery of chemotherapeutics: tumor-acti-
`vated prodrug therapy,” Advanced Drug Delivery Reviews 3 1 :89-104
`(1998).
`Spector et al., “Study of the Biologic Effects of Lapatinib, a Revers-
`ible Inhibitor of ErbBl and ErbB2 Tyrosine Kinases, on Tumor
`Growth and Survival Pathways in Patients With Advanced Malignan-
`cies,” Jour. of Clin. Onc. 23(11):2502-2512 (2005).
`Aasland et al., “Expression of oncogenes in thyroid tumours:
`Coexpression of c-erbBZ/neu and c-erbB,”Br. J Cancer, vol. 57, pp.
`358-363 (1988).
`Bacus et al ., “Differentiation of Cultured Human Breast Cancer Cells
`(AU-565 and MCF-7) Associated With Loss of Cell Surface HER—2/
`neu Antigen,”Molecular Carcinogenesis, vol. 3, pp. 350-362 (1990).
`Baselga et al., “Phase II Study of Weekly Intravenous Recombinant
`Humanized Anti-p185HER2 Monoclonal Antibody in Patients With
`HER2/neu-Overexpressing Metastatic Breast Cancer,” J. Clin.
`Oncol., vol. 14, pp. 737-744 (1996).
`Borst et al., “Oncogene Alterations in Endometrial Carcinoma,”
`Gynecol Oncol., vol. 38, pp. 364-366 (1990).
`Carter et al., “Humanization of anti-p185HER2 antibody for human
`cancer therapy ” Proc. Natl. Acad. Sci. USA, vol. 89, pp. 4285-4289
`(1992).
`
`PHIGENIX
`
`Exhibit 1001-02
`
`

`

`US 8,337,856 B2
`
`Page 3
`
`Chari et al., “Immunoconjugates Containing Novel Maytansinoids:
`Promising Anticancer Drugs,” CancerResearch, vol. 52, pp. 127-131
`(1992).
`Cobleigh et al., “Multinational Study of the Efficacy and Safety of
`Humanized Anti-HER2 Monoclonal Antibody in Women Who Have
`HER2-Overexpressing Metastatic Breast Cancer That Has Pro-
`gressed After Cehmotherapy for Metastatic Disease,” J Clin. Oncol.,
`vol. 17, pp. 2639-2648 (1999).
`Cohen et al., “Expression pattern of the neu (NGL) gene-encoded
`growth factor receptor protein (p185"e”) in normal and transformed
`epithelial tissues of the digestive tract,” Oncogene, vol. 4, pp. 81-88
`(1989).
`Drebin et al., “Monoclonal antibodies reactive with distinct domains
`of the neu oncogene-encoded p185 molecule exert synergistic anti-
`tumor effects in vivo,” Oncogene, vol. 2, pp. 273-277 (1988).
`Drebin et al., “Down-Modulation of an Oncogene Protein Product
`and Reversion of the Transformed Phenotype by Monoclonal Anti-
`bodies,” Cell, vol. 41, pp. 695-706 (1985).
`D’Souza et al., “Overexpression of ERBB2 in human mammary
`epithelial cells signals inhibition of transcription of the E-cadherin
`gene,” Proc. Natl. Acad. Sci. USA, vol. 91, pp. 7202-7206 (1994).
`Guérin et al., “Overexpression of Either c-myc or c-erbB-2/neu
`Proto-Oncogenes in Human Breast Carcinomas: Correlation with
`Poor Prognosis,” Oncogene Research, vol. 3, pp. 21-31 (1988).
`Gu et al., “Overexpression ofher-2/neu in human prostate cancer and
`benign hyperplasia,” Cancer Letters, vol. 99, pp. 185-189 (1996).
`Harweth et al., “Monoclonal Antibodies against the Extracellulr
`Domain ofthe erbB-2 Receptor Function as Partial Ligand Agonists,”
`The Journal ofBiological Chemistry, vol. 267, No. 21, pp. 15160-
`15167 (1992).
`Hudziak et al., “p185H’SR2 Monoclonal Antibody Has Antiprolifera-
`tive Effects In Vitro and Sensitizes Human Brest Tumor Cells to
`Tumor Necrosis Factor,” Molecular and Cellular Biology, vol. 9, No.
`3, pp. 1165-1172 (1989).
`Klapper et al., “A subclass of tumor-inhibitory monoclonal antibod-
`ies to ErbB-2/HER2 blocks crosstalk with growth factor receptors,”
`Oncogene. vol. 14. pp. 2099-2109 (1997).
`Kraus et al., “Isolation and characterization of ERBB3 , a third mem-
`ber ofthe ERBB / epidermal grwoth factor receptor family: Evidence
`for overexpression in a subset of human mammary tumors,” Proc.
`Natl. Acad. Sci. USA, vol. 86, pp. 9193-9197 (1989).
`Kumar et al., “Regulation of Phosphorylation of the c-erb8—2/HER2
`Gene Product by a Monoclonal Antibody and Serum Growth Fac-
`tor(s) in Human Mammary Carcinoma Cells,” Molecular and Cellu—
`lar Biology, vol. 11, no. 2, pp. 979-986 (1991).
`Lewis et al.,“Differential responses of human tumor cell lines to
`anti-p185HER2 monoclonal
`antibodies,” Cancer
`Immunol.
`Immunother., vol. 37, pp. 255-263.
`McCann et al., “c -erbB-2 Oncoprotein Expression in Primary Human
`Tumors,” Cancer, vol. 65, pp. 88-92 (1990).
`McKenzie et al., “Generation and characterization of monoclonal
`antibodies specific for the human neu oncogene product, p185 ”
`Oncogene, vol. 4, pp. 543-548 (1989).
`Myers et al., “Biological Effects of Monoclonal Antireceptor Anti-
`bodies Reactive with neu Oncogene Product, p185"e”,” Methods in
`enzymology,vol. 198, pp. 277-290 (1991).
`Pietras et al., “Antibody to HER-2/neu receptor blocks DNA repair
`after cisplatin in human breast and ovarian cancer cells,” Oncogene,
`vol. 9, pp. 1829-1838 (1994).
`Plowman et al., “Heregulin induces tyrosine phosphorylation of
`HER4/P1805123“? Letters to Nature, vol. 366, pp. 473—475 (1993).
`Plowman et al., “Ligand-specific activation of HER4 /p180 "B4, a
`fourth member ofthe epidermal growth factor receptor family,” Proc.
`Natl. Acad. Aci. USA, vol. 90, pp. 1746-1750 (1993).
`Liu et al., “Eradication of large colon tumor xenografts by targeted
`delivery of maytansinoids ” Proc. Natl. Acad. Sci. USA, vol. 93, pp.
`8618-8623 (1996).
`Ross et al., “Prognostic Significance of HER-2/neu Gene Amplifica-
`tion Status by Fluorescence In Situ Hybridization of Prostate Carci-
`noma.” Cancer, vol. 79. pp. 2162-2170 (1997).
`Ross et al., “Her-2/neu Gene Amplification Status in Prostate Cancer
`by Fluorescense In Situ Hybridization,” Human Pathology, vol. 28,
`No.7, pp. 827-833 (1997).
`
`Sadasivan et al., “Overexpression of HER-2/NEU May be an Indi-
`cator of Poor Prognosis in Prostate Cancer,” The Journal ofUrology,
`vol. 150, pp. 126—131(1993).
`Schaefer et al., “y-Heregulin: a novel heregulin isoform that is an
`autocrine growth factor for the human breast cancer cell line, MDA-
`MB-175,” Oncogene, vol. 15, pp. 1385-1394 (1997).
`Scott et al., “p185HER2 Signal Transduction in Breast Cancer Cells,”
`The Journal ofBiological Chemistry, vol. 266, No. 22, pp. 14300-
`14305 (1991).
`Shepard et al., “Monoclonal Antibody Therapy of Human Cancer:
`Taking the HER2 Protooncogene to the Clinic,” Journal of clinical
`Immunology, vol. 11, No. 3 (1991).
`Slamon et al., “Human Breast Cancer: Correlation of Relapse and
`Survival with Amplification of the HER-2/neu Oncogene,” Science,
`vol. 235, pp. 177-182 (1987).
`Slamon et al., “Studies of the HER—2/neu Proto—oncogene in Human
`Breast and Ovarian Cancer” Science, vol. 244, pp. 707-712 (1989).
`Sliwkowski et al., “Coexpression of erbB2 and erbB3 Proteins
`Reconstitutes a High Affinity Receptor for Heregulin,” The Journal
`ofBiological Chemistry, vol. 269, No. 20, pp. 14661-14665 (1994).
`Stancovski et al., “Mechanistic aspects of the opposing effects of
`monoclonl antibodies to the ERBB2 receptor on tumor growth,”
`Proc. Natl. Acad. Sci. USA, vol. 88, pp. 8691-8695 (1991).
`Tagliabue et al., “Selection of Monoclonal Antibodies Which Induce
`Internalization and Phosphorylation of p185HER2 and Growth Inhi-
`bition of Cells with HER2/NEU Gene Amplification,” Int. J Cancer,
`vol. 47, pp. 933-937 (1991).
`Williams et al., “Expression of c-erbB-2 in Human Pancreatic
`Adenocarcinomas,” Pathobiology, vol. 59, pp. 46-52 (1991).
`Xu et al., “Antibody-Induced Growth Inhibition is Mediated Through
`Immunochemically and Functionally Distinct Epitopes on the
`Extracellular Domain of the c-erbB-2 (HER-2/neu) Gene Product,”
`vol. 53, pp. 401-408 (1993).
`Zhau et al., “Amplification and Expression of the c-erb B-2/neu
`Proto-Oncogene
`in Human Bladder Cancer,” Molecular
`Carcinogenesisvol. 3. pp. 254-257 (1990).
`King et al., “Amplification of a Novel v-erbB-Related Gene in a
`Human Mammary Carcinoma,” Science, vol. 229, pp. 974-976
`(1985).
`Fukushige et al., “Localization of a Novel v-erbB-Related Gene,
`c-erbB-2, on Human Chromosome 17 and Its Amplification in a
`Gastric Cancer Cell Line,” Molecular and Cellular Biology, vol. 6,
`No. 3, pp. 955-958 (1986).
`Database Chemabs 'Online!, Chemical Abstracts Service, Columbus,
`Ohio, US; Brechbiel, Martin W. et al: “Synthesis and evaluation of
`antiproliferative
`activity
`of
`a
`geldanamycin-herceptin
`immunoconjugate.” Retrieved from STN Dambase accession No.
`2000:796068, XP002164006, abstract & ABSTR. PAPiAM.
`CHEM. SOC. (2000), 220m, MEDI-071.
`Arteaga, C. L., et al., “p1856'e'bB'2 Signaling Enhances Cisplatin—
`Induced Cytotoxicity in Human Breast Carcinoma Cells: Association
`Between an Oncogenic Receptor Tyrosine Kinase and Drug-Induced
`DNA Repair” Cancer Research, vol. 54, pp. 3758-3765 (1994).
`Bacus, S. S. et al., “Tumor-inhibitory Monoclonals Antibodies to the
`HER-2/Neu Receptor Induce Differentiation of Human Breast Can-
`cer Cells”, Cancer Research, vol. 52, pp. 2580-2589 (1992).
`Fendly, B. M. et al., “Characterization of Murine Monoclonal Anti-
`bodies Reactive to Either the Human Epidermal Growth Factor
`Receptor or HER2/neu Gene Product”, Cancer Research, vol. 50, pp.
`1550-1558 (1990).
`Hancock, MC. et al., A Monoclonal Antibody Against the c-erbB-2
`Protein
`Enhances
`the
`Cytotoxicity
`of
`cis-Diam-
`minedichloroplatinum Against Human Breast and Ovarian Tumor
`Cell Lines:, vol. 51, pp. 4575-4580 (1991).
`Issell, B. F. et al., “Maytansine”, Cancer Treatment Reviews, vol. 5,
`pp. 199-207 (1978).
`Karsprzyk, P. G. et al., “Therapy of an Animal Model of Human
`Gastric Cancer Using a Combination of Anti-erbB-2 Monoclonals
`Antibodies”, Cancer Research, vol. 52, pp. 2771-2776 (1992).
`Kern,
`J. A.
`et
`al.,
`“p185"e" Expression in Human Lung
`Adenocarcinomas Predicts Shortened Survival”, Cancer Research,
`vol. 50, pp. 5184-5191 (1990).
`
`PHIGENIX
`
`Exhibit 1001-03
`
`

`

`US 8,337,856 B2
`
`Page 4
`
`Lewis, G.D. et al., “Growth Regulation of Human Breast and Ovarian
`Tumor Cells by Heregulin: Evidence for the Requirement of ErbB2
`as a Critical Component in Mediating Heregulin Responsiveness”
`Cancer Research, vol. 56, pp. 1457-1465 (1996).
`Maier, L. A. et al., “Requirements for the Internalization of a Murine
`Monoclonal Antibody Directed Against the Her-2/neu Gene Product
`c-erbB-2” Cancer Research, vol. 51, pp. 5361-5369 (1991).
`Park, Joo-Bae et al., “Amplification, Overexpression, and Rearrange-
`ment of the erbB-2 Protooncogene in Primary Human Stomach Car-
`cinomas”, Cancer Research, vol. 49, pp. 6605-6609 (1989).
`Database Chemabs Online! Chemical Abstracts Service, Columbus,
`Ohio, US; Skrepnik, Neboj sa et al., “Effects of anti-erbB-2 (HER-2/
`neu) Recombinant Oncotoxin Ar209 on Human Non-Small Cell
`Lung Carcinoma Grown Orthotopically in Athymic Nude Mice”
`retrieved
`from STN Database Accession No.
`126: 14452
`XP002164007, Abstract & Clin. Cancer Research Res. (1996), 2(11),
`1 85 1 -1857.
`
`Sarup, J. C. et al., “Characterization ofan Anti-p185HER2 Monoclonal
`Antibody that Stimulates Receptor Function and Inhibits Tumor Cell
`Growth”, Growth Regulation, vol. 1, pp. 72-82 (1991).
`Shawver, L. K. et al., “Ligand-like Effects Induced by Anti-c-erbB2
`Antibodies Do Not Correlate with and Are Not Required for Growth
`Inhibition of Human Carcinoma Cells”, Cancer research, vol. 54, pp.
`1367-1373 (1994).
`Skrepnik, N. et al., “Effects ofAnti-erbB2 (Her-2/neu) Recombinant
`Oncotoxin AR209 on Human Non-Small Cell Lung Carcinoma
`Grown Orthotopically in Athymic Nude Mice”, Clinical Cancer
`Research, vol. 2, pp. 1851-1857 (1996).
`Vitetta, E. S. et al., “Monoclonal Antibodies as Againsts: An
`Expanded Role for their Use in Cancer Therapy”, Cancer Research,
`vol. 54, pp. 5301-5309 (1994).
`Weiner, D. B. et al., “Expression of the neu Gene-encoded Protein
`(P185"e”) in Human Non-Small Cell Carcinomas of the Lung”, Can-
`cer Research, vol. 50, pp. 421-425 (1990).
`Yokota, J. et al., “Amplification of c-erbB2 Oncogene in Human
`Adenocarcinomas in Vivo”, The Lancet, vol. 1, pp. 765-767 (1986).
`Yonemura. Y. et al., “Evaluation of Immunoreactivity for erbB-2
`Protein as a Marker ofPoor Short Term Prognosis in Gastric Cancer”,
`Cancer Research, vol. 51, pp. 1034-1038 (1991).
`Aasland et al., “Expression of Oncogenes in Thyroid Tumours
`Coexpression of c-erbB2/neu and c-erbB”, Br. J. Cancer, vol. 57, pp.
`358-363 (1988).
`Bacus et a1 ., “Differentiation of Cultured Human Breast Cancer Cells
`(AU-565 and MCF-7) Associated with Loss of Cell Surface HER-2/
`neu Antigen”, Molecular Carcinogenesis, vol. 3, pp. 350-362 (1990).
`Baselga et al., “Phase II Study of Weekly Intravenous Recombinant
`Humanized Anti-pi85HER2 Monoclonal Antibody in Patients with
`HER2/neu Overexpressing Metastatic Breast Cancer”,
`J. Clin.
`Oncol., vol. 14, pp. 737-744 (1996).
`Borst et al., “Oncogene Alterations in Endometrial Carcinoma”,
`Gynecol. Oncol., vol. 38, pp. 364—366 (1990).
`Carter et al., “Humanization of anti-p185HER2 Antibody for Human
`Cancer Therapy”, Proc. Natl. Acad. Sci. USA. vol. 89, pp. 4285-4289
`(1992).
`Chari et al., “Immunoconjugates Containing Novel Maytansinoids:
`Promising Anticancer Drugs”, Cancer Research, vol. 52, pp. 127-131
`(1992).
`Chari et al., “Targeted Delivery of Chemotherapeutics: Tumor-Acti-
`vated Prodrug Therapy”, Advanced Drug Delivery Reviews, vol. 31,
`pp. 89-104 (1998).
`Cobleigh et al., “Multinational Study of the Efficacy and Safety of
`Humanized Anti-HER2 Monoclonal Antibody in Women Who Have
`HER2-Overexpressing Metastatic Breast Cancer that has Progressed
`after Cehmotherapy for Metastatic Disease”, J. Clin. Oncol., vol. 17,
`pp. 2639-2648 (1999).
`Cohen et al., “Expression Pattern of the neu (NGL) Gene-Coded
`Growth factor Receptor Protein (p185”e”) in Normal and Trans-
`formed Epithelial Tissues of the Digestive Tract”, Oncogene, vol. 4,
`pp. 81-88 (1989).
`Drebin et al., “Monoclonal Antibodies Reactive with Distinct
`Domains of the neu Oncogene-Encoded p185 Molecule Exert Syn-
`ergistic Anti-tumor Effects in Vivo”, Oncogene, vol. 2, pp. 273-277
`(1988).
`
`Drebin et al., “Down-Modulation of an Oncogene Protein Product
`and Reversion of the Transformed Phenotype by Monoclonal Anti-
`bodies”, Cell, vol. 41, pp. 695—706 (1985).
`D’Souza et al., “Overexpression of ERBB2 in Human Mammary
`Epithelial Cells Signals Inhibition of Transcription of the E-cadherin
`Gene”, Proc. Natl. Acad. Sci., USA, vol. 91, pp. 7202-7206 (1994).
`Guerin et al., “Overexpression of Either c-myc or c-erbB-2/neu
`Proto-Oncogenes in Human Breast Carcinomas: Correlation with
`Poor Prognosis” Oncogene Research, vol. 3, pp. 21-31 (1988).
`Gu et al., “Overexpression of her-2/neu in Human Prostate Cancer
`and Benign Hyperplasia”, Cancer Letters, vol. 99, pp. 185-189
`(1996).
`Harweth et al., “Monoclonal Antibodies Against the Extracelluler
`Domain of the erbB-2 Receptor Function as Partial Ligand
`Agonists”, The Journal ofBiological Chemistry, vol. 267, No. 21, pp.
`15160—15167(1992).
`Hudziak et al., “p185HER2 Monoclonal Antibody has Antiprolifera-
`tive Effects in Vitro Effects in Vitro and Sensitizes Huamn Breast
`Tumor Cells to Tumor Necrosis Factor”, Molecular and Cellular
`Biology, vol. 9, No. 3, pp. 1165-1172 (1989).
`Klapper et al., A Subclass of Tumor-inhibitory Monoclonal Antibod-
`ies to ErbB-2/HER2 Blocks Crosstalk with Growth Receptors:,
`Oncogene, vol. 14, pp. 2099-2109 (1997).
`Kraus et al., Isolation and Characterization of ERBB3, a Third Mem-
`ber of the ERBB/epidermal Growth Factor Receptor Family: Evi-
`dence for Overexpression in a Subset of Human Mammry Tumors:
`Proc. Natl. Acad. Sci. USA, vol. 86, pp. 9193-9197 (1989).
`Kumar et al., “Regulation of Phosphorylation of the c-erbB-2/HER2
`Gene Product by a Monoclonal Antibody and Serum Growth Fac—
`tor(s) in Human Mammry Carcinoma Cells”, Molecular and Cellular
`Biology, vol. 11, No. 2, pp. 979-986 (1991).
`Lewis et al., “Differential Responses of Human Tumor Cell Lines to
`Anti-p185HER2 Monoclonal Antibodies”, Cancer
`Immunol.
`Immunother, vol. 37, pp. 255-263 (1993).
`McCann et al., “c -erbB-2 Oncoprotein Expression in Primary Human
`Tumors”, Cancer, vol. 65, pp. 89-92 (1990).
`McKenzie et al., “Generation and Characterization of Monoclonal
`Antibodies Specific for the Human neu Oncogene Product, p185”,
`Oncogene, vol. 4, pp. 543-548 (1989).
`Myers et al., “Biological Effects of Monoclonal Antireceptor Anti-
`bodies Reactive with neu Oncogene Product, p185"e””, Methods in
`Enzymology, vol. 198, pp. 277-290 (1991).
`Pietras et al., “Antibody to HER-2/neu Receptor Blocks DNA Repair
`after Cisplatin in Human Breast and Ovarian Cancer Cells”,
`Oncogene, vol. 9, pp. 1829-1838 (1994).
`Plowman et al., “Heregulin Induces Tyrosine Phosphorylation of
`HER4/P1805RBZ’4”, Letters to Nature, vol. 366, pp. 473—475 (1993).
`Plowman et al., “Ligand-specific Activation of HER4/p1809’B4, a
`Fourth Member of the Epidermal Growth Factor Receptor Family”,
`Proc. Natl. Acad. Sci. USA, vol. 90, pp. 1746-1750 (1993).
`Liu et al., “Eradication of Large Colon Tumor Xenografts by Tar-
`geted Delivery of Maytansinoids”, Proc. Natl. Acad. Sci. USA, vol.
`93, pp. 8618-8623 (1996).
`Ross et al., “Prognostic Significance of HER-2/neu Gene Amplifica-
`tion Status by Fluorescence in Situ Hybridization of Prostate Carci-
`noma”, Cancer, vol. 79, pp. 2162-2170 (1997).
`Ross et al., “HER-2/neu Gene Amplification Status in Prostate Can-
`cer by Fluorescense in Situ Hybridization”, Human Pathology, vol.
`28, No. 7, pp. 827-833 (1997).
`Sadasivan et al., “Overexpression of HER-2/NEU May be an Indi-
`cator of Poor Prognosis in Prostate Cancer”, The Journal of Urology,
`vol. 150, pp. 126-131(1993).
`Schaefer et al., “y-Heregulin: A Novel Heregulin Isoform that is an
`Autocrine Growth Factor for the Human Breast Cancer Cell Line,
`MDA-MB-175”, Oncogene, vol. 15, pp. 1385-1394 (1997).
`Scott et al., “p185HER2 Signal Transduction in Breast Cancer Cells”,
`The Journal of Biological Chemistry, vol. 266, No. 22, pp. 14300-
`14305 (1991).
`Shepard et al., “Monoclonal Antibody Therapy of Human Cancer:
`Taking the HER2 Protoocogene to the Clinic”, Journal of Clinical
`Immunology, vol. 11, No. 3 (1991).
`
`PHIGENIX
`
`Exhibit 1001-04
`
`

`

`US 8,337,856 B2
`Page 5
`
`Slamon et al., “Human Breast Cancer: Correlation of Relapse and
`Survival with Amplification of the HER-2/neu Oncogene”, Science,
`vol. 235, pp. 177-182 (1987).
`Slamon et al., “Studies of the HER-2/neu Proto-Oncogene in Human
`Breast and Ovarian Cancer”, Science, vol. 244, pp. 707-712 (1989).
`Sliwkowski et al., “Coexpression of erB2 and erB3 Proteins Recon-
`stitutes a High Affinity Receptor for Heregulin”, Yhe Journal of
`Biological Chemistry, vol. 269, No. 20, pp. 14661-1665 (1994).
`Spector et al., “Study of the Biologic Effects of Lapatinib, a Revers-
`iblc Inhibitor of ErBl and ErB2 Tyrosinc Kinascs, on Tumor Growth
`and Survival Pathyways in Patients with Advanced Malignancies”,
`Jour. ofCLin. Onc., vol. 23, No. 11, pp. 2502-2512 (2005).
`Stancovski et al., “Mechanistic Aspects of the Opposing Effects of
`Monoclonal Antibodies to the ERBB2 Receptor on Tumor Growth”,
`Proc. Natl. Acad. Sci. USA, vol. 88, pp. 8691-8695 (1991).
`Tagliabue et al., “Selection of Monoclonal Antibodies which Induce
`Internatlization and Phosphorylation of p185HER2 and Growth Inhi-
`bition of Cells with HER2/NEU Gene Amplification”, Int. J. Cancer,
`vol. 47, pp. 933-937 9 (1991).
`Williams et al., “Expression of c-erbB-2 in Human Pancreatic
`Adenocarcinomas”, Pathobiology, vol. 59, pp. 46-52 (1991).
`Xu et a1 ., “Antibody-Induced Growth Inhibition is Mediated Through
`Immunochemically and Functionally Distinct Epitopes on the
`Extracellular Domain of the c-erB-2 (HER-2/neu) Gene Product”,
`Int. J. Cancer, vol. 53, pp. 401-408 (1993).
`Zhau et al., “Amplification and Expression of the c-erb B-2/neu
`Proto-Oncogene
`in Human Bladder Cancer”, Molecular
`Carcinogenesis, vol. 3, pp. 254-257 (1990).
`King et al., “Amplification of a Novel v-erbB-Realted Gene in a
`Human Mammary Carcinoma”, Science, vol. 229, pp. 974-976
`(1985).
`Fukushige et al., “Localization of a Novel v-erbB-Related Gene,
`c-erbB-2, on Human Chromosome 17 and its Amplification in a
`Gastric Cancer Cell Line”, Molecular and Cellular Biology, vol. 6,
`No.3, pp. 955-958 (1986).
`Database Chemabs Onlinel, Chemical Abstracts Service, Columbus,
`Ohio. US; Brechbiel. Martin W. et al.: “Synthesis and Evaluation of
`Antiproliferative
`Activity
`of
`a
`Geldanamycin-herceptin
`Immunoconjugate”Retrieved from STN Database Accession No.
`2000:796068, XP002164006, Abstracts & Abstr. Pap-Am. Chem.
`Soc. (2000), 220m, Medi-071.
`English translation of Technical Report No. GLMR11/00004
`received Apr. 6, 201 1, as issued in Costa Rica Patent Application No.
`8319.
`Extended European Search Report dated Mar. 17, 2011, as issued in
`European Patent Application No. 101846723.
`Luduena, R. F., et al., “Contrasting effects of maytansine and
`vinblastine on the alkylation of tubulin sulthydryls”, Archives of
`Biochemistry and Biophysics, vol. 210, No. 2, pp. 498-504, Sep. 1,
`1981.
`Yalowich, J. C., “Effects ofmicrotubule inhibitors on etoposide accu—
`mulation and DNA damage in human K562 cells in vitro”, Cancer
`Research, vol. 47., No. 4, pp. 1010-1015, Feb. 15, 1987.
`Iwahashi, M., et al., “CDR substitutions of a humanized monoclonal
`antibody (CC49): contributions of individual CDRs to antigen bind-
`ing and immunogenicity”, Molecular Immunology, vol. 36, pp. 1079-
`1091, 1999.
`Partial European Search Report dated Dec. 3, 2010, as issued in
`European Patent Application No. 101846723.
`European Office Action dated Nov. 24, 2010, as issued in European
`Patent Application No. 00 970 516.1.
`Chou, T. C., et al., “Quantitative analysis ofdo se-effect relationships:
`the combined effects of multiple drugs or enzyme inhibitors”,
`Advances in Enzyme Regulation, vol. 22, pp. 27-55, 1984.
`Chaemmaghami et al., “New Agents in the Treatment of Small Cell
`Lung Cancer”, Chest, 113(1 Suppl):86S-91S (1998).
`Epstein et al., “Use of the Immunotoxin N901-Blocked Ricin in
`Patients with Small-Cell Lung Cancer”, Int. J. Cancer Suppl., 8:57-
`59 (1994).
`“Today’s Drug Therapy”Nankodo Co., Ltd, Jun. 5, 1999, the second
`impression ofthe 21th edition, pp. 134 and 142- 143 (1999 Edition).
`Notice of Reasons for Rejection dated Oct. 27, 2010, for JP Patent
`Application No. 2007-284684.
`
`Technical Report No. GLMR11/00004 received Apr. 6, 2011, as
`issued in Costa Rica Patent Application No. 8319.
`Tolcher, Anthony W., et al., “Phase I Pharmacokinetic and Biologic
`Correlative Study of Mapatumumab, a Fully Human Monoclonal
`Antibody with Agonist Activity to Tumor Necrosis Factor-Related
`Apoptosis-Inducing Ligand Receptor-1”, Journal of Clinical Oncol-
`ogy, vol. 25, No. 11, pp. 1390-1396, Apr. 10, 2007.
`English translation of Japanese Office Action dated Jan. 4, 2011, as
`issued in Japanese Application No. 2006-533951.
`Arano, Y. ct al., “A newly designed radioimmuno-conjugatc releasing
`a hippurate-like radiometal chelate for enhanced target/non-target
`radioactivity”, Nuclear Medicine and Biology, vol. 2, No. 1, pp.
`63-69, Jan. 1, 1994.
`Hamann, P. R., “Monoclonal Antibody-Drug Conjugates”, Expert
`Opinion on Therapeutic Patents, vol. 15, No. 9, pp. 1087-1103, Jan.
`1, 2005.
`in Drug-Antibody
`“Recent Advances
`al.,
`et
`L.
`Lam,
`Immunoconjugates for the Treatment of Cancer”, Drugs of the
`Future, vol. 28, No. 9, pp. 905-910, Jan. 1, 2003.
`Supplementary European Search Report dated Jul. 1, 2010, as issued
`in European Patent Application No. 047938964.
`Chahinian, A. P., et al., “Treatment of invasive or metastatic
`thyrnoma: report of eleven cases”, Cancer, vol. 47, No. 7, pp. 1752-
`176 1, 198 1 .
`Aoe, et al., “Synergistic effect of docetaxel (DCT) and vinorelbine
`(VNB) against in vitro growth of a human small-cell lung cancer cell
`line”, Proceedings ofthe American Association for Cancer Research,
`vol. 37:375 (1996), Abstract No. 2560.
`Queen, C., et a1 ., “A Humanized antibody that binds to the interleukin
`2 receptor”, Proc. Natl. Acad. Sci. USA, vol. 86, pp. 10029-10033,
`Dec. 1989.
`US. Appl. No. 60/488,447, filed Jul. 21, 2003, Gillian Payne, et a1.
`Apelgren et al, Cancer Research, 50:3540-3 544 (1990).
`Bai et al., Cancer Research, 56:4398-4406(1996).
`Burris III, “Docetaxel (Taxotere) in HER-2-positive patients and in
`combination with Trastuzumab (Herceptin)”, Seminars in Oncology,
`27(No. 2. Suppl. 3):19-23 (2000).
`Chan et al., “Synergistic effects of doxorubicin and modulators of
`mu