THE UNITED ST ATES PATENT AND TRADEMARK OFFICE
`
`Applicant
`Serial No.
`Filing Date
`Customer No.:
`Title:
`
`10/356,824
`
`Virginia E. Paton
`
`Attorney Docket#:
`Group Art Unit
`Examiner:
`02/03/2003
`Confirmation No.:
`35489
`TREATMENT WITH ANTI-ErbB2 ANTIBOD.IES
`
`GNE-0329RIDI
`1643
`Holleran, Anne L.
`4326
`
`FILED VIA E~'S - OCTOBER 15, 2009
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`DECLARATIQN: OF MARK X. SLIWKOW~~IJ>h.D.
`
`Tj MARK X. SLIWKOWSKI, Ph.D. declare and say as follows: -
`
`I obtained a B.S. in Animal Science and Agricultural Biochemistry from the
`l.
`University of Delaware, a Ph_D. in Biochemistry with minor in Physical Chemistry from North
`Carolina State University, and completed postdoctoral training at the National Institutes of
`Health, National Heart, Lung and Blood Jnstimte, Laboratory of Biochemistry.
`
`After six years of research experience at Triton Biosciences, Inc. (Berlex
`2.
`Biosciences, Jnc.), I joined Genentech, lnc. in I 991 as a senior scientist, where my current title is
`Staff Scientist, Research Oncology.
`
`During my employment at Genentech, l have worked on a number of programs
`3.
`involving drugs directed against the human epidermal growth factor receptor family (also known
`as the HER or ErbB family). The HER or ErbB family, is frequently activated in a number of
`proliferative diseases including cancer. Our laboratory focuses on studying various aspects of
`this receptor activation process including the biochemical nature of the receptor complexes, the
`activation of signal transduction pathways, and the resultant biological outcomes. These
`
`UBC/3691560.1
`
`Declaration ofMiirk X. Sliwkowski, Ph.D.
`U.S. Application No. 10/356,824
`Attomey Docket No. GNE-0329R1DI
`
`1 of 98
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`investigations have contributed to the development of a number of therapeutic approaches that
`target the receptor family such as Herceptin® (trastuzumab) and Tarceva® (crlotinib), which
`have received U.S. Food and Drug Administration (FDA) approval. Working closely with the
`Molecular Diagnostics and Pathology Departments, our current effort deals primarily with
`identifying a molecular profile that may aid in selecting patients who benefit from treatment with
`the dimcrization inhibitor anti-HER2 antibody, pertuzumab. We are also actively investigating
`combination therapeutic approaches for the treatment of cancer.
`
`My Scientific Curriculum Vitae, including my lb1 of publications, patents,
`4.
`pending patent applications, and awards, is enclosed as Exhibit A and forms part of this
`Declaration.
`
`lam familiar with and understand the disclosure of the above-identilied patent
`5.
`application, including the claims currently pending. I am also familiar with and understand the
`Office Action mailed on March 20, 2009 in connection with the above-identified patent
`application, and the prior art references cited in that Office Action. The pending claims are
`directed to the treatment of human patients with breast cancer that overexpresses ErbB2 by
`administration of a combination of an anti-ErbB2 antibody, a tax.aid, and a further therapeutic
`agent, such as a growth inhibitory agent, where the anti·ErbB2 antibody binds cpitopc 405
`within the ErbB2 extracellular domain sequence. A prototype of antibodies that binds epitope
`405 within the ErbB2 extracellular domain sequence is Herceptin® (trastuzumab), and
`representative taxoids are paclitaxel and docctaxcl.
`
`According to the Office Action, the invention claimed would have been obvious
`6.
`to one of ordinary skill in the art at the time the invention was made. Ooe of the references cited
`in support of this conclusion is an Abstract by Baselga, J, et al (Proceedings of the American
`Association for Cancer Research, 35:380, Abstract #2262, 1994), which reports on the antitumor
`activity of paclitaxel and docetaxel in combination with the murine anti-HER2 antibody 4D5 in
`the treatment of human breast cancer xenografls in nude mice. According to the authors, their
`results suggest synergy between paclitaxel and 4D5,
`
`LIBC/369 J 560, 1
`
`2
`
`Declaration of Mark X. Sliwkowski, Ph.D.
`U.S. Application No. 10/356,824
`Att\)rney Docket No. GNE-0329RlD1
`
`2 of 98
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`Drugs used in the tTeatment of cancer are known to exert their effects at different
`7.
`points within the cell cycle. For example, mitotic inhibitors, such as taxoids, stabilize
`microtubules in their polymerized state and lead to a G2/M block in the cell cycle. In contrast,
`so called "targeted therapies" such as tamoxifon and trastuzumab, arrest cells in the CJO~G l/S
`transition of the cell cycle. Before the 1997 priority date of this application, it was known that
`treatment of cancer cells with paclitaxel (Taxol®) disrupts the formation of normal spindles at
`metaphase, leading to arrest of the cells in the G2/M phase of the cell cycle and ultimately to
`apoptotic cell death (see, e.g. Woods et al., Mol. Med. 1 :506-526, 1995 - Exhibit B). It was
`forther known that antibody 4D5 has cytostatic eftcct, i.e. inhibits cell growth (Huzdiak ct al.,
`Molecular and Cellular Biology 9(3):1165-1172, 1989-.Exhibit C). It was also reported that
`treatment with 4D5 antibody reduces the percentage of tumor cells in the S phase of cell cycle,
`which precedes the 02 phase (see, e.g. Lewis et al., Cancer Research 56: 1457-1465, 1996 "'~
`.Exhibit D). These initial findings were subsequently confirmed and refined by Lane, Heidi A.,
`ct al., (Molecular and Cellular Biology, 20(9):3210-3223, 2000-Exhibit E) and others. Based
`on the pre-1997 reports, at the priority date of this application a skilled scientist would have
`anticipated that pacHtaxcl would provide little or no additional benefit to treatment with
`trastuzumab alone, since trastuzumab would arrest the cell cycle before paclitaxel would be able
`to act
`
`An antagonistic interaction between trastuzumab and paclitaxel would have been
`8.
`viewed as a reasonable possibility based on prior knowledge, such as prior experience with the
`combined administration oftamoxifen and anthracyclines. Tamoxifen is used in women with
`breast cancer whose tumors express the estrogen receptor. Binding of tamoxifon inhibits
`estrogen from binding to estrogen receptor and prevents its ability to promote cell cycle
`progression. Women, who are first diagnosed with breast cancer, are now treated with multiple
`therapeutic modalities that frequently include surgery, radiation, chemotherapy, endocrine
`therapy, and monoclonal antibody therapy. Two decades ago it was recognized that the addition
`of the anti-estrogen, tamoxifen, to standard chemotherapy regimens resulted in little or no benefit
`with either advanced breast cancer or in the adjuvant setting. (Osborne et al., Journal Clinical
`Oncology, 7(6):710-717 ( 1989) - Exhibit F) A mechanistic basis for this apparent antagonism
`that is observed in the clinic was provided by Woods et al. (Biochem Pharmacol 47(8):1449-
`3
`
`Declaration of Mark X. Sliwkowski, Ph.D.
`l.J.S_ Application No. 10/356,824
`Attorney Docket No. GNF.-0329RlD1
`
`LIBC/3691560.1
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`1452, 1994 - Exhibit G). In this report, experimental data demonstrated that the antagonism
`with anthracyline and tamoxifen is likely related to the capacity oftamoxifen to decrease the
`growth of estrogen-receptor positive tumors and to an-est these cells in the GO-G 1 phase of the
`cell cycle, so that the cell cycle is arrested before the anthracyclines could exert their activity.
`Based on the antagonistic interaction between tamoxifen and anthracyclines~ despite the 1994
`Baselga et al. abstract, one of ordinary skill at the priority date of the present application would
`have had reasons to expect that trastuzumab, or other m1ti-HER2 antibodies acting by inducing
`cell cycle arrest in the G 1 phase, would antagonize the effect of taxoids, such as paclitaxel, since
`they arrest cell cycle before it reaches the G2/M phase, where taxoids exert their apoptotic
`antitumor activity.
`
`ln addition, even in the absence of knowledge about the seemingly incompatible
`9.
`mechanisms of action of taxoids and trastuzumab, based on the data reported in the Baselga et al.
`1994 abstract one of ordinary skill at the priority date of this application would not have had a
`reasonable expectation of successfully using a combination of a i:axoid, and an anti~ ErbB2
`antibody that binds cpitope 405 within the ErbB2 extracellular domain sequence, along with an
`additional growth inhibitory agent in the treatment of human patients with ErbR2 overexpressing
`cancer. Although human tumor xenografts have been extensively LL')ed for rapid screening of the
`efficacy of anticancer drugs, significant controversy exists about the usefulness of these
`preclinical models in predicting response of human patients to therapy, because many agents
`which show high activity in xenograft models prove to be inactive, or show disappointingly low
`or different activity, in the clinical setting. Thus~ for example, after a decade of screening in
`various preclinical models, scientists of the National Cancer Institute reported that their
`xenograft models had only moderate predictive value. (Johnson, JL, et al, British Journal of
`Cancer (2001) 84(1 ), 1424-1431 - Exhibit H) According to the authors, "[ff or 39 agents with
`both xenograft data and Phase Tl clinical trial results available, in vivo activity in a particular
`histology in a tumour model did not closely correlate with activity in the same human cancer
`histology, casting doubt on the correspondence of the pre-clinical models to clinical results."
`(Abstract) Indeed, while breast cancer xenografts are described as most useful for predicting
`clinical response against any disease; correlation with clinical activity was found against NSCL,
`melanoma, and ovarian cancer, but not with clinical breast cancer! (page 1426; 2nd column)
`4
`
`Declaration ~)fMark X. Sliwkowski, Ph.D.
`U.S. Application No. 10/356,824
`Attorney Docket No. GNE-0329RlDl
`
`LIBC/3691560.1
`
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`Based on my many years of personal experience and familiarity with the development of
`anticancer drugs, individual xenogratl models of human tumors, such as the breast cancer
`xenograft model used by Baselga et al., do not mimic closely enough the biological
`characteristics and do not capture the inherent variability of human tumors, which greatly limits
`their value in predicting patient response in a human clinical situation. This unpredictability
`applies not only to the testing of single agents, but also to the combinations of two or more
`anticancer agents, essentially for the same reasons.
`
`On the basis of the explanation set forth in paragraphs 7-9 of this Declaration, and
`10.
`the enclosed evidence, it is my considered scientific opinion that the xenograft data reported in
`the 1994 Baselga Abstract would not have motivated one of ordinary skill in the art at the
`priority date of the present application to treat a human breast cancer patient whose cancer
`overexpresses ErbB2 with combined administration of an antibody that binds to epit.ope 405
`within the ErbB2 extracellular domain and a taxoid. It is further my considered scientific
`opinion that, while at the 1997 priority date of this patent application, the clinical efficacy of 4D5
`and paclitaxel, as single agents, in the treatment of human breast cancer was demonstrated, one
`of ordinary skill at that time would not have had a reasonable expectation that a combination of
`an anti-ErbB2 antibody binding to the 405 epitope and a taxoid, such as paclitaxel could be
`successfully used to treat human breast cancer patients, or that the reported synergistic
`interaction between 405 and paclitaxel would also hold true to human breast cancer patients.
`
`I declare further that all statements made in this Declaration of my own
`11.
`knowledge are true and that all statements made on information and belief are believed to be true
`and further, that these statements are made with ihe knowledge that winful statements and the
`like so made are punishable by fine or imprisonment, or both, rn~dcr Section 1001 of Title 18 of
`the United States Code and that such willful false statements may jeopardize the validity of the
`application or any patent granted thereon.
`
`MARK X. SLTWKOWSKI, Ph.D.
`
`5
`
`Declaration of Mark X. Sliwkowski. Ph.D.
`U.S. Application No. 10/356,824
`Attorney Docket No. GNE-0329R.ID l
`
`LlBC/3691560, I
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`EXHIBIT A
`EXHIBIT A
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`MARK X. SLIWKOWSKI
`
`Home
`42 Oak Creek Lane
`San Carlos, CA 94070
`650 / 364-8217
`
`Genentech, Inc.
`Research Oncology
`1 DNA Way, MS 72 Room 10.489
`South San Francisco, CA 94080
`650/225-1247 Ph.
`650 / 438-4759 Cell
`650/225-5770Fax
`marks@gene.com
`
`EDUCATION
`National Institutes of Health (1982-1985)
`National Heart, Lung and Blood Institute, Laboratory of Biochemistry
`Staff Fellow with Dr. Thressa C. Stadtman
`
`North Carolina State University (1978-1981)
`Ph.D. in Biochemistry with minor in Physical Chemistry
`Advisor: Dr. Harold E. Swaisgood
`
`University of Delaware (1972-1976)
`B.S. in Animal Science and Agricultural Biochemistry (Pre-Vet)
`
`EXPERIENCE
`
`GENENTECH, INC.
`
`Staff Scientist
`
`2002-present
`
`HER3-EGFR Dual Antibody Project (DAF) (2006-present) Late Stage Research Team Leader
`responsible for moving project into Early Clinical Development (ECD). Current member of ECD
`core team.
`
`Armed Antibody Program (2003-present) Lead multi-disciplinary research and development team
`efforts to assess arming monoclonal with cytotoxic agents. Served as the major liaison in
`coordinating collaboration with outside companies.
`
`Trastuzumab-DM1 Program (2004) Research team leader and early development team leader.
`Considered prototype for armed antibody platform. Current member of T-DM1 core team.
`Participate in development program.
`
`Director
`
`2003-2008
`
`Formed Translational Oncology Department. Managed expansive growth from 2004-2007, including
`small molecule expertise. Managed Director of Assay & Automation Technology from 2005-2007.
`
`Senior Scientist
`
`1991-2001
`
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`MARK X. SLIWKOWSKI
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`Curriculum Vitae
`Page2
`
`Heregulin (1991-1996) Participated in the initial characterization of heregulin. Helped define a role
`for HER2/ErbB2 as a co-receptor with HER3, HER4 and EGFR.
`
`HERCEPTIN® (1993-present) Member of the core project team throughout Phase II and Phase III
`clinical development. Responsibilities included studies on the development of an in vitro diagnostic
`assay, mechanism of action, mechanism of cardiotoxicity, coordinating biological and biochemical
`assays, obtaining data to support new clinical indications and designing studies to test novel
`chemotherapeutic combinations. Also responsible for managing all extramural research activities.
`
`Pertuzumab (1997-present) As part of our heregulin studies, recognized the potential of blocking
`ligand-activated HER2 as an anti-cancer therapy. Led research and developmental research teams.
`Participated on developmental assessment team that resulted in rhuMAb 2C4/ pertuzumab being
`moved into development in August 2000. Helped facilitate Roche decision to co-develop rhuMAb
`2C4. Currently lead research effort and serve on pertuzumab core team.
`
`Tarceva®(2000-2007) One of several Genentech employees that encouraged Business Development
`to pursue in-licensing OSI-774. Participated in due diligence team. Led research effort on Tarceva
`and serve on Tarceva core team.
`
`Triton Biosciences, Inc. (Berlex Biosciences, Inc.)
`
`Staff Scientist
`1990 -1991
`Initiated a program for the identification and isolation of ligands for receptor tyrosine kinases.
`Participated in project to establish structure-activity relationship for TGFa. Supervised protein and
`peptide chemistry laboratories consisting of 2 scientists and 5 research associates.
`
`Senior Research Scientist
`1987 - 1990
`Project Leader for development stage of HTL V-1 program. (Interdisciplinary team consisting of 3
`scientists and 8 research associates.) Developed folding procedure for TGFa. Collaborated
`extensively with Immunology group on projects involving differentiation and cytotoxicity.
`
`Research Scientist
`1985 - 1987
`One of the first bench scientists hired. Established protein chemistry laboratory purified
`recombinant retroviral proteins for development of diagnostic viral immunoassay.
`
`NIH Postdoctoral Position
`1982 -1985
`Studied mechanisms by which selenium is incorporated into bacterial proteins. Purified several
`selenium-containing proteins and gained extensive experience in peptide mapping.
`
`AWARDS
`Genentech Inc. Outstanding Commercial Collaborator Award, 2008
`North Carolina State University Outstanding Alumni Award, 2008
`Genentech Inc. Most Commercially Significant Patent Award, 2007 (Patent No. 7,097,840)
`Genentech Inc. Most Commercially Significant Patent Award, 2006 (Patent No. 6,949,245)
`Industry Scientist of the Year, Pharmaceutical Achievement Award, 2005
`Triton R&D Award, 1989
`Industrial Initiative for Science and Math Education Award, 1989
`American Society of Biological Chemistry Travel Grant, 1985
`Phi Lambda Upsilon Chemistry Honor Society, 1981
`Gamma Delta Sigma Agricultural Honor Society, 1981
`
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`MARK X. SLIWKOWSKI
`
`Curriculum Vitae
`Page3
`
`Outstanding Graduate Student Teaching Award, 1979
`
`PROFESSIONAL AFFILIATIONS
`American Society of Clinical Oncology
`American Association for Cancer Research
`American Society for Biochemistry and Molecular Biology
`
`INVITED PRESENTATIONS (SINCE 2006)
`Van Andel Research Institute, Grand Rapids, June 2009
`Keystone Symposium, Whistler, BC, March 2009
`European Antibody Congress, Geneva, December 2008
`Istituto Nazionale Tumori of Milan, April 2008
`Oncology Leaders' Forum Boston, November 2007
`ASTRO Los Angeles, October 2007
`F ASEB Symposium, Tucson, August 2007
`ESMO Congress, Istanbul, Turkey October 2006
`Congress of the International Assoc. for Breast Cancer Research, Montreal September 2006
`SPORE Breast Cancer Workshop, Baltimore, July 2006
`Stanford University May 2006
`Chair of New Biological Agents on the Horizon AACR Annual Meeting, Washington DC, April 2006
`Conference on Obstacles to Translational Medicine, San Francisco, March 2006
`Vanderbilt University, January 2006
`
`PEER REVIEW ACTIVITIES
`Department of Defense Breast Cancer Program
`Nature ad hoc
`Oncogene ad hoc
`Cancer Research ad hoc
`Clinical Cancer Research ad hoc
`Cancer Cell ad hoc
`
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`MARK X. SLIWKOWSKI
`
`PUBLICATIONS
`
`Curriculum Vitae
`Page4
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`1.
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`4.
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`7.
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`11.
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`Yao E, Zhou W, Lee-Hoeflich ST, Truong T, Haverty PM, Eastham-Anderson J, Lewin-Koh N, Gunter
`B, Belvin M, Murray LJ, Friedman LS, Sliwkowski MX, Hoeflich KP. Suppression of HER2/HER3-
`mediated growth of breast cancer cells with combinations ofGDC-0941 PBK inhibitor, trastuzumab, and
`pertuzumab. Clin Cancer Res 2009;15:4147-56.
`
`Polson AG, Sliwkowski MX. Toward an effective targeted chemotherapy for multiple myeloma. Clin
`Cancer Res 2009;15:3906-7.
`
`Makhija S, Amler LC, Glenn D, Ueland FR, Gold M, Dizon DS, Paton V, Lin C-Y, Januario T, Ng K,
`Strauss A, Kelsey SM, Sliwkowski MX, Matulonis U. Clinical activity of gemcitabine plus pertuzumab
`in platinum-resistant ovarian cancer, fallopian tube, or primary peritoneal cancer: low mRNA expression
`of the HER2-coreceptor HER3 may be predictive ofpertuzumab activity. J Clin Oncol 2009;in press.
`
`Krop IE, Beeram M, Modi S, Holden SN, Yu W, Girish S, Tibbitts J, Yi J-H, Sliwkowski MX, Jacobson
`FS, Lutzker SG, Burris HA. A Phase I Study of Trastuzumab-DMl, HER2 Antibody-Drug Conjugate,
`Given Every 3 Weeks to Patients with HER2+ Metastatic Breast Cancer J Clin Oncol 2009; to be
`submitted.
`
`Junttila TT, Parsons K, Olsson C, Lu Y, Xin Y, Theriault J, Meng G, Totpal K, Kelley RF, Sliwkowski
`MX. Superior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2 amplified breast
`cancer. to be submitted 2009.
`
`Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski
`MX. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively
`inhibited by the PBK inhibitor GDC-0941. Cancer Cell 2009; 15 :429-40.
`
`Hollmen M, Maatta JA, Bald L, Sliwkowski MX, Elenius K. Suppression of breast cancer cell growth by
`a monoclonal antibody targeting cleavable ErbB4 isoforms. Oncogene 2009;28: 1309-19.
`
`Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari
`RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD,
`Sliwkowski MX. Targeting HER2-positive breast cancer with trastuzumab-DMl, an antibody-cytotoxic
`drug conjugate. Cancer Res 2008;68:9280-90.
`
`Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stem HM. A
`central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res
`2008;68:5878-87.
`
`Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, Tsai SP, Dennis MS,
`Lu Y, Meng YG, Ng C, Yang J, Lee CC, Duenas E, Gorrell J, Katta V, Kim A, McDorman K, Flagella
`K, Venook R, Ross S, Spencer SD, Lee Wong W, Lowman HB, Vandlen R, Sliwkowski MX, Scheller
`RH, Polakis P, Mallet W. Site-specific conjugation of a cytotoxic drug to an antibody improves the
`therapeutic index. Nat Biotechnol 2008;26:925-32.
`
`Carey KD, Garton AJ, Romero MS, Kahler J, Thomson S, Ross S, Park F, Haley JD, Gibson N,
`Sliwkowski MX. Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows
`increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer
`Res 2006;66:8163-71.
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`
`Curriculum Vitae
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`Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybpal N, McKeever K, Sliwkowski MX.
`Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization
`inhibitor, pertuzumab. Cancer Immunol Immunother 2006;55:717-27.
`
`Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF, Allison DE,
`Sliwkowski MX, Lieberman G, Kelsey SM, Fyfe G. Phase I clinical study ofpertuzumab, a novel HER
`dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005;23:2534-43.
`
`Jackson JG, St Clair P, Sliwkowski MX, Brattain MG. Blockade of epidermal growth factor- or
`heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent
`downstream signaling and growth effects. Cancer Res 2004;64:2601-9.
`
`Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB
`signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004;5:317-28.
`
`Austin CD, De Maziere AM, Pisacane PI, van Dijk SM, Eigenbrot C, Sliwkowski MX, Klumperman J,
`Scheller RH. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab
`and geldanamycin. Mol Biol Cell 2004;15:5268-82.
`
`Sliwkowski MX. Ready to partner. Nat Struct Biol 2003;10:158-9.
`
`Miller K, Meng G, Liu J, Hurst A, Hsei V, Wong WL, Ekert R, Lawrence D, Sherwood S, Deforge L,
`Gaudreault J, Keller G, Sliwkowski M, Ashkenazi A, Presta L. Design, construction, and in vitro
`analyses of multivalent antibodies. J Immunol 2003; 170:4854-61.
`
`Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski
`MX, Ward CW, Yokoyama S. An open-and-shut case? Recent insights into the activation ofEGF/ErbB
`receptors. Mol Cell 2003;12:541-52.
`
`Akita RW, Sliwkowski MX. Preclinical studies with Erlotinib (Tarceva). Semin Oncol 2003;30:15-24.
`
`Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain
`alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002;277:46265-72.
`
`Ranson M, Sliwkowski MX. Perspectives on anti-HER monoclonal antibodies. Oncology 2002;63 Suppl
`1:17-24.
`
`Penuel E, Akita RW, Sliwkowski MX. Identification of a region within the ErbB2/HER2 intracellular
`domain that is necessary for ligand-independent association. J Biol Chem 2002;277:28468-73.
`
`Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP,
`Maiese K, Scher HI, Sliwkowski MX. Targeting ligand-activated ErbB2 signaling inhibits breast and
`prostate tumor growth. Cancer Cell 2002;2:127-37.
`
`Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol
`2001;2:127-37.
`
`Penuel E, Schaefer G, Akita RW, Sliwkowski MX. Structural requirements for ErbB2 transactivation.
`Semin Oncol 2001 ;28:36-42.
`
`O'Shea S, Johnson K, Clark R, Sliwkowski MX, Erickson SL. Effects of in vivo heregulin betal
`treatment in wild-type and ErbB gene-targeted mice depend on receptor levels and pregnancy. Am J
`Pathol 2001;158:1871-80.
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`38.
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`39.
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`40.
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`41.
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`42.
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`43.
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`Mann M, Sheng H, Shao J, Williams CS, Pisacane PI, Sliwkowski MX, DuBois RN. Targeting
`cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology
`2001 ;120:1713-9.
`
`Lee H, Akita RW, Sliwkowski MX, Maihle NJ. A naturally occurring secreted human ErbB3 receptor
`isoform inhibits heregulin-stimulated activation ofErbB2, ErbB3, and ErbB4. Cancer Res 2001;61:4467-
`73.
`
`Koeppen HK, Wright BD, Burt AD, Quirke P, McNicol AM, Dybdal NO, Sliwkowski MX, Hillan KJ.
`Overexpression of HER2/neu in solid tumours: an immunohistochemical survey. Histopathology
`2001;38:96-104.
`
`Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol 2000;27: 17-24.
`
`Patel NV, Acarregui MJ, Snyder JM, Klein JM, Sliwkowski MX, Kern JA. Neuregulin-1 and human
`epidermal growth factor receptors 2 and 3 play a role in human lung development in vitro. Am J Respir
`Cell Mol Biol 2000;22:432AO.
`
`Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT, Arteaga CL.
`Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action
`against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 2000;60:5887-94.
`
`Carter P, Fendly BM, Lewis GD, Sliwkowski MX. Development of herceptin. Breast Dis 2000;11:103-
`11.
`
`Agus DB, Akita RW, Fox WD, Lofgren JA, Higgins B, Maiese K, Scher HI, Sliwkowski MX. A
`potential role for activated HER-2 in prostate cancer. Semin Oncol 2000;27:76-83; discussion 92-100.
`
`Zheng JL, Frantz G, Lewis AK, Sliwkowski M, Gao WQ. Heregulin enhances regenerative proliferation
`in postnatal rat utricular sensory epithelium after ototoxic damage. J Neurocytol 1999;28:901-12.
`
`Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal growth factor receptor 2.
`Curr Oncol Rep 1999; 1: 16-22.
`
`Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies
`addressing the mechanism of action oftrastuzumab (Herceptin). Semin Oncol l 999;26:60-70.
`
`Schaefer G, Akita RW, Sliwkowski MX. A discrete three-amino acid segment (LVI) at the C-terminal
`end of kinase-impaired ErbB3 is required for transactivation ofErbB2. J Biol Chem 1999;274:859-66.
`
`Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowski M, Coombs D, Baly D, Kabbinavar F,
`Slamon D. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used
`for treatment of human breast cancers. Oncogene 1999;18:2241-51.
`
`Kern JA, Wakita R, Sliwkowski MX. Neuregulin receptor-mediated gene transfer by human epidermal
`growth factor receptor 2-targeted antibodies and neuregulin-1. Cancer Gene Ther 1999;6:537-45.
`
`Jones JT, Akita RW, Sliwkowski MX. Binding specificities and affinities of egf domains for ErbB
`receptors. FEBS Lett 1999;447:227-31.
`
`Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF, Pietras RJ, Pisacane P,
`Sliwkowski MX, Slamon DJ. Biologic effects of heregulin/neu differentiation factor on normal and
`malignant human breast and ovarian epithelial cells. Oncogene 1999;18:6050-62.
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`Curriculum Vitae
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`53.
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`55.
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`56.
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`Sundaresan S, Roberts PE, King KL, Sliwkowski MX, Mather JP. Biological response to ErbB ligands in
`nontransformed cell lines correlates with a specific pattern of receptor expression. Endocrinology
`1998; 139:4756-64.
`
`Jones JT, Ballinger MD, Pisacane PI, Lofgren JA, Fitzpatrick VD, Fairbrother WJ, Wells JA, Sliwkowski
`MX. Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by
`alanine scanning mutagenesis. J Biol Chem 1998;273:11667-74.
`
`Fitzpatrick VD, Pisacane PI, Vandlen RL, Sliwkowski MX. Formation of a high affinity heregulin
`binding site using the soluble extracellular domains of ErbB2 with ErbB3 or ErbB4. FEBS Lett
`1998;431:102-6.
`
`Fairbrother WJ, Liu J, Pisacane Pl, Sliwkowski MX, Palmer AG, 3rd. Backbone dynamics of the EGF(cid:173)
`like domain of heregulin-alpha. J Mol Biol 1998;279: 1149-61.
`
`Ballinger MD, Jones JT, Lofgren JA, Fairbrother WJ, Akita RW, Sliwkowski MX, Wells JA. Selection
`of heregulin variants having higher affinity for the ErbB3 receptor by monovalent phage display. J Biol
`Chem 1998;273: 11675-84.
`
`Zrihan-Licht S, Lim J, Keydar I, Sliwkowski MX, Groopman JE, Avraham H. Association of csk(cid:173)
`homologous kinase (CHK) (formerly MATK) with HER-2/ErbB-2 in breast cancer cells. J Biol Chem
`1997;272:1856-63.
`
`Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski
`PJ. Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc
`Natl Acad Sci US A 1997;94:9562-7.
`
`Westphal M, Meima L, Szonyi E, Lofgren J, Meissner H, Hamel W, Nikolics K, Sliwkowski MX.
`Heregulins and the ErbB-2/3/4 receptors in gliomas. J Neurooncol 1997;35:335-46.
`
`Schaefer G, Fitzpatrick VD, Sliwkowski MX. Gamma,heregulin: a novel heregulin isoform that is an
`autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 1997;15:1385-
`94.
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`Sadick MD, Sliwkowski MX, Nuijens A, Bald L, Chiang N, Lofgren JA, Wong WL. Analysis of
`heregulin-induced ErbB2 phosphorylation with a high-throughput Kinase receptor activation enzyme(cid:173)
`linked immunosorbant assay. Anal Biochem 1996;235:207-14.
`
`Mincione G, Bianco C, Kannan S, Colletta G, Ciardiello F, Sliwkowski M, Yarden Y, Normanno N,
`Pramaggiore A, Kim N, Salomon DS. Enhanced expression of heregulin in c-erb B-2 and c-Ha-ras
`transformed mouse and human mammary epithelial cells. J Cell Biochem 1996;60:437-46.
`
`Li W, Park JW, Nuijens A, Sliwkowski MX, Keller GA. Heregulin is rapidly translocated to the nucleus
`and its transport is .correlated with c-myc induction in breast cancer cells. Oncogene 1996;12:2473-7.
`
`Li RH, Sliwkowski MX, Lo J, Mather JP. Establishment of Schwarm cell lines from normal adult and
`embryonic rat dorsal root ganglia. J Neurosci Methods 1996;67:57-69.
`
`Li R, Chen J, Hammonds G, Phillips H, Armanini M, Wood P, Bunge R, Godowski PJ, Sliwkowski MX,
`Mather JP. Identification ofGas6 as a growth factor for human Schwann cells. J Neurosci 1996;16:2012-
`9.
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`Curriculum Vitae
`Page8
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`Lewis GD, Lofgren JA, McMurtrey AE, Nuijens A, Fendly BM, Bauer KD, Sliwkowski MX. 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 Res 1996;56:1457-65.
`
`Jacobsen NE, Abadi N, Sliwkowski MX, Reilly D, Skelton NJ, Fairbrother WJ. High-resolution solution
`structure of the EGF-like domain ofheregulin-alpha. Biochemistry 1996;35:3402-17.
`
`Carver RS, Sliwkowski MX, Sitaric S, Russell WE. Insulin regulates heregulin binding and ErbB3
`expression in rat hepatocytes. J Biol Chem 1996;271 :13491-6.
`
`Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, Gorman CM, Par