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`PHIGENIX
`PHIGENIX
`Exhibit 1016
`Exhibit 101 6
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`
`
`Filed on behalf of PhigeniX, Inc.
`Ping Wang, M.D., Esq.
`Gregory Porter, Esq.
`Michael Ye, Ph.D., Esq.
`ANDREWS KURTH, LLP
`
`1350 I Street, NW
`Suite 1100
`
`Washington, DC. 20005
`Tel.: (202) 662-2700
`Fax: (202) 662-2739
`Email: PingWang@AndrewsKurth.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`PHIGENIX, INC.
`Petitioner
`V.
`
`IMMUNOGEN, INC.
`Patent Owner of
`
`US. Patent No. 8,337,856 to Walter Blattler, et al.
`
`Issued on December 25, 2012
`Appl. No. 11/949,351 filed on December 3, 2007
`
`IPR Trial No. 2014-TBD
`
`DECLARATION OF MICHAEL G. ROSENBLUM, PH.D.
`
`PHIGENIX
`
`Exhibit 1016-01
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`
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`I, Michael Rosenblum, Ph.D., do hereby declare as follows:
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`1. After receiving my BS. in chemistry from the University of South
`
`Carolina in 1972, I earned a MS. in pharmacology from the Medical University of
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`South Carolina in 1974 and a Ph.D. in pharmacology from the University of
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`Arizona College of Medicine in 1978.
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`I received my post-doctoral training at the
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`MD Anderson Cancer Center from 1978 to 1981. Currently, I am a Professor and
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`the Head of the Immunopharmacology and Targeted Therapy Laboratory,
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`Department of Experimental Therapeutics, Division of Cancer Medicine, MD.
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`Anderson Cancer Center. I was also previously the Director of Research
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`Development, Department of Experimental Therapeutics, MD. Anderson Cancer
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`Center, from 2008 to 2013.
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`2.
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`I have substantial personal experience in developing immunoconjugates
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`for cancer diagnosis and therapy.
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`I am familiar with the construction of
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`immunoconjugates with non-humanized or humanized monoclonal antibodies, the
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`characterization of such immunoconjugates in both in vitro and in vivo settings.
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`Since 1991, I have conducted and supervised research pertaining to immunotoxins
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`directed against breast cancer and other tumor types. One of my research projects
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`involved the evaluation of in vitro cytotoxicity, pharmacokinetics and in vivo
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`efficacy of immunoconjugates comprising humanized antibodies directed at the
`
`Page 2 of 35
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`PHIGENIX
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`Exhibit 1016-02
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`
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`extracellular domain of ErbB2 in breast cancer cells in vitro and in xenograft
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`models of breast cancer.
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`3.
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`I have authored or co-authored over 188 peer-reviewed publications and
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`obtained 14 US. Patents in the field of immunoconjugates and cancer treatment.
`
`I
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`co-authored a book chapter with one of my graduate students entitled “Design,
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`Development and Characterization of Recombinant Immunotoxins Targeting
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`HER2/new, in Antibody-Drug Conjugates and Immunotoxins: From Pre-Clinical
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`Development to Therapeutic Applications.” I served as Associate Editor of the
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`journal Molecular Biotherapy (2003-2006) and as Senior Editor of Molecular
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`Cancer Therapeutics (2007-2014).
`
`I am currently Associate Editor of
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`Pharmacological Reviews, and I have served as an ad hoc reviewer of several
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`journals including Cancer Research, Clinical Cancer Research, Journal of
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`Immunology, Journal of Pharmacology and Experimental Therapeutics, Molecular
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`Cancer Therapeutics, and Cancer Immunology and Immunotherapy. I also served
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`as a grant reviewer in the US Army Breast Cancer Program from 1995 to 1996,
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`and in the NIH Study Section for cancer immunobiology and immunotherapy from
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`2007 to 2009. Details of my publications and other activities relating to
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`immunoconjugates and breast cancer are listed in the copy of my curriculum vitae
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`which is submitted as an Exhibit to this Declaration (Ex. 1032).
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`Page 3 of 35
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`PHIGENIX
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`Exhibit 1016-03
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`4.
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`I understand that an administrative proceeding in the United States Patent
`
`Office, called an Inter Partes Review, is being requested by PhigeniX, Inc.
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`I make
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`this Declaration in support of PhigeniX, Inc.’s Petition for Inter Partes Review of
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`US. Patent No. 8,337,856 (Ex. 1001).
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`5. My compensation for work with respect to this Inter Partes Review will
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`not be affected by the outcome of this Inter Partes Review. My scientific
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`investigations are funded from several sources, which are set forth in my
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`curriculum vitae (EX. 1032).
`
`6.
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`I have reviewed US. Patent No. 8,337,856 (hereinafter “the ‘856 patent,”
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`Ex. 1001), by inventors Walter Blattler and Ravi Chari and, in particular, Claims
`
`1-8 of the ‘856 patent. In addition, I have reviewed the Declaration of Dr. Mark
`
`Sliwokoswki (EX. 1028) and the Declaration of Dr. Barbara Klencke (EX. 1029).
`
`I have been informed by counsel of PhigeniX that although the ‘856 patent was
`
`filed as application number 11/949,351 on December 3, 2007, I am to evaluate the
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`‘856 patent and claims as though it was filed on March 16, 2000, the earliest
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`priority date claimed by the ‘856 patent. Furthermore, I understand from counsel
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`of PhigeniX that the intended audience for a given patent is a person of “ordinary
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`skill in the art,” as opposed to an expert in the field.
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`Page 4 of 35
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`PHIGENIX
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`Exhibit 1016-04
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`7. In my opinion, a person of “ordinary skill” in the art would be a person
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`having an MD. degree, and/or a Ph.D. degree in a Chemistry-, Pharmacology-, or
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`Biology-related field, and at least five years of experience working with antibodies
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`and immunoconjugates. An individual with such credentials and experience as of
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`March, 2000, would be well versed in techniques for producing immunoconjugates,
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`as well as methods for testing the immunoconjugates in in vitro and in vivo
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`systems.
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`8. As reflected in my curriculum vitae (Ex. 1032), I have substantial
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`personal experience related to immunoconjugates and breast cancer research, both
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`in research and literature review. My observations set forth below are within and
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`supported by my personal knowledge and experience, and may additionally be
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`supported by reference to specific publications. In formulating my opinions, I
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`have considered the literature broadly related to fundamentally important research
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`on immunoconjugates, anti-ErbB2 antibodies and maytansinoids from 1985 to
`
`present. In particular, I have reviewed the following documents:
`
`Exhibit 1001
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`US. Patent 8,337,856 ("the ‘856 patent," Blattler)
`
`Exhibit 1004
`
`Phillips, et al., Cancer Res. 69: 9280-9290 (2008)
`
`(Phillips 2008)
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`Exhibit 1008
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`HERCEPTIN® Label
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`Exhibit 1012
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`Chari, et al., Cancer Res., 1992, 52:127-131 (Chari 1992)
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`Page 5 of 35
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`PHIGENIX
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`Exhibit 1016-05
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`
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`Exhibit 10 13
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`Batra, et al., Proc. Natl. Acad. Sci., USA, 1992, 89:5867-
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`5871 (Batra 1992)
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`Exhibit 10 1 5
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`Chari, et al., Adv. Drug. DeliV. ReV., 1998, 31 (102): 89-
`
`104 (Chari 1998)
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`Exhibit 10 17
`
`US. Patent 5,770,195 (”the ‘195 patent," Hudziak)
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`Exhibit 10 1 8
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`Rosenblum, et al., Clin. Cancer Res., 1999, 5: 865-874
`
`(Rosenblum 1999)
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`Exhibit 10 19
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`Baselga, et al., Cancer Res., 1999, 5: 865-874
`
`(Baselga, 1999)
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`Exhibit 1020
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`Pegram, et al., Oncogene, 1999, 18: 2241-2251
`
`(Pegram, 1999)
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`Exhibit 1 02 1
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`Morgan, et al., Mol. Immunol, 1990, 27 (3): 273-292
`
`(Morgan, 1990)
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`Exhibit 1022
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`Carter, et al., Proc. Natl. Acad. Sci., USA, 1992,89,
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`4285- 4289 (Carter, 1992)
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`Exhibit 1023
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`Liu, et al., Proc. Natl. Acad. Sci., USA, 1996, 93: 8618-
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`8623 (Liu, 1996)
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`Exhibit 1024
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`US. Patent 5,208,020 (the ‘020 patent, Chari)
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`Exhibit 1025
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`US. Application No. 2003/0170325 (Cohen 1999)
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`Exhibit 1028
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`Declaration by Mark Sliwkowski, PhD.
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`Page 6 of 35
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`PHIGENIX
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`Exhibit 1016-06
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`Exhibit 1029
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`Declaration by Barbara Klencke, MD.
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`Exhibit 1030
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`Suzuki et al., Biol Pharm Bull, 1995, 18:1279-1282
`
`(Suzuki 1995)
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`Exhibit 1031
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`Drewinko et al. Cancer Res. 1981, 41,2328-2333
`
`(Drewinko 1981)
`
`9.
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`I have been asked by counsel of Phigenix to form an opinion as to
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`whether it would be obVious to a person of ordinary skill in the art to make and use
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`the immunoconjugate specified in Claims 1-8 of the ‘856 patent, based on the
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`available references and knowledge in the art regarding the huMAb4D5-8 antibody,
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`maytansinoid and antibody-maytansinoid immunoconjugates as of March, 2000.
`
`10. In addition, I have been asked to provide opinions on the “incompatible
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`mechanisms of action theory” described in the Declaration of Dr. Mark
`
`Sliwkoswki (Ex. 1028) and on the “unexpected results” described in the
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`Declaration of Dr. Barbara Klencke (Ex. 1029).
`
`The ‘856 Patent
`
`11. The ‘856 patent purports to describe an immunoconjugate comprising
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`huMAb4D5-8 and a maytansinoid. The immunoconjugate can be used for the
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`treatment of breast cancer. Independent Claim 1 of the ‘856 patent recites an
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`immunoconjugate comprising an anti-ErbB2 antibody conjugated to a
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`Page 7 of 35
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`PHIGENIX
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`Exhibit 1016-07
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`
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`maytansinoid, wherein the antibody is huMAb4D5-8. Dependent Claims 2-8
`
`further recite the structure of the immunoconjugate and a pharmaceutical
`
`composition comprising the immunoconjugate (Ex. 1001, Claims).
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`12. In the 1990s, several investigators published studies describing the
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`construction, characterization and in vitro and in vivo efficacy of numerous
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`antibody-drug conjugates using a variety of different drugs, linker technologies and
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`targeting antibodies. Antibodies targeting the c-erbB2(p185, Her2/neu, Her2)
`
`protooncogene were also well described at that time. In addition, numerous
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`antibody-drug conjugates using a number of cytotoxic moieties including toxins
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`and chemotherapeutic agents had also been published well before the priority date
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`of the ‘856 application. In 1992, Chari et a1. (Chari 1992, Ex. 1012) published a
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`well-documented study describing an antibody-drug conjugate composed of a
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`mouse antibody (designated TAl) targeting the external domain of the human
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`HER2/neu protooncogene. For the drug payload, Chari incorporated a novel,
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`highly potent tubulin inhibitor, maytansine, which is in the class of
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`chemotherapeutic agents with a mechanism of action identical to that of the
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`chemotherapeutic agent Taxol. This study described conjugation conditions for the
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`generation of the conjugate and the addition of between 1 and 6 maytansine drug
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`molecules per antibody molecule and demonstrates the cytotoxic concentrations for
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`each ratio against target tumor cells in culture. This study also explored the impact
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`Page 8 of 35
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`PHIGENIX
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`Exhibit 1016-08
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`
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`of different linkers between the antibody and drug and found excellent, specific
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`cytotoxicity of several conjugates against Her2-expressing breast tumor cells. This
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`cytotoxicity was demonstrated to be dependent on binding of the antibody to the
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`target cells and intracellular delivery of the maytansine molecule. They describe
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`low toxicity of the construct after administration to mice as well as excellent, long-
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`lasting blood levels of the antibody-drug conjugate after administration to mice
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`suggesting excellent stability in vivo and favorable pharrnacokinetics. These are
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`important attributes for any potential cancer therapeutic. Finally, the last sentence
`
`of the Discussion states “The development of “humanized” antibodies will offer an
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`opportunity to produce drug conjugates that would be less immunogenic than
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`similar conjugates of murine antibodies.” The HERCEPTIN® Label teaches a
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`humanized antibody which binds to Her2 (designated huMAB4D5-8) as
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`envisioned by Dr. Chari in Chari 1992 (Ex. 1012, p. 130, bottom left col.). The
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`HERCEPTIN® Label teaches that huMAB4D5-8 is a humanized antibody
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`derivative of the murine 4D5 antibody which selectively binds with high affinity to
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`HER2. Further, huMAB4D5-8 had been approved for use in humans and clinical
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`studies indicated that huMAB4D5-8 works well in combination with microtubule-
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`directed chemotherapy agents for the treatment of breast cancer (Ex. 1008, p. 1,
`
`left col.).
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`Page 9 of 35
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`PHIGENIX
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`Exhibit 1016-09
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`
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`13. It would be obvious to an ordinarily skilled artisan to simply substitute
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`the mouse anti-HER2 mAb TA.1 in the immunoconjugate of Chari 1992 with the
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`humanized mAb huMAB4D5-8 to produce a maytansinoid-huMAB4D5-8
`
`conjugate based on the teachings of Chari 1992 and the HERCEPTIN® Label. An
`
`ordinarily skilled artisan would be motivated to substitute the mouse mAb TA.1 in
`
`the immunoconjugate of Chari 1992 with the humanized mAb huMAB4D5-8,
`
`because it was well known in the art in 2000 (1.6., the time the ‘856 patent was
`
`filed) that compared to mouse mAbs, humanized mAbs exhibited reduced
`
`immunogenicity in human patients. Therefore, humanized mAbs, such as
`
`huMAB4D5-8, were preferred over their mouse-derived counterparts for clinical
`
`applications. Therefore, for the reasons set forth above, it is my opinion that
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`Claims 1-8 of the ‘856 patent describing an antibody-drug conjugate composed of
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`a humanized antibody conjugated with maytansine would be obvious over Chari
`
`1992 (Ex. 1012) and the HERCEPTIN® Label (Ex. 1008).
`
`14. In my opinion, substituting a mouse anti-ErbB2 antibody in an
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`immunoconjugate with a humanized anti-ErbB2 antibody is no more than a simple
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`substitution of one known element for another to obtain predictable results. Indeed,
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`in Chari 1992, the section in Materials and Methods (EX. 1012, p127, col. 2) is
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`entitled “Conjugation of Maytansinoids with Antibodies” envisioning that the
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`described process is generally applicable to all antibodies allowing one skilled in
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`Page 10 of 35
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`PHIGENIX
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`Exhibit 1016-10
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`
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`the art to perform the well-described process to obtain the desired antibody-
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`maytansine conjugate with an antibody:drug ratio of 1-6 and other essential
`
`characteristics described. Therefore, based on the detailed description in Chari
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`1992 and the general knowledge in the art about conjugation of maytansinoids with
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`antibodies, an ordinarily skilled artisan would have known how to substitute the
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`mouse mAb TA.1 in the immunoconjugate of Chari 1992 with huMAB4D5-8 to
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`produce an immunoconjugate of maytansinoid and huMAB4D5-8. For example,
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`the conjugation process described in Chari 1992 can also be used for the
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`production of a maytansinoid-huMAB4D5-8 conjugate. In fact, the general ability
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`of antibodies to serve as specific carriers of toxic molecules directed to tumor cells
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`had been well-known for many years prior to the priority date of the ‘856 patent
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`application. Specifically, it was also well-known that antibodies targeting the Her2
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`cell-surface domain were specific, internalized into tumor cells rapidly upon
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`binding and were effective carriers of a number of toxic molecules. Prior art with
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`respect to published patent applications and issued patents also appear to enVision
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`anti-Her2 antibodies conjugated to cytotoxic moieties for the targeted destruction
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`of Her2 expressing tumor cells. Hudziak describes in US Patent 5,770,195 both
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`murine and humanized antibodies binding to Her2 (Ex. 1017). Claims 2 and19 of
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`the ‘ 195 patent are clearly meant to cover any antibody, including a humanized
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`4D5, “conjugated to a cytotoxic moiety.” In addition, antibodies targeting Her2
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`Page 11 of 35
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`PHIGENIX
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`Exhibit 1016-11
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`
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`had been conjugated to cytotoxic drugs such as the chemotherapeutic agent
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`Adriamycin (Suzuki 1995, Ex. 1030) and protein toxins such as pseudomonas
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`exotoxin (Batra 1992, Ex. 1013).
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`15. In my opinion, an ordinarily skilled artisan would have a reasonable
`
`expectation of success for using huMAB4D5-8-maytansinoid conjugate in the
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`treatment of breast cancer. It had been demonstrated that huMAB4D5-8 is more
`
`effective in treating breast cancer when used in combination with the microtubule
`
`targeting drug, paclitaxel as described in HERCEPTIN® Label (Ex. 1008, p.1, left
`
`col.). Further, Chari 1992’s maytansinoid conjugates were capable of targeting the
`
`same cells as huMAB4D5-8, to deliver a more cytotoxic microtubule targeting
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`drug DMl than paclitaxel (Ex. 1012). In addition, an ordinarily skilled artisan
`
`would recognize that an immunoconjugate containing a “humanized” antibody
`
`would be less immunogenic than an immunoconjugate containing a mouse
`
`antibody and, therefore, render the antibody-maytansinoid immunoconjugate more
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`effective in humans.
`
`16. I also note that Hudziak 1998 (Ex. 1017) discloses that by inhibiting
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`HER2 function with an anti-HER2 4D5 monoclonal antibody, cell growth is
`
`inhibited and the cells are rendered more susceptible to cytotoxic factors such as
`
`the antimicrotubule drug vinblastine (Ex. 1017, col. 5, lines 10-12, col. 6, lines 60-
`
`65). Hudziak 1998 thus teaches a method to inhibit ErbB2 receptor function and
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`Page 12 of 35
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`PHIGENIX
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`Exhibit 1016-12
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`
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`sensitize the tumor cells to increased cell death by administering an anti-HER2
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`antibody in combination with a chemotherapeutic agent, such as the
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`antimicrotubule drug vinblastine.
`
`17. Further, before the priority date of the ‘856 patent, I myself described
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`(Rosenblum 1999, Ex. 1018) immunotoxins (L6, immunoconjugates) comprised of
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`either a murine or a humanized monoclonal antibody directed against the
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`extracellular domain of ErbB2 (TAB-250 and EACH-250 respectively) chemically
`
`conjugated to the ribosome-inhibiting plant toxin gelonin (rGel). Both conjugates
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`containing the murine TAB-250 and humanized EACH-250 immunoconjugates
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`were internalized efficiently in the SKBR-3 breast cancer cell line, the same cells
`
`responsive to Herceptin®. In addition, of the six different cell lines expressing
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`various levels of the ErbB2 receptor, the cytotoxic activity of the TAB-250 and the
`
`EACH-250 immunoconjugates was highest against the SKBR-3 cell line (Ex. 1018,
`
`p. 869, left col). We also conducted in vivo studies utilizing a tumor cell line
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`(SKOV-3) overexpressing ErbB2/HER-2 at levels that may approximate those
`
`found in patients with HER2 overexpressing tumors. Under these circumstances,
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`the immunotoxin was found to have impressive antitumor effects, as compared
`
`with the tumor growth behavior seen in the control groups in both the
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`subcutaneous (sc) tumor model and the intraperitoeneal (lip) tumor model (Ex.
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`1018, Abstract, p. 871, bottom right col. and Figs. l2, 13). In particular, in
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`Page 13 of 35
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`PHIGENIX
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`Exhibit 1016-13
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`
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`athymic mice bearing s.c. or i.p. SKOV-3 tumors, immunotoxin treatment of the
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`corresponding mouse Ab derived immunoconjugate slowed tumor growth by 99%
`
`and 94% at days 35 and 49 after implantation, respectively, and lengthened the
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`median survival by 40% (from 30 to 50 days) in mice bearing lethal i.p. tumors
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`(Ex. 1018, Abstract, Figs. 12 and 13). In this study, we clearly demonstrate the
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`interchangeable equivalence of a murine antibody and its humanized counterpart
`
`both binding to the HER2 target.
`
`18. The teachings from Hudziak 1998 and Rosenblum 1999 provide further
`
`motivation and rationale for an ordinarily skilled artisan to substitute the anti-
`
`ErbB2 mouse mAb in the immunoconjugate of Chari 1992 with the humanized
`
`anti- ErbB2 mAb described in the HERCEPTIN® Label. There would have been a
`
`reasonable expectation of success for doing so, at least for the reasons discussed
`
`above and further in view of the in vivo efficacy data of a similar
`
`immunoconjugate provided by Rosenblum 1999 (Ex. 1018, Figs. 12 and 13).
`
`19. In 1998, Baselga et al. (Baselga 1998, Ex.1019) demonstrated that
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`treatment of HER2 positive tumor cells with HERCEPTIN sensitized these cells to
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`the cytotoxic effects of the chemotherapeutic agents taxol and doxorubicin. This
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`was an extension of their previous work which demonstrated similar findings with
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`an antibody to HERl which also resulted in increased sensitivity to doxorubicin
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`and taxol(Ex.1019, p2825, right column, line 15). An enhanced, concentration-
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`Page 14 of 35
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`PHIGENIX
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`Exhibit 1016-14
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`
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`dependent inhibition of growth in cultures of ErbB2 overeXpressing human cancer
`
`cell lines was observed. The combination treatment showed striking antitumor
`
`effects in breast carcinoma xenografts, resulting in the cure of well-established
`
`tumors (Ex. 1019, p. 2825, right col., 2nd para). Baselga 1998 teaches that “[t]he
`
`simplest explanation for the observed interaction between paclitaxel and rhuMAb
`
`HER2 is that it is the result of the summation of effects of two anticancer drugs
`
`that act on different targets; rhuMAb HER2 acts on the HER2 receptor signaling
`
`pathway and paclitaxel acts on tubulin” (EX. 1019, paragraph abridging pp. 2829-
`
`2830).
`
`20. Pegram et al. (Pegram 1999, EX. 1020) discloses in vivo studies
`
`addressing ways to optimize the use of HERCEPTIN® in combination with a
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`variety of established cancer therapeutics, including antimicrotubule
`
`chemotherapeutic agents paclitaxel (TAX) and vinblastine (VBL)(EX. 1020, p.
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`2241, right col., p. 2242, right col.). Significantly superior anti-tumor efficacy of
`
`HERCEPTIN® in combination with TAX, VBL and a number of other
`
`chemotherapeutic agents was observed when compared to effects of
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`HERCEPTIN® alone or each chemotherapeutic drug alone (Ex. 1020, p. 2248,
`
`paragraph abridging left and right cols.). Pegram 1999 teaches that most of the
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`HERCEPTIN®/drug combinations demonstrate additive interactions, suggesting
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`that the majority of the observed antiproliferative effects are due to a mechanism of
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`Page 15 of 35
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`PHIGENIX
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`Exhibit 1016-15
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`
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`action involving each agent acting independently. In particular, Pegram 1999
`
`notes that the mechanisms of action of many of the drugs demonstrating additivity
`
`do not involve direct DNA damage, but rather disruption of microtubule
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`polymerization/depolymerization (taxanes and vinca alkaloids) (Ex. 1020, p. 2248,
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`left col. 2nd para). Pegram 1999 specifically teaches that “[t]he synergistic
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`interaction of rhuMab HER2 with alkylating agents... .as well as the additive
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`interaction with taxanes,
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`in HER-Z/neu-overexpressing breast cancer cells
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`demonstrates that these are rational combinations to test in human clinical trials”
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`(Ex. 1020, Abstract, emphasis added).
`
`21. Baselga 1998 states, “ The mechanisms responsible for the observed
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`interaction between paclitaxel and rhuMAB HER2 are unknown” ( Ex. 1019,
`
`p2829, last column, last para), and Pegram 1999 postulates that the interaction may
`
`involve DNA repair activity, but neither provide direct experimental data in
`
`support for these hypotheses. It is my opinion that Baselga 1998 and Pegram 1999
`
`suggest that HERCEPTIN® and maytansinoid may act in concert through a
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`mechanism that was not well-defined at the time of the priority date of the ‘856
`
`patent. However, what was clear at the time was that the Herceptin antibody and
`
`the class of chemotherapeutic agents having microtubule inhibition mechanism (eg
`
`taxol and maytansines) have an additive effort in inhibiting the growth of breast
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`tumor cells in vitro and in vivo. According to the HERCEPTIN® Label, clinical
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`Page 16 of 35
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`PHIGENIX
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`Exhibit 1016-16
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`
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`trial results of combination therapy of the microtubule inhibitor TAXOL and the
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`HERCEPTIN® antibody demonstrate better clinical efficacy than either agent alone,
`
`confirming the Baselga and Pegram observations in vitro and in tumor xenografts.
`
`These references and the HERCEPTIN® Label add further weight to the motivation
`
`and expectation of success for modifying Chari 1992’s TA. 1-maytansinoid
`
`conjugate into a HERCEPTIN®-maytansinoid conjugate as suggested by the
`
`combined teachings of Chari 1992 and the HERCEPTIN® Label.
`
`22. Well before the priority date of the ‘856 application and continuing to
`
`the present, linker technology for the creation of antibody drug conjugates and
`
`antibody toxin conjugates has continued to evolve. Morgan et al. (Morgan 1990,
`
`Ex. 1021) compares linkage properties for immunoconjugates comprising disulfide
`
`or thioether bonds linking a monoclonal antibody to a Pseudomonas toxin.
`
`Morgan 1990 teaches that “[t]he efficiency and kinetics of thioether formation
`
`were much higher with SMCC than with other maleimide reagents as well as more
`
`efficient than disulfide linkers. Thioether linkage resulted in immunotoxin
`
`consistently more potent and more selective in vitro than disulfide bonded
`
`conjugates. In addition, thioether bonded conjugates also proved to have other
`
`favorable in vivo properties compared to disulfide conjugates: (1) a longer half-life
`
`in serum; (2) increased tumor localization; and (3) reduced toxicity” (Ex. 1021,
`
`Abstract).
`
`Page 17 of 35
`
`PHIGENIX
`
`Exhibit 1016-17
`
`
`
`23. It is my opinion that, in view of the combined teachings of Chari 1992,
`
`HERCEPTIN® Label and Morgan 1990, it would have been particularly obvious
`
`for an ordinarily skilled artisan to select Chari’s thioether-bonded
`
`immunoconjugate (TA.1(noncleavable linker-May)4) for substitution with the
`
`HERCEPTIN® antibody in HERCEPTIN® Label because HERCEPTIN®
`
`antibody will reduce the immunogenicity of the immunoconjugate and the
`
`noncleavable SMCC linker would provide more favorable in vivo properties, such
`
`as longer half-life, increased tumor localization and reduced toxicity, compared to
`
`disulfide conjugates (Ex. 1021, abstract).
`
`24. Although Chari 1992 notes that the TA.1(noncleavable linker-May)
`
`conjugate was less potent than the TA. 1(cleavable linker-May) conjugate in an in
`
`vitro cytotoxicity assay (Ex. 1012, page 129, left col.), it is unclear whether this
`
`difference is also present in an in vivo setting. A compromise between a slight
`
`decrease in the in vitro activity to attain favorable pharrnacokinetics, increased
`
`stability and improved in vivo efficacy would be easily justified by one of ordinary
`
`skill in the art. Further, in view of the highly potent nature of maytansinoids (lle. ,
`
`100- to 1000-fold higher cytotoxicity) (Ex. 1012, Abstract), one would,
`
`nevertheless, have a reasonable expectation of success with respect to potency and
`
`toxicity.
`
`Page 18 of 35
`
`PHIGENIX
`
`Exhibit 1016-18
`
`
`
`25. In my opinion, Claims 1-8 would be obvious over Chari 1992 (EX. 1012)
`
`and Carter 1992 (EX. 1022). As noted above, Chari 1992 teaches that the anti-
`
`ErbB2 antibody-maytansinoid conjugates exhibited high antigen-specific
`
`cytotoxicity for cultured human breast cancer cells, low systemic toxicity in mice,
`
`and good pharmacokinetic behavior (EX. 1012, Abstract). Carter 1992 teaches that
`
`mouse monoclonal antibody mumAb4D5 selectively binds to HER2, and that the
`
`efficacy of mumAb4D5 in human cancer therapy is likely to be limited by a human
`
`anti-mouse antibody response and lack of effector functions. Carter 1992 further
`
`teaches that humAB4D5-8 is much more efficient in supporting antibody-
`
`dependent cellular cytotoxicity against SK-BR-3 cells than mumAb4D5 (EX. 1022,
`
`Abstract). In addition, humAB4D5-8 had been approved for use in humans and
`
`clinical studies indicated that humAB4D5-8 works well in combination with
`
`microtubule-directed chemotherapy agents for the treatment of breast cancer (EX.
`
`1008, p. 1, left col.).
`
`26. Therefore, based on the teachings of Chari 1992 and Carter 1992, it
`
`would be obvious to an ordinarily skilled artisan, at the time the ‘856 patent was
`
`filed, to substitute the mouse mAb TA.1 in the immunoconjugate of Chari 1992
`
`with the humanized mAb humAB4D5-8 of Carter 1992, because the efficacy of
`
`mouse mAb TA.1 in human cancer therapy is likely to be limited by a human anti-
`
`mouse antibody response and because humAB4D5-8 has been shown to be
`
`Page 19 of 35
`
`PHIGENIX
`
`Exhibit 1016-19
`
`
`
`effective in supporting antibody-dependent cellular cytotoxicity against her2
`
`positive tumor cells. As discussed above, an ordinarily skilled artisan would know
`
`how to make such conjugate and would have a reasonable expectation of success
`
`with respect to potency and toxicity of the conjugate.
`
`27. In my opinion, Claims 1-8 would also be obvious over Liu et 01]., (Liu
`
`1996, Ex. 1023) and the HERCEPTIN® Label (Ex. 1008). Specifically, Liu 1996
`
`discloses an immunoconjugate comprising a maytansinoid chemically linked to an
`
`antibody (Ex. 1023, Fig. 1). Liu 1996 further discloses that the maytansinoid is
`
`DM1 and that the antibody is chemically linked to the maytansinoid via a disulfide
`
`at “R” position and that the immunoconjugate comprises 4 maytansinoid molecules
`
`per antibody molecule (Ex. 1023, p 8619, right col. para 4). Liu 1996 also
`
`discloses that the antibody and the maytansinoid are conjugated by a chemical
`
`linker SPDP (Ex. 1023, p. 8618, right col. para. 3, cited reference 15 1). While Liu
`
`1996 does not explicitly mention huMAB4D5-8, HERCEPTIN® Label describes
`
`the clinical use of humAB4D5-8 for the treatment of patients with metastatic breast
`
`cancer.
`
`1 Ref 15 is US 5,208,020 (Ex. 1024) which provides a disulfide-containing
`
`maytansinoid-antibody conjugate with SPDP linker (Ex. 1024, col. 11, lines 25-
`
`30 and col. 21, lines 15-25).
`
`Page 20 of 35
`
`PHIGENIX
`
`Exhibit 1016-20
`
`
`
`28.
`
`It would be obvious to an ordinarily skilled artisan, at the time the ‘856
`
`patent was filed, to substitute the C242 antibody (which binds to the CanAg of
`
`colon cancer cells) in the immunoconjugate of Liu 1996 with the humanized mAb
`
`huMAB4D5-8 for the treatment of breast cancer. Liu 1996 would provide all
`
`necessary guidance to an ordinarily skilled artisan, at the time the ‘856 patent was
`
`filed to allow the production of a pharmaceutical composition comprising the
`
`maytansinoid-huMAB4D5-8 conjugate and a pharmaceutically acceptable carrier,
`
`based on the teachings of Liu 1996 and HERCEPTIN® Label, as well as the
`
`general knowledge in the art at that time. An ordinarily skilled artisan would be
`
`motivated to substitute the C242 antibody in the immunoconjugate of Liu 1996
`
`with the humanized mAb huMAB4D5-8 for the treatment of breast cancer, because:
`
`(1) the immunoconjugate of Liu 1996 is highly cytotoxic towards cultured cancer
`
`cells in an antigen-specific manner and shown remarkable anti-tumor efficacy in
`
`vivo (EX. 1023, Abstract); (2) huMAB4D5-8 selectively binds to ErbB2 with high
`
`affinity and has been approved for use in humans (EX. 1008, p. 1, left col), and (3)
`
`clinical studies indicated that huMAB4D5-8 works well in combination with
`
`microtubule-directed chemotherapy agents for the treatment of breast cancer (EX.
`
`1008, p. 1, left col.).
`
`Page 21 of 35
`
`PHIGENIX
`
`Exhibit 1016-21
`
`
`
`29. There would have been a reasonable expectation of success for an
`
`immunoconjugate comprising huMAB4D5-8 conjugated to a microtubule-targeting
`
`drug, such as maytansinoid, because huMAB4D5-8 is effective in treating breast
`
`cancer when used in combination with the microtubule targeting drug, paclitaxel
`
`(Ex. 1008) and maytansinoid is also a microtubule targeting drug but is more
`
`potent than anticancer drugs that were in clinical use at that time (Ex. 1023,
`
`Abstract). Further, huMAB4D5-8 selectively binds to ErbB2 with high affinity
`
`and has been approved for use in humans (Ex. 1008, p. 1, left col.). In addition, an
`
`immunoconjugate containing an “humanized” antibody would be less
`
`immunogenic in humans.
`
`30. In addition, studies by Morgan (Morgan 1990) teach that higher doses of
`
`immunoconjugates containing the non-cleavable succinimidyl-4-(N—
`
`maleimidomethyl) cyclohexane-l-carboxylate (SMCC) linker could be safely
`
`administered to primates, while providing a markedly improved yield, thereby
`
`improving the eventual efficiency and cost effectiveness of therapy with these
`
`agents (Ex. 1021, page 274, left col). Morgan 1990 noted, “[w]hen tested for
`
`toxicity in both mice and monkeys, thioether conjugates were consistently 2-10
`
`fold less toxic than comparable disulfide conjugates” (Ex. 1021, page 280, right
`
`col). Morgan 1990 further teaches that “[t]he evidence from both long term (3
`
`days or more) in vitro assays and animal toxicology experiments suggests that
`
`Page 22 of 35
`
`PHIGENIX
`
`Exhibit 1016-22
`
`
`
`significant disruption of disulfide bonds can occur, leading to the release of PE that
`
`appears to be more toxic in free than conjugated form” and that “thioether bonded
`
`conjugates had a significantly longer serum half-life than disulfide conjugates,
`
`additional evidence for disulfide bond reduction in viva” (EX. 1021, page 281, left
`
`col.). In view of the combined teachings of Liu 1996, HERCEPTIN® Label and
`
`Morgan 1990, it would have been obvious for an ordinarily skilled artisan to
`
`prepare a HERCEPTIN®-maytansinoid immunoconjugate with an SMCC linker
`
`for the treatment of breast cancer, because HERCEPTIN® antibody will reduce the
`
`immunogenicity of the immunoconjugate and the noncleavable SMCC linker
`
`would provide more favorable in vivo properties, such as longer half-life, increased
`
`tumor localization and reduced toxicity, compared to disulfide conjugates (EX.
`
`1021, abstract).
`
`31. In my opinion, Claims 1-8 would be obvious over Cohen 1999 and
`
`Chari 1992. In particular, Cohen 1999 teaches immunoconjugates comprising a
`
`maytansinoid chemically linked to an antibody (Ex. 1025, para [0113]) and
`
`humanized versions of the murine anti-ErbB2 antibody 4D5 (huMab4D5-8) (EX.
`
`1025, para [0155]). C
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