`Us 7,449,184 132
`(10) Patent No.:
`Allison et al.
`(45) Date of Patent:
`Nov. 11, 2008
`
`USOO7449184B2
`
`(54) FIXED DOSING OF HER ANTIBODIES
`
`(75)
`
`Inventors: David E.Allison, San Mateo, CA (US);
`Rene Bruno, Marseilles (FR);
`Jian-Feng Lu, Foster City, CA (US);
`Chee M. Ng 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 121 days.
`
`(21) Appl. No.: 11/1543091
`
`(22)
`
`(65)
`
`Filed:
`
`Jun. 153 2005
`.
`.
`.
`Pmr Pubhcatlon Data
`US 2006/0165702 A1
`Jul. 27, 2006
`
`Related US. Application Data
`
`(60) Provisional application No. 60/645,697, filed on Jan.
`21, 2005.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 39/365
`(2006.01)
`C07K 16/30
`(52) us. Cl.
`.............. 424/1381; 424/1301; 424/141.1;
`424/143.1; 530/3871; 530/3881; 530/3888;
`530/38885; 514/2
`
`(58) Field of .Class1ficatlon Search ...............: ....... None
`See app11cat10n file for complete search hlstory.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,935,341 A
`6/1990 Bargmann etal.
`4,968,603 A
`11/1990 Slamon et a1.
`5,183,884 A
`2/1993 Kraus et a1.
`5,288,477 A
`2/1994 Bacus
`5,401,638 A
`3/1995 Carney et a1.
`5,480,968 A
`1/1996 Kraus et a1.
`5,514,554 A
`5/1996 Bacus
`5,571,894 A
`11/1996 Wels et al.
`5,587,458 A
`12/1996 King et a1.
`5,604,107 A
`2/1997 Carney et a1.
`5,641,869 A
`6/1997 Vandlen et al.
`5,648,237 A
`7/1997 Carter
`5,677,171 A
`10/1997 Hudziak et al.
`5,705,157 A
`1/1998 Greene
`5’720’937 A
`2/1998 Hudziak et al.
`5,720,954 A
`2/1998 HudZIak et al.
`5,725,856 A
`3/1998 Hudziak et a1.
`5,747,261 A
`5/1998 King et a1.
`5,770,195 A
`6/1998 Hudziak et al.
`5,772,997 A
`6/1998 Hudziak et a1.
`5,783,186 A
`7/1998 Arakawa et a1.
`5,783,404 A
`7/1998 Koski
`5,804,396 A
`9/1998 Plowman
`5,821,337 A
`10/1998 Carter et al.
`5,824,311 A
`10/1998 Greene et a1.
`
`5,837,243 A
`5,846,749 A
`5,856,089 A
`5,877,305 A
`5,910,486 A
`5,922,845 A
`5,925,519 A
`2:332:33: :
`5,985,553 A
`5,994,071 A
`6,015,567 A
`6,028,059 A
`6,054,297 A
`6,123,939 A
`
`6,127,526 A
`6,165,464 A
`
`6,214,388 B1
`6,267,958 B1
`6,270,765 B1
`6,333,169 B1
`6,333,348 B1
`6,333,398 B1
`6,339,142 Bl
`6,358,682 B1
`6,387,371 131
`6,395,272 B1
`6,399,063 B1
`6,403,630 B1
`6,407,213 B1
`6,417,335 B1
`22:32:: E;
`’
`’
`
`11/1998 Deo et a1.
`12/1998 Slamon et al.
`1/ 1999 Wang et 31
`3/1999 Huston et a1.
`6/1999 Curiel et a1.
`7/1999 Deo et al.
`7/1999 Jensen et a1.
`131333 fiiiiilél.
`11/1999 King et a1.
`11/1999 Ross et al.
`1/2000 Hudziak et a1.
`2/2000 Curiel et a1.
`4/2000 Carter et 31.
`9/2000 Shawver et a1.
`
`10/2000 Blank
`12/2000 Hudziak et al.
`
`4/2001 Benz et a1.
`7/2001 Andya et al.
`8/2001 Deo et al.
`12/2001 Hudziak et al.
`12/2001 Vogel et al.
`12/2001 Blank
`1/2002 Basey et 31
`3/2002 Jaffee et al.
`5/2002 Hudziak et a1.
`5/2002 Deo et al.
`6/2002 Hudziak et al.
`6/2002 Dannenberg et a1.
`6/2002 Carter et al.
`7/2002 Basey et a1.
`£4588; 3:133:31.
`y
`'
`(Continued)
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`
`FOREIGN PATENT DOCUMENTS
`0 599 274 A1
`6/1994
`0 616 812 B1
`9/1994
`0 656 367 A1
`6/1995
`0412116 B1
`“/1995
`0494 135 B1
`4/1996
`0 502 812 B1
`8/1996
`0 711565 B1
`8/1998
`0 554 441 B1
`1/1999
`1006 194 A2
`6/2000
`0 444 181 B1
`10/2001
`1 357 132 A2
`10/2003
`
`.
`(commued)
`OTHER PUBLICATIONS
`
`Animal Dosage “Dose Calculator”, p. 1.*
`.
`(Commued)
`Primary ExamineriLarry R. Helms
`.
`.
`Asszslanl ExammeriLaura B Goddard
`(74) Attorney, Agent, or Firm7Wendy M. Lee
`
`(57)
`
`ABSTRACT
`
`.
`.
`.
`.
`The present mventlon concerns fixed dosmg of HER ant1bod-
`1655511011 as PeITUZUmah
`
`32 Claims, 18 Drawing Sheets
`
`Mylan V. Janssen (IPR2020-00440) EX. 1014 p. 001
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 001
`
`
`
`US 7,449,184 B2
`
`Page 2
`
`US. PATENT DOCUMENTS
`
`6,512,097 Bl
`6,573,043 Bl
`6582919 132
`6,602,670 132
`6,627,196 Bl
`6,632,979 32
`6,639,055 Bl
`6,685,940 132
`6719971 Bl
`6,767,541 132
`6,797,814 32
`6,800,738 Bl
`6,821,515 Bl
`7041192 Bl
`7097340 132
`2001/0014326 A1
`2002/0001587 A1
`2002/0031515 A1
`2002/0051785 A1
`2002/0064785 A1
`2002/0076408 A1
`2002/0076695 A1
`2002/0090662 A1
`2002/0141993 A1
`2002/0142328 A1
`2002/0155527 A1
`2002/0192211 A1
`2002/0192652 A1
`2003/0022918 A1
`2003/0059790 A1
`2003/0068318 A1
`2003/0086924 A1*
`2003/0103973 A1
`2003/0108545 A1
`2003/0134344 A1
`2003/0144252 A1
`2003/0147884 A1
`2003/0152572 A1
`2003/0152987 A1
`2003/0157097 A1
`2003/0165840 A1
`2003/0170234 A1
`2003/0175845 A1
`2003/0202972 A1
`2003/0202973 A1
`2003/0211530 A1
`2003/0228663 A1
`2004/0013297 A1
`2004/0013667 A1
`2004/0037823 A9
`2004/0037824 A1
`2004/0082047 A1
`2004/0106161 A1
`2004/0138160 A1
`2004/0209290 A1
`2004/0236078 A1
`2004/0258685 A1
`2005/0002928 A1
`2005/0208043 A1
`2005/0238640 A1
`2005/0244417 A1
`2006/0013819 A1
`2006/0018899 A1
`2006/0034840 A1
`2006/0034842 A1
`2006/0073143 A1
`2006/0083739 A1
`2006/0088523 A1
`2006/0121044 A1
`2006/0188509 A1
`2006/0193854 A1
`
`1/2003 Marksetal
`6/2003 Cohen etal
`60003 Danenberg
`80003 Danenberg
`9/2003 Baughman etal~
`10/2003 Erickson etal~
`10/2003 CarteretaL
`20004 Andyaetal~
`4/2004 CarteretaL
`7/2004 Slamon etal~
`9/2004 Blank
`10/2004 CarteretaL
`11/2004 ClelandetaL
`5/2006 Sliwkowski
`8/2006 Erickson etal~
`8/2001 Andyaetal.
`1/2002 Erickson et al.
`3/2002 Caligiurietal~
`5/2002 s1amon et a1.
`5/2002 Mass
`6/2002 Buchsbaum
`6/2002 Ross
`7/2002 Ralph
`10/2002 Ashkenazi et a1.
`10/2002 Danenberg
`10/2002 Stuart eta1.
`12/2002 Hudziak eta1.
`12/2002 Danenberg
`1/2003 Horak eta1.
`3/2003 Jaffee eta1.
`4/2003 O’Brien eta1.
`5/2003 Sliwkowski .............. 424/143.1
`6/2003 Rockwell et a1.
`6/2003 Rockwell et a1.
`7/2003 Mass
`7/2003 Fun
`8/2003 Paton eta1.
`8/2003 Homma eta1.
`8/2003 Cohen eta1.
`8/2003 Noguchi et a1.
`9/2003 Danenberg
`9/2003 Hellmann
`9/2003 Kalbag eta1.
`10/2003 Andya eta1.
`10/2003 Pieczenik
`11/2003 Danenberg
`12/2003 Lowman eta1.
`1/2004 L0
`1/2004 Kelseyet a1.
`2/2004 Paton eta1.
`2/2004 Baughman eta1.
`4/2004 Jefferson eta1.
`6/2004 Bossenmaier eta1.
`7/2004 Nato eta1.
`10/2004 Cobleigh eta1.
`11/2004 Carter et a1.
`12/2004 Brunetta eta1.
`1/2005 Hellmann
`9/2005 Adams et a1.
`10/2005 Sliwkowski
`11/2005 Ashkenazi et a1.
`1/2006 Kelsey
`1/2006 Kao et a1.
`2/2006 Agus
`2/2006 Adams et a1.
`4/2006 Adams et a1.
`4/2006 Sliwkowski
`4/2006 Andya et a1.
`6/2006 Amler eta1.
`8/2006 Derynck et a1.
`8/2006 Adams et a1.
`
`2006/0198843 A1
`2006/0204505 A1
`
`9/2006 Adams et a1.
`9/2006 Sliwkowski eta1.
`
`2006/0210561 A1
`2006/0216285 A1
`2006/0228745 A1
`2006/0275305 A1
`2006/0275306 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
`2008/0050385 A1
`
`9/2006 Baughmanetal.
`9/2006 Adams et al.
`10/2006 Mass
`12/2006 Bryant
`12/2006 Andyaetal.
`1/2007 Sliwkowski eta1.
`2/2007 Ashkenazi eta1.
`2/2007 Moecks et al.
`4/2007 Cartereta1.
`7/2007 Mass
`8/2007 Sliwkowski
`8/2007 Mass
`9/2007 Friess et al.
`11/2007 Kelseyeta1.
`12/2007 Hellmann
`2/2008 Amleretal.
`2/2008 Cohen
`2/2008 Friess et a1.
`
`FOREIGN pATENT DOCUMENTS
`
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`W0 87/07646 A2
`W0 89/ 10412 A1
`W0 91/02062 A2
`W0 91/05264 A1
`W0 93/03741 A1
`W0 93/12220 A1
`W0 93/16185 A2
`W0 93/21232 A1
`W0 93/21319 A1
`W0 94/00136 A1
`W0 94/22478 A1
`W0 96/07321 A1
`W0 96/16673 A1
`W0 96/40789 A1
`W0 97/00271 A1
`W0 97/20858 A1
`W0 97/38731 A1
`W0 98/02463 A1
`W0 98/ 17797 A1
`W0 98/18489 A1
`W0 98/33914 A1
`W0 98/45479 A1
`W0 99/31140 A1
`W0 99/48527 A1
`W0 99/55367 A1
`W0 00/09160 A1
`W0 00/61145 A1
`W0 00/61185 A1
`W0 00/69460 A1
`W0 00/78347 A1
`W0 01/00238 A1
`W0 01/00244 A2
`W0 01/00245 A2
`W0 01/09187 A2
`W0 01/ 15730 A1
`W0 01/20033 A1
`W0 01/32155 A2
`W0 01/53354 A2
`W0 01/56604 A1
`W0 01/64246 A2
`W0 01/76586 A1
`W001/76630 A1
`W0 01/87334 A1
`W0 01/87336 A1
`W0 01/89566 A1
`W0 02/05791 A2
`W0 02/11677 A2
`W0 02/44413 A2
`W0 02/45653 A2
`W0 02/009754 A1
`
`12/1987
`11/1989
`2/1991
`4/1991
`3/1993
`6/1993
`8/1993
`10/1993
`10/1993
`1/1994
`10/1994
`3/1996
`6/1996
`12/1996
`1/1997
`6/1997
`10/1997
`1/1998
`4/1998
`5/1998
`8/1998
`10/1998
`6/1999
`9/1999
`11/1999
`2/2000
`10/2000
`10/2000
`11/2000
`12/2000
`1/2001
`1/2001
`1/2001
`2/2001
`3/2001
`3/2001
`5/2001
`7/2001
`8/2001
`9/2001
`10/2001
`10/2001
`11/2001
`11/2001
`11/2001
`1/2002
`2/2002
`6/2002
`6/2002
`7/2002
`
`Mylan V. Janssen (IPR2020-00440) EX. 1014 p. 002
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`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 002
`
`
`
`US 7,449,184 132
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`Page 3
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`W0
`W0
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`W0
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`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`W0 02/055106 A2
`W0 02/070008 A1
`W0 02/087619 A1
`W0 02/089842 A1
`W0 03/006509 A2
`W0 03/012072 A2
`W0 03/028638 A2
`W0 03/041736 A2
`W0 03/086467 A1
`W0 03/087131 A2
`W0 04/000094 A2
`WO 2004/008099 A2
`WO 2004/024866 A2
`WO 2004/048525 A2
`WO 2004/053497 A2
`WO 2004/063709 A2
`WO 2005/099756 A2
`WO 2006/007398 A1
`WO 2006/033700 A2
`WO 2006/044908 A2
`WO 2006/063042 A2
`WO 2006/091693 A2
`WO 2006/096861 A2
`WO 2007/013950 A2
`WO 2007/019899 A2
`WO 2008/031531 A1
`
`7/2002
`9/2002
`11/2002
`11/2002
`1/2003
`2/2003
`4/2003
`5/2003
`10/2003
`10/2003
`12/2003
`1/2004
`3/2004
`6/2004
`6/2004
`7/2004
`10/2005
`1/2006
`3/2006
`4/2006
`6/2006
`8/2006
`9/2006
`2/2007
`2/2007
`3/2008
`
`OTHER PUBLICATIONS
`
`White et al. (2001, Ann. Rev. Med., 2001, 52:125-145).*
`Agus et al., “Clinical Activity in a Phase I Trial of HER2-Targeted
`rhuMAb 2C4 (pertuzumab) in Patients with Advanced Solid Malig-
`nancies” (Slides presented at the 2003 ASCO Annual Meeting) pp.
`1-32 (2003).
`Agus et al., “Efficacy and safety of single agent pertuzumab (rhuMAb
`2C4) , a HER dimerization inhibitor, in hormone refractory prostate
`cancer after failure of taxane-based therapy” Journal of Clinical
`Oncology (Abstract 4624 from the 4 1 st Annual Meeting ofASCO) 23
`(16S):408s (Jun. 1, 2005).
`Agus, D. et al., “Efficacy and safety of single agent pertuzumab
`(rhuMAb 2C4), a HER dimerization inhibitor, in hormone refractory
`prostate cancer after failure of taxane-based therapy” (Poster 4624
`from the 41st Annual Meeting of the American Society of Clinical
`Oncology) (May 15, 2005).
`Allison et al., “Pharmacokinetics (PK) ofpertuzumab (rhuMAb 2C4)
`in Phase II Studies of Ovarian, Breast, Prostate, and Lung Cancers”
`(Poster 2532 presented at the 2005 ASCO Meeting) (May 2005).
`Allison et al., “Pharmacokinetics of HER2-Targeted rhuMAb 2C4
`(OMNITARG) in Patients with Advanced Solid Malignancies: Phase
`Ia Results” (Poster 790 from the 2003 ASCO Annual Meeting)
`(2003).
`Amler et al., “Identification of a predictive expression pattern for
`phosphorylated HER2 as
`a potential diagnostic marker
`for
`pertuzumab (OMNITARG) activity in ovarian cancer” (Poster 4497
`presented at
`the Apr. 2006 American Association for Cancer
`Research Meeting) (Apr. 2006).
`Bossenmaier et al., “Presence of HER2/HER3 heterodimers predicts
`antitumor effects of pertuzumab (OMNITARG) in different human
`xenograft models” Proc AM Assoc Cancer Res (Abstract 5342)
`45: 1232 (Mar. 2004).
`Cortes et al., “Open label, randomized, phase II study of pertuzumab
`(OMNITARG) in patients with metastatic breast cancer (MBC) with
`low expression ofHER2” (Poster 3068 from the 4 1 st Annual Meeting
`of the American Society of Clinical Oncology (ASCO) ) (May 15,
`2005).
`Cortes et al., “Open label, randomized, phase II study of pertuzumab
`(P) in patients (pts) with metastatic breast cancer (MBC) with low
`expression of HER2” Journal of Clinical Oncology (Abstract 3068
`from the 41st Annual Meeting of ASCO) 23 (16s):208s (Jun. 1,
`2005).
`de Bono et al., “An open label, phase II, multicancer study to evaluate
`the efficacy and safety ofpertuzumab in chemotherapy-naive patients
`with Hormone-Refractory Prostate Cancer (HRPC)” (Poster 4609
`
`from the 41st Annual Meeting of the American Society of Clinical
`Oncology (ASCO)) (May 15, 2005).
`de Bono et al., “An open label, phase II, multicenter, study to evaluate
`the efficacy and safety of pertuzumab (P) in chemotherapy naive
`patients (pts) with Hormone Refractory Prostate Cancer (HRPC)”
`Journal ofClinical Oncology (Abstract 4609; 4 1 st Annual Meeting of
`ASCO) 23(16S):405a (Jun. 1, 2005).
`ERBITUX (CETUXIMAB) (product information) (Jun. 2004).
`Friess et al., “Combination treatment with erlotinib and pertuzumab
`against human tumor xenografts is superior to monotherapy” Clinical
`Cancer Research 11(14) :5300-5309 (Jul. 15, 2005).
`Friess et al., “In vivo activity of recombinant humanized monoclonal
`antibody 2C4 in xenografts is independent of tumor type and degree
`ofHER2 overexpression” European Journal ofCancer (Abstract 496
`from the EORTC-NCI-AACR conference in Frankfurt, Germany
`Nov. 19-22, 2002.) 38 (Suppl. 7) :Sl49 (2002).
`Gelman et al., “Model checking and improvement” Bayesian Data
`Analysis, Boca Raton: Chapman & Hall/CRC, Chapter 6, pp. 157-196
`(2004).
`Gelman et al., “Model checking and model improvement” Markov
`Chain Monte Carlo in Practice, W. R. Gilks, S. Richardson, and DJ.
`Spiegelhalter, Boca Raton:Chapman & Hall/CRC, Chapter 11, pp.
`189-201 (1996).
`Gordon et al., “Clinical activity of pertuzumab (rhuMab 2C4) in
`advanced, refractory or recurrent ovarian cancer (OC), and the role of
`HER2 activation status” Journal of Clinical Oncology (Abstract
`#5051 from the 4 1 st Annual Meeting ofASCO) 23(16S) :467s (Jun.
`1, 2005).
`Gordon et al., “Clinical activity of pertuzumab (rhuMab 2C4) in
`advanced, refractory or recurrent ovarian cancer and the role of
`HER2 activation status” (Poster #5051 from the 41st Annual Meeting
`of the American Society of Clinical Oncology (ASCO) ) (May 15,
`2005).
`for
`Harris et al., “A population pharmacokinetic (PK) model
`HERCEPTIN(H) and implications for clinical dosing” (Poster pre-
`sented at the 2002 ASCO Annual Meeting) (2002).
`Hasmann et al., “Pertuzumab (Omnitarg) Potentiates Antitumor
`Effects on NSCLS Xenografts Without Increasing Toxicity when
`Combined with Cytotoxic Chemotherapeutic Agents” American
`Association for Cancer Research (Abstract #B213; supplement to
`Clinical Cancer Research) 9(16) (Dec. 1, 2003).
`HERCEPTIN (Trastuzumab) (product information) (2004).
`Lu et al., “When should dose be adjusted to body size? A population
`pharmacokinetic (PPK) simulation” Clinical Pharmacology &
`Therapeutics (Abstract PIII-89. Poster is attached.) pp. P86 (Feb.
`2003).
`Malik et al., “Dose-Response Studies of Recombinant Humanized
`Monoclonal Antibody 2C4 (Pertuzumab) in Tumor Xenograft Mod-
`els” (Poster No. 773 presented at the American Association for Can-
`cer Research meeting) (2003).
`Agus et al., “Phase I clinical study of pertuzumab, a novel HER
`dimerization inhibitor, in patients with advanced cancer” Journal of
`Clinical Oncology 23(11) :2534-2543 (Apr. 10, 2005).
`Baselga, J., “Phase I and II clinical trials of trastuzumab” Annals of
`Oncology 12 (Suppl 1) :S49-855 (2001).
`Franklin et al., “Insights into ErbB signaling from the structure ofthe
`ErbB2-pertuzumab complex” Cancer Cell 5(4)
`:317-328 (Apr.
`2004).
`Leyland-Jones, B., “Dose schedulingiHerceptin” Oncology 61
`(Suppl 2) :31-36 (2001).
`Malik et al., “Dose-Response Studies of Recombinant Humanized
`Monoclonal Antibody 2C4 in Tumor Xenograft Models” Proceed—
`ings oftheAmerican Associationfor Cancer Research (Abstract No.
`773) 44: 150 (Jul. 2003).
`Ng et al., “Rationale for fixed dosing of pertuzumab by population
`pharmacokinetic (POP PK) modeling” Clinical Pharmacology &
`Therapeutics (Abstract PI-97) 77(2) :P33 (2005).
`Aasland et al., “Expression of Oncogenes in Thyroid Tumours:
`Coexpression of c-erbB2/neu and c-erbB” British Journal ofCancer
`57(4) :358-363 (Apr. 1988).
`Agus et al., “Clinical Activity in a Phase I Trial of HER-2-Targeted
`rhuMAb 2C4 (pertuzumab) in Patients with Advanced Solid Malig-
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 003
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 003
`
`
`
`US 7,449,184 132
`Page 4
`
`nancies (AST)”Proceedings oftheAmericanAssociationfor Cancer
`Research (Abstract No. 771) 22: 192 (2003).
`Agus et al., “Targeting ligand-activated ErbB2 signaling inhibits
`breast and prostate tumor growth” Cancer Cell 2(2) :127-137 (Aug.
`2002).
`Allison et al., “Pharmacokinetics (PK) ofpertuzumab (rhuMAb 2C4)
`in Phase II Studies of Ovarian, Breast, Prostate, and Lung Cancers”
`Journal of Clinical Oncology (Jun.
`1 Supplement) 23(16S) :2532
`(2005).
`Allison et al., “Pharmacokinetics of HER2-Targeted rhuMAb 2C4
`(pertuzumab) in Patients with Advanced Solid Malignancies: Phase
`Ia Results” Meeting Proceedings oftheAmerican Society ofClinical
`Oncology (Abstract No. 790) 22: 197 (2003).
`Artega et al., “p185“‘erbB'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 54(14) :3758-3765 (Jul. 15, 1994).
`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 3 (6) :350-362 (1990).
`Bacus et al., “Tumor-inhibitory Monoclonal Antibodies to the HER-
`2/Neu Receptor Induce Differentiation of Human Breast Cancer
`Cells” Cancer Research 52(9) :2580-2589 (May 1, 1992).
`Baker et al., “Role of body surface area in dosing of investigational
`anticancer agents in adults, 1991-2001” J Natl. Cancer Institute
`94(24) :1883-1888 (Dec. 18, 2002).
`Baselga and Mendelsohn, “Receptor Blockade With Monoclonal
`Antibodies As Anti-Cancer Therapy” Pharmac. Ther. 64:127-154
`(1994).
`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. 14(3) :737-744 (Mar. 1996).
`Borst et al., “Oncogene Alterations in Endometrial Carcinoma”
`Gynecologic Oncology 38(3) :364-366 (Sep. 1990).
`Carraway and Cantley, “A Neu Acquaintance for ErbB3 and ErbB4:
`A Role for Receptor Heterodimerization in Growth Signaling” Cell
`78:5-8 (Jul. 15, 1994).
`Carraway et al., “Neuregulin-2, A New Ligand of ErbB3/ErbB4-
`Receptor Tyrosine Kinases” Nature 387:512-516 (May 1997).
`Chang et al., “Ligands For ErbB-Family Receptors Encoded By a
`Neuregulin-Like Gene” Nature 387:509-512 (May 29, 1977).
`Cho et al., “Structure ofthe extracellular region of HER2 alone and in
`complex with the Herceptin Fab” Nature 421(6924) :756-760 (Feb.
`13, ).
`Cohen et al., “Expression Pattern of the neu (NGL) Gene-Encoded
`Growth Factor Receptor Protein (p185“e“) in Normal and Trans-
`formed Epithelial Tissues of the Digestive Tract” Oncogene 4(1):
`81-88 (Jan. 1989).
`Cronin et al., “Measurement of gene expression in archival paraffin-
`embedded tissues: development and performance of a 92-gene
`reverse transcriptase-polymerase chain reaction assay” Am. J Path.
`164(1) :35-42.
`D’Souza and Taylor-Papadimitriou., “Overexpression of ERBB2 in
`Human Mammary Epithelial Cells Signals Inhibition of Transcrip-
`tion of the E-Cadherin Gene” Proc. Natl. Acad Sci. USA 91(15):
`7202-7206 (Jul. 19, 1994).
`influence on
`de Jong et al., “Flat-fixed dosing of irinotecan:
`pharmacokinetic and pharmacodynamic variability” Clinical Cancer
`Research (Part 1) 10(12) :4068-4071 (Jun. 15,2004).
`de Jongh et al., “Body-surface area-based dosing does not increase
`accuracy of predicting cisplatin exposure” J. Clin. Oncol. 19(17):
`3733-3739 (Sep. 1, 2001).
`Drebin et al., “Down-Modulation of an Oncogene Protein Product
`and Reversion of the Transformed Phenotype by Monoclonal Anti-
`bodies” Cell 41(3) :695-706 (Jul. 1985).
`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 2:273 -277 (1988).
`Earp et al., “Heterodimerization and Functional Interaction Between
`EGF Receptor Family Members: A New Signaling Paradigm With
`Implications For Breast Cancer Research” Breast Cancer Res and
`Treatment 35: 115-132 (1995).
`
`Egorin, M., “Horseshoes, hand grenades, and body-surface area-
`based dosing: aiming for a target” Journal of Clinical Oncology
`21(2):182-183 (Jan. 15,2003).
`Felici et al., “Dosing strategies for anticancer drugs: the good, the bad
`and body-surface area” European Journal of Cancer 38(13) :1677-
`1684 (Sep. 2002).
`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 50:1550-
`1558 (Mar. 1,1990).
`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 & Cellular Biology 6(3) :955-
`958 (Mar. 1986).
`Gelman et al. Bayesian Data Analysis, Boca Raton:Chapman &
`Hall/CRC (2004).
`Gelman et al. Model Checking and Model Improvement, W. R. Gilks,
`S. Richardson, and DJ. Spiegelhalter, Boca Raton:Chapman & Hall/
`CRC pp. 189-192 (1996).
`Groenen et al., “Structure-Function Relationships for the EGF/
`TGF-OL Family of Mitogens” Growth Factors 11:235-257 (1994).
`Gu et al., “Overexpression of her-2/neu in Human Prostate Cancer
`and Benign Hyperplasia” Cancer Letters 99: 185-189 (1996).
`Guerin et al., “Overexpression of Either c-myc or c-erbB-2/neu
`Proto-Oncogenes in Human Breast Carcinomas: Correlation with
`Poor Prognosis” Oncogene Res 3:21-31 (1988).
`Hancock et al., “A Monoclonal Antibody Against the c-erbB-2 Pro-
`tein Enhances the Cytotoxicity of cis-Diamminedichloroplatinum
`Against Human Breast and Ovarian Tumor Cell Lines” Cancer
`Research 51:4575-4580 (Sep. 1, 1991).
`Harari et al., “Molecular mechanisms underlying ErbB2/HER2
`action in breast cancer” Oncogene 19(53) :6102-6114 (Dec. 11,
`2000).
`Harari et al., “Neuregulin-4: A Novel Growth Factor That Acts
`Through the ErbB-4 Receptor Tyrosine Kinase” Oncogene 18:2681-
`2689 (1999).
`for
`Harris et al., “A population pharmacokinetic (PK) model
`trastuzumab (Herceptin) and implications for clinical dosing” Proc
`Am Soc Clin Oncol (Abstract #488) 21: 123a (2002).
`Harwerth et al., “Monoclonal Antibodies Against the Extracellular
`Domain ofthe erbB-2 Receptor Function as Partial Ligand Agonists”
`Journal of Biological Chemistry 267(21): 15160-15167 (Jul. 25,
`1992).
`Holmes et al., “Identification of Heregulin, A Specific Activator of
`PisserbBZ” Science 256: 1205-1210 (May 22, 1992).
`Hudziak et al., “p185HER2 Monoclonal Antibody Has Antiprolifera-
`tive Effects In Vitro and Sensitizes Human Breast Tumor Cells to
`Tumor Necrosis Factor” Molecular & Cellular Biology 9(3) :1165-
`1172 (Mar. 1989).
`Kasprzyk et al., “Therapy of an Animal Model of Human Gastric
`Cancer Using a Combination of Anti-erbB-2 Monoclonal Antibod-
`ies” Cancer Research 52(10) :2771-2776 (May 15, 1992).
`Kern et al., “p185neu Expression in Human Lung Adenocarcinomas
`Predicts Shortened Survival” Cancer Research 50(16) :5184-5191
`(Aug. 15, 1990).
`King et al., “Amplification of a Novel v-erbB-Related Gene in a
`Human Mammary Carcinoma” Science 229:974-976 (Sep. 1985).
`Klapper et al., “A Subclass of Tumor-Inhibitory Monoclonal Anti-
`bodies to ErbB-2/HER2 Blocks Crosstalk With Growth Factor
`Receptors” Oncogene 14:2099-2109 (1997).
`Kotts et al., “Differential Growth Inhibition of Human Carcinoma
`Cells Exposed to Monoclonal Antibodies Directed against
`the
`Extracellular Domain ofthe HER2/ERBB2 Protooncogene” In Vitro
`(Abstract #176) 26 (3) :59A (1990).
`Kraus et al., “Isolation and Characterization of ERBB3, A Third
`Member of the ERBB/Epidermal Growth Factor Receptor Family:
`Evidence for Overexpression in a Subset of Human Mammary
`Tumors” Proc. Natl. Acad. Sci. USA 86:9193-9197 (Dec. 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 Mammary Carcinoma Cells” Molecular & Cellular
`Biology 11(2) :979-986 (Feb. 1991).
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 004
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 004
`
`
`
`US 7,449,184 132
`Page 5
`
`Lee et al., “Transforming Growth Factor 0t: Expression, Regulation,
`and Biological Activities” Pharmacological Reviews 47(1) :51-85
`(Mar. 1995).
`Lemke, G., “Neuregulins in Development” Molecular and Cellular
`Neuroscience 7:247-262 (1996).
`Levi et al., “The Influence of Heregulins on Human Schwann Cell
`Proliferation” J Neuroscience 15(2) :1329-1340 (Feb. 1995).
`Lewis et al., “Differential Responses of Human Tumor Cell Lines to
`Anti-p185HER2 Monoclonal Antibodies” Cancer
`Immunol.
`Immunother. 37:255-263 (1993).
`Lewis 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 56:1457-1465 (Mar. 15, 1996).
`Leyland-Jones et al., “Pharmacokinetics, safety, and efficacy of
`trastuzumab administered every three weeks in combination with
`paclitaxel”J. Clin. Oncol. 21(21) :3965-3971 (Nov. 1, 2003).
`Loos et al., “Inter- and intrapatient variability in oral topotecan
`pharmacokinetics: implications for body-surface area dosage regi-
`mens” Clin. Cancer Res. 6(7) :2685-2689 (Jul. 2000).
`Lu et al., “A Population Pharmacokinetic Model for Bevacizumab”
`ClinicalPharmacology & Therapeutics (Abstract PII-149) 75(2) :91
`(2004).
`VIa et al., “A two-gene expression ratio predicts clinical outcome in
`breast cancer patients treated with tamoxifen” Cancer Cell 5(6) :607-
`616 (Jun. 2004).
`VIaier et al., “Requirements for the Internalization of a Murine
`VIonoclonal Antibody Directed against the HER-2/neu Gene Product
`c-erbB-2” Cancer Research 51(19) :5361-5369 (Oct. 1, 1991).
`VIalik et al., “Dose-Response Studies of Recombinant Humanized
`VIonoclonal Antibody 2C4 in Tumor Xenograft Models” Proceed—
`ings oftheAACR (Abstract No. 773) 44:176-177 (Mar. 2003).
`VIasui et al., “Growth Inhibition of Human Tumor Cells in Athymic
`VIice by Anti-Epidermal Growth Factor Receptor Monoclonal Anti-
`bodies” Cancer Research 44(3) :1002-1007 (Mar. 1984).
`VIathijssen et al., “Impact of body-size measures on irinotecan clear-
`ance: alternative dosing recommendations” Journal of Clinical
`Oncology 20(1) :81-87 (Jan. 1, 2002).
`VIcCann et al., “c -erbB-2 Oncoprotein Expression in Primary Human
`Tumors” Cancer 65(1) :88-92 (Jan. 1, 1990).
`VIcKensie et al., “Generation and Characterization of Monoclonal
`Antibodies Specific for the Human neu Oncogene Product, p185”
`Oncogene 4 :543-548 (1989).
`VIorrissey et al., “Axon-Induced Mitogenesis of Human Schwann
`Cells Involves Heregulin and p185“sz ”Proc. Natl. Acad. Sci. USA
`92:1431-1435 (Feb. 1995).
`VIyers et al., “Biological Effects of Monoclonal Antireceptor Anti-
`bodies Reactive with neu Oncogene Product, p185neu” Methods in
`Enzymology 198:277-290 (1991).
`Park et al., “Amplification, Overexpression, and Rearrangement of
`the erbB-2 Protooncogene in Primary Human Stomach Carcinomas”
`Cancer Research 49(23) :6605-6609 (Dec. 1, 1989).
`Pietras et al., “Antibody to HER-2/neu Receptor Blocks DNA Repair
`After Cisplatin in Human Breast and Ovarian Cancer Cells”
`Oncogene 9: 1829-1838 (1994).
`Plowman et al., “Heregulin Induces Tyrosine Phosphorylation of
`HER4/p1805rbB4” Nature (Letters to Nature) 366:473-475 (Dec. 2,
`1993).
`Plowman et al., “Ligand-Specific Activation of HER4/p1806rbB4, A
`Fourth Member of the Epidermal Growth Factor Receptor Family”
`Proc. Natl. Acad. Sci. USA 90:1746-1750 (Mar. 1993).
`Ross et al., “HER-2/neu Gene Amplification Status in Prostate Can-
`cer by Fluorescence in Situ Hybridization” Hum. Pathol. 28(7) :827-
`833 (Jul. 1997).
`Ross et al., “Prognostic Significance of HER-2/neu Gene Amplifica-
`tion Status by Fluorescence In Situ Hybridization of Prostate Carci-
`noma” Cancer 79(11) :2162-2170 (Jun. 1, 1997).
`Sadasivan et al., “Overexpression of Her-2/Neu May Be An Indicator
`of Poor Prognosis in Prostate Cancer” J Urol. 150:126-131 (Jul.
`1993).
`
`
`
`Sarup et al., “Characterization of an Anti-P185HER2 Monoclonal
`Antibody that Stimulates Receptor Function and Inhibits Tumor Cell
`Growth” Growth Regulation 1:72-82 (1991).
`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 15:1385-1394 (1997).
`Scott et al., “p185HER2 Signal Transduction in Breast Cancer Cells”
`Journal of Biological Chemistry 266(22):14300-14305 (Aug. 5,
`1991).
`Shawver et al., “Ligand-Like Effects Induced by Anti-c-erbB-2 Anti-
`bodies Do Not Correlate with and Are Not Required for Growth
`Inhibition of Human Carcinoma Cells” Cancer Research 54(5):
`1367-1373 (Mar. 1, 1994).
`Shepard et al., “Monoclonal Antibody Therapy of Human Cancer:
`Taking the HER2 Protooncogene to the Clinic” J Clin. Immunol.
`11(3): 1 17-127 (1991).
`Slamon et al., “Human Breast Cancer: Correlation of Relapse and
`Survival with Amplification of the HER-2/neu Oncogene” Science
`235:177-182 (Jan. 9, 1987).
`Slamon et al., “Studies of the HER-2/neu Proto-Oncogene in Human
`Breast and Ovarian Cancer” Science 244:707-712 (May 12, 1989).
`Sliwkowski et al., “Coexpression of erbB2 and erbB3 Proteins
`Reconstitutes a High Affinity Receptor for Heregulin” Journal of
`Biological Chemistry 269(20) :14661-14665 (May 20, 1994).
`Sliwkowski et al., “Ready to partner” Nat. Struct. Biol. 10(3) :158-
`159 (Mar. 2003).
`Stancovski et al., “Mechanistic Aspects of the Opposing Effects of
`Monoclonal Antibodies to the ERBB2 Receptor on Tumor Growth”
`Proc. Natl. Acad. Sci. USA 88(19) :8691-8695 (Oct. 1, 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” International
`Journal ofCancer 47(6) :933-937 (Apr. 1, 1991).
`Vitetta and Uhr, “Monoclonal Antibodies as Agonists: An Expanded
`Role for Their Use in Cancer Therapy” Cancer Research 54 (20):
`5301-5309 (Oct. 15, 1994).
`Weiner et al., “Expression of the neu Gene-encoded Protein
`(P185mu) in Human Non-Small Cell Carcinomas of the Lung” Can—
`cer Research 50(2) :421-425 (Jan. 15, 1990).
`Williams et al., “Expression of c-erbB-2 in Human Pancreatic
`Adenocarcinomas” Pathobiology 59(1) :46-52 (1991).
`Wu et al., “Apoptosis Induced By an Anti-Epidermal Growth Factor
`Receptor Monoclonal Antibody in a Human Colorectal Carcinoma
`Cell Line and Its Delay By Insulin” Journal ofClinical Investigation
`95(4) :1897-1905 (Apr. 1995).
`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
`p185” International Journal of Cancer 53(3) :401-408 (Feb. 1,
`1993).
`Yano et al., “Evaluating Pharmacokinetic/Pharmacodynamic Models
`Using the Posterior Predictive Check” Journal ofPharmacokinetics
`and Pharmacodynamics 28(2) :171-192 (2001).
`Yarden et al., “Untangling of the erbB signalling network” Nat. Rev.
`Mol. Cell. Biol. 2(2) :127-137 (Feb. 2001).
`Yokota et al., “Amplification of c-erbB-2 Oncogene in Human
`Adenocarcinomas in Vivo”Lancet 1 (8484) :765-767 (Apr. 5, 1986).
`Yonemura et al., “Evaluation of Immunoreactivity for erbB-2 Protein
`as a Marker of Poor Short Term Prognosis in Gastric Cancer” Cancer
`Research 51(3) :1034-1038 (Feb. 1, 1991).
`Zhang et al., “Neuregulin-3 (NRG3): A novel neural tissue-enriched
`protein that binds and activates ErbB4” Proc. Natl. Acad. Sci. USA
`94:9562-9567 (Sep. 22, 1997).
`Zhau et al., “Amplification and Expression of the c-erb B-2/neu
`Proto-Oncogene
`in Human Bladder Cancer” Molecular
`Carcinogenesis 3(5) :254-257 (1990).
`
`* cited by examiner
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 005
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1014 p. 005
`
`
`
`U.S. Patent
`
`Nov. 11, 2008
`
`Sheet 1 of 18
`
`US 7,449,184 B2
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`
`
`
`US. Patent
`
`Nov. 11,2008
`
`Sheet 2 of 18
`
`US 7,449,184 B2
`
`VARIABLE LIGHT
`
`10
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`20
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`40
`
`DTVMTQSHKIMSTSVGDRVSITC [KASQDVSIGVA] WYQQRP
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`FIG._2A
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`
`20
`
`30
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`
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