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`PHIGENIX
`PHIGENIX
`Exhibit 1028
`Exhibit 1028
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`THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Applicant:
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`Sharon Erickson
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`Attorney Docket #:
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`GNE-OO73
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`Serial No.
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`11/949,35l
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`Group Art Unit
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`1643
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`Filing Date
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`12/03 /2007
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`Examiner:
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`Natarajan, Meera
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`Customer No.:
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`3 5489
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`Confirmation No.:
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`4598
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`Title:
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`METHODS OF TREATMENT USING ANTI-ErbB ANTIBODY
`MAYTANSINOID CONJUGATES
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`Commissioner for Patents
`PO. Box 1450
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`Alexandria, VA 22313—1450
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`FILED VIA EFS
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`DECLARATION OF MARK X. SLIWKOWSKI PILD.
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`1, MARK X. SLIWKOWSKI, PhD. declare and say as follows: -
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`l.
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`I obtained a BS. in Animal Science and Agricultural Biochemistry from the
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`University of Delaware, a‘PhD. in Biochemistry with minor in Physical Chemistry from North
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`Carolina State University, and completed postdoctoral training at the National Institutes of
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`Health, National Heart, Lung and Blood Institute, Laboratory of Biochemistry.
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`2.
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`After six years of research experience at Triton Biosciences, Inc. (Berlex
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`Biosciences, 1110.), I joined Genentech, Inc. in 1991 as a senior scientist, where my current title is
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`Senior Staff Scientist, Research Oncology.
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`3.
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`During my employment at Genentech, I have worked on a number of pro grams
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`involving drugs directed against the human epidermal growth factor receptor family (also known
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`as the HER or ErbB family). Members of the ErbB family are frequently activated in a number
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`of proliferative diseases including cancer. Along with colleagues at Genentech, Ihave studied
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`various aSpects of the ErbB receptor activation process including the biochemical nature ofthe
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`receptor complexes, the activation of signal transduction pathways, and the resultant biological
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`outcomes. Our studies have also focused on research toward the deveIOpment of ErbB inhibitors
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`for treating proliferative disorders such as cancer, as Well as the elucidation of the molecular
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`mechanisms by which such inhibitors act. Our investigations and those of my predecessors at
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`Genentech have contributed to the development of a number of therapeutic approaches that
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`PHIGENIX
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`Exhibit 1028-01
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`target the ErbB receptor family, including the anti—BrbB2 antibody trastuzumab, which is
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`marketed under the tradename Herceptin®. Working closely with other groups at Genentech and
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`in collaboration with IrnmunoGen, Inc., we have also developed T-DMl , a therapeutic
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`immunoconjugate in which trastuzumab is conjugated to the cytotoxic maytansinoid “DMl” for
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`the treatment of tumors that express ErbB2.
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`4.
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`My Scientific Curriculum Vitae, including my list ofpublications, patents,
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`pending patent applications, and awards, is enclosed as Exhibit A and forms part of this
`Declaration.
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`5.
`I am familiar with and understand the disclosure of the above-identified patent
`application and the pending claims, including the new claims added concurrently with filing the
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`present Declaration. Independent Claim 40 is directed to an immunoconjugate comprising the
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`humanized anti-ErbBZ antibody huMAb4D5-8 conjugated to a maytansinoid. The antibody
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`huMAb4D5-8 is the same antibody as trastuzumab and is a humanized form of the mouse
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`monoclonal antibody “4D5.” (See the above-identified patent application at page 61 , para.
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`[0216].) All other claims depend, directly or indirectly, from claim 40. I am also familiar with
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`and understand the Office Action mailed on June 81h, 2010, in connection with the above-
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`identified patent application, and the references cited in that Office Action.
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`6.
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`According to the Office Action, the claimed invention would have been obvious
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`to one of ordinary skill in the art at the time the invention was made over the combination of U.S.
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`Patent No. 5,208,020 (referred to hereinafier as “Chari et a1.”) and U.S. Patent No. 6,054,297
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`(referred to hereinafier as “Carter et al.”). Chari et al. allegedly teach a composition comprising
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`one or more maytansinoids (col. 6-8) linked to a monoclonal antibody or antibody fragment,
`where the monoclonal antibody is selective for tumor cell antigens. Carter is cited for disclosing
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`humanized 4D5 antibodies, including huMAb4D5-8, and for allegedly teaching that the
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`humanized 4D5 antibodies maybe used as immunotoxins, conjugated with a cytotoxic moiety
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`(col. 44). The Examiner recognizes that Chari et al. do not teach an anti-ErbB2 antibody
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`conjugated to a maytansinoid, let alone conjugates comprising the specific humanized anti-
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`ErbB2 antibody, huMAb4D5-8, conjugated to a maytansinoid. The finding ofobviousness is
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`based on the assertion that one of ordinary skill would have been motivated to make the claimed
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`PHIGENIX
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`Exhibit 1028-02
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`antibody—maytansinoid conjugates because such conjugates fall within the scope of the
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`immunotoxins of Carter et a1. and because Carter et al. teach that ErbB2 is amplified or
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`overexpressed in human malignancies.
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`7.
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`The conclusion drawn by the Examiner from the combined disclosures of Char-i et
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`a1. and Carter et al. disregards a large body of additional relevant knowledge in the pertinent art
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`at the time the present invention was made, and is therefore incorrect.
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`8.
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`As it is recognized in the Office Action, at the time the present invention was
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`made it was known that ErbB2 (also known as HERZ) is amplified and overexpressed in breast
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`and ovarian cancers, and such overexpression is correlated with poor prognosis. (See Carter et al.
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`and application at page 2, para. [0006].) HER2 was also known to be overexpressed in a number
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`of other carcinomas. (Id) It was also known that HER2 is expressed in normal tissues at levels
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`similar to those found in non-HERZ-amplified, non—HERZ-overexpressing breast cancers and
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`breast cancer cell lines. For example, HER-2 protein was identified on cell membranes of
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`normal epithelial cells in the gastro-inteslinal, respiratory, reproductive, and urinary tract as well
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`as in the skin, breast and placenta, demonstrating that HER2 is normally a membrane constituent
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`of a variety of epithelial cell types. (See abstract, Press et al., Oncogene 5(7):953-62, 1990 —
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`Exhibit B.)
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`'
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`9.
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`The Office Action also recognizes that at the time the present invention was made
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`huMAb4D5 -8 (marketed under the tradenarne Herceptin®) was known (see, Carter et al. cited in
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`the Office Action). Indeed, Herceptin® was approved by the FDA in 1998 (well prior to the
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`March 16, 2000 priority date ofthis application) for the treatment of metastatic HERZ-
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`overexpressing breast cancer, either as an initial treatment in combination with chemotherapy
`(paclitaxel), or as a'monotherapy afier prior treatment with chemotherapy. Herceptin® was later
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`approved in 2006 as part of a mu lti-agent regimen for the adjuvant (post-surgical) treatment of
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`HERZ-overexpressing breast cancer. In 2008, Herceptin® received further approvals fiom the
`FDA for treatment in the adjuvant setting. Although Herceptin® is a breakthrough in the
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`treatment of HERZ—overexpressing breast cancer, most patients treated with Herceptin® in the
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`metastatic setting relapsed after experiencing a period of clinical benefit. (See application, page
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`5, para. [0014].)
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`PHIGENIX
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`Exhibit 1028-03
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`10.
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`At the time the present invention was made, maytansinoids were also known as a
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`family of cytotoxic molecules that include maytansine and its derivative DMl. Before the
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`priority date ofthe present application, it was reported that maytansine acts as a very potent
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`mitotic inhibitor by inhibiting microtubule polymerization. (See, Rao et al., Cancer Research
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`39:3152—3155, 1979 — Exhibit C; and Remillard eta1., Science 189:1002-1005, 1975 — Exhibit
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`D.) Microtubules are necessary for segregation of chromosomes during mitosis, and disruption
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`ofmicrotubules blocks mitosis, thereby inhibiting cell proliferation. Treatment of human cells in
`vitro with maytansine was reported to result in up to approximately 75% of cells accumulating in
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`mitosis, depending on the concentration of maytansine and duration of exposure. (See Exhibit C,
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`e.g., Chart 1.) Indeed, it was reported that sensitivity ofcells to the cytotoxic effect of
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`maytansine was cell cycle-dependent, with cells synchronized in GI being the most resistant to
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`maytansine. (See Exhibit C, e.g., abstract and page 3 155, col. 1, last para.) Thus, it was known
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`before the priority date that maytansine and related maytansinoids, such as DMl, were cytotoxic
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`agents that exerted their cytotoxic effects during M—phase mitosis.
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`11.
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`However, in addition to the state of the art knowledge detailed in paragraphs 8—10,
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`at the time the present invention was made one of ordinary skill in the art would have been also
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`aware of studies into the mechanism of action ofthe antibody 4D5. Those studies demonstrated
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`that 4D5 is cyto static (not cytotoxic), meaning that 4D5 acts on tumors expressing ErbB2 by
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`arresting the cell cycle. The enclosed article by Lewis et al. (Cancer Research 56:1457—1465,
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`1996 — Exhibit E) shows that 4D5 has a cytostatic effect, and in particular, it reduces the number
`of S-phase cells, thus suggesting that 4D5 causes a G0/G1 block. (See Lewis, e.g., at page 1460,
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`-
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`column 2, lines 11-13; page 1461, column 1, to 1462, column 2, lst paragraph; Figure 5; and
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`page 1464, lines 32-33 .) Those findings were consistent with earlier studies reporting that 4D5
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`had a cytostatic, anti-proliferative effect in vitro on SK—BR-3 cells grown in monolayer, and 4D5
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`completely suppressed colony formation by SK—BR—3 cells in soft agar. (See Hudziak et al.,
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`Molecular and Cellular Biology 9(3):l 165-1172, 1989 — Exhibit F, e.g., at page 1168, cc]. 2,
`through page 1169, col. 1; and page 1171, col. 1, para. 3) Taken together, those findings
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`indicated that 4D5, and therefore huMAb4D5-8, act at least in part by arresting breast cancer
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`cells in the GO/Gl phase of the cell cycle, which precedes the subsequent S, G2 and M (mitosis)
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`phases of the cell cycle. Thosc findings, which were made before the priority date of the present
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`application, were subsequently confirmed after the priority date by Lane et al., who reported that
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`PHIGENIX
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`Exhibit 1028-04
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`4D5 arrested 96% of BT474 cells, a breast carcinoma cell line that overexpresses HERZ, in the
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`G1 phase of the cell cycle. (See Lane et al., Molecular and Cellular Biology, 20(9):3210—3223,
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`2000 —Exhibit G, e.g., at page 3214, col. 2.)
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`12.
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`Thus, it was known well before the present invention was made that the cytostatic
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`mechanism of the 4D5 antibody and, consequently, humanized huMab4D5—8, works in
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`opposition to the cytotoxic mechanism of maytansinoids, which inhibit mitosis by inhibiting
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`microtubu 1e polymerization, and therefore require cells to be proliferating in order to act.
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`Accordingly, contrary to the Office Action, at the time the present invention was made, one of
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`skill in the art would not have been motivated to select huMAb4D5-8 as a humanized anti-HER2
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`antibody for conjugation to a maytansinoid, such as DMl, since it would have expected that
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`huMAb4D5 -8 would arrest cancer cells in the pre-mitotic GO/Gl phase of the cell cycle before
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`DMl would even have the opportunity to act. Therefore, based on the seemingly incompatible
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`mechanisms ofhuMAb4D5-8 and DM1 , one skilled in the art at the time'the present invention
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`was made would have expected huMAb4D5-8 to oppose and possibly prevent the effects of
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`DM1 , if those two agents were linked together in an immunoconjugate. Indeed, recent data from
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`my lab oratory here at Genentech demonstrate that huMAb4D5-8 retains all of its biological
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`mechanisms of action, including its cytostatic activity, when conjugated to DMl .
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`13.
`Moreover, before the priority date, the utility of immunoconjugates was ofien
`limited due to the expression ofthe targeted antigen on normal as well as cancerous cells, even
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`where the antigen was expressed at higher levels on cancerous cells relative to normal cells. For
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`example, Trail and Bianchi cautioned that “[i]t is therefore necessary to balance the relative
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`selectivity of the MAb [i.e., the selectivity of the targeting monoclonal antibody for cancerous
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`cells over normal cells] with the potency ofthe agent delivered.” (See Trail and Bianchi, Current
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`Opinion in Immunology 11:584—588, 1999 — Exhibit H, page 584, col. 1, para. 2.) Ifthat balance
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`is not achieved, e.g., if a potent cytotoxic agent exerts its effect on too many normal cells, then
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`toxicity may result. Trail and Bianchi further cautioned that “[t]he use of extremely toxic drugs
`requires carefiJl MAb [monoclonal antibody] selection as even low levels ofexpression ofthe
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`targeted antigen by normal cells may lead to significant toxicity.” (Exhibit H, page 585, col. 1,
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`para. 1, emphasis added.)
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`PHIGENIX
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`Exhibit 1028-05
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`l4. Accordingly, even if huMAb4D5-8 had not negated the cytotoxicity of DM1 (an
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`outcome which would not have been expected), it would nonetheless have been unpredictable as
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`to whether a huMAb4D5-8—DM1 immunconjugate would have achieved an apprOpriate balance
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`between antibody selectivity (i.e., for cancerous cells versus normal cells) and potency of the
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`cytotoxic agent. HER2 is expressed on normal cells as well as being overexpressed on certain
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`breast cancer cells and other cancer cells. Therefore, even if DMl exerted its cytotoxicity
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`notwithstanding its being conjugated to huMAb4D5-8, it would have been unpredictable whether
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`such an immunoconjugate would have been unacceptably toxic due to delivery of DM1 to
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`normal cells expressing HER2. The present application addresses this unpredictability, reporting
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`that “HERCEPTHV®-DMI does not kill normal human cells, indicating a selective activity,”
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`based on studies in which “[t]he effect of various concentrations of HERCEPT[N®—DM1 on
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`hummman [sic, human] mammary epithelial cells, human hepatocytes and human small airway
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`epithelial cells was‘investigated.” (Application at pages 65—66, para. [0229], emphasis added.)
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`I
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`have personal knowledge of those studies, and I confirm that the human cells used in those
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`studies expressed HER2 at levels similar to those found in non—HERZ—amplified, non-HER2—
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`overexpressing breast cancers and breast cancer cell lines, consistent with the observations of
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`. Press at al. (Exhibit B). At the time the invention was made, it would have been expected that
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`the level ofHER2 expression on normal cells would lead to unacceptable cytotoxic side—effects
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`for such an immunoconjugate. However, surprisingly, we found that this was not the case.
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`Moreover, the present application reports extensive dose—reSponse studies in a novel mouse
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`model for HER2 non—responsive breast cancer, concluding that “[t]he fact that the effect of
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`HERCEPTIN®-DM1 is do se—dependent suggests that in an actual clinical setting, the strategy is
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`likely to provide a considerable maneuver of doses to achieve the best anti—tumor activity.” (See
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`application at page 69, para. [0237].) Those findings enhanced the likelihood that a therapeutic
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`window could be achieved and that toxicity in a clinical setting could be managed. Thus, even if
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`huMAb4D5-8 did not negate the cytotoxicity of DM1 (an outcome which would not have been
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`predicted), the present application addresses the unpredictability in the art as to whether a
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`huMAb4D5—8—DM1 immunoconjugate would have struck an appropriate balance between
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`antibody selectivity and potency of the cytotoxic agent.
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`PHIGENIX
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`Exhibit 1028-06
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`15.
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`On the basis of the explanations set forth in this Declaration and the enclosed
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`evidence, it is my considered scientific opinion that at the time the present invention was made
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`one of ordinary skill in the art would have expected huMAb4D5—8 to oppose the action of a
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`maytansinoid such as DM1 and therefore would not have been motivated to select huMAb4D5—8
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`as a humanized anti-HER2 antibody for conjugation to a maytansinoid, nor would it have been at
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`all predictable that a huMAb4D5—8mmaytansinoid conjugate would effectively and safely treat
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`HER2 overexpressing cancer with a reasonable expectation of success.
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`16.
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`I declare further that all statements made in this Declaration of my own
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`knowledge are true and that all statements made on information and belief are believed to be true
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`and further, that these statements are made with the knowledge that willful statements and the
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`like so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of
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`the United States Code and that such willful false statements may jeopardize the validity of the
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`application or any patent granted thereon.
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`mmfifiégfi/fl
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`_
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`MARK X. SLIWKOWSKI, Ph.D.
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`PHIGENIX
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`Exhibit 1028-07
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`EXHIBIT A
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`PHIGENIX
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`xhibit 1028-08
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`MARK X. S LIWKOWSKI
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`Home
`42 Oak Creek Lane
`San Carlos, CA 94070
`650/ 364—8217
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`Genentech, Inc.
`.
`Research Oncology
`1 DNA Way, MS 72 Room 10.489
`South San Francisco, CA 94080
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`650/225—1247 Ph.
`650/438—4759 Cell
`650/ 225—5770Fax
`marks@gene.com
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`EDUCATION
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`National Institutes of Health (1982-1985)
`National Heart, Lung and Blood Institute, Laboratory of Biochemistry
`Staff Fellow with Dr. Thressa C. Stadtman
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`North Carolina State University (1978-1981)
`PhD. in Biochemistry with minor in Physical Chemistry
`Advisor: Dr. Harold E. Swaisgood
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`University of Delaware (1972—1976)
`BS. in Animal Science and Agricultural Biochemistry (Pre-Vet)
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`EXPERIENCE
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`GENENTECH, INC.
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`Staff Scientist
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`'
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`2002-present
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`HERB-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.
`~
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`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.
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`Trastuzumab—DMI 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.
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`Director
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`2003-2008
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`Formed Translational Oncology Department. Managed expansive growth from 2004-2007, including
`small molecule expertise. Managed Director of Assay & Automation Technology from 2005-2007.
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`Senior Scientist
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`‘
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`1991-2001
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`PHIGENIX
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`Exhibit 1028-09
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`MARK X. SLIWKOWSKI
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`Curriculum Vitae
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`Page 2
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`Heregulin (1991-1996) Participated in the initial characterization of heregulin. Helped define a role
`for HERZ/ ErbBZ as a co—receptor with HER3, HER4 and EGFR.
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`HERCEPTIN® (1993-present) Member of the core project team throughout Phase II and Phase HI
`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.
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`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.
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`.
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`Tarceva®(2000-2007) One of several Genentech employees that encouraged Business Development
`to pursue iii-licensing OBI—774. Participated in due diligence team. Led research effort on Tarceva
`and serve on Tarceva core team.
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`Triton Biosciences, Inc. jBerlex Biosciences‘ Inc!
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`Staff Scientist
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`1990 — 1991
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`Initiated a program for the identification and isolation of ligands for receptor tyrosine kinases.
`Participated in project to establish structure—activity relationship for TGFoc. Supervised protein and
`peptide chemistry laboratories consisfing of 2 scientists and 5 research associates.
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`Senior Research Scientist
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`1987 - 1990
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`Project Leader for development stage of HI‘LV-l program. (Interdisciplinary team consisting of 3
`scientists and 8 research associates.) Developed folding procedure for TGFOL. Collaborated
`extensively with Immunology group on projects involving differentiation and cytotoxicity.‘
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`Research Scientist
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`.
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`1985 - 1987
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`One of the first bench scientists hired. Established protein chemistry laboratory purified
`recombinant retroviral proteins for development of diagnostic viral immunoassay.
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`NIH Postdoctoral Position
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`1982 - 1985
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`' Studied mechanisms by which selenium is incorporated into bacterial proteins. Purified several
`selenium-containing proteins and gained extensive experience in peptide mapping.
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`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
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`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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`PHIGENIX
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`Exhibit 1028-10
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`MARK X. SLIWKOWSKI
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`Curriculum Vitae
`Page 3
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`Outstanding Graduate Student Teaching Award , 1979
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`PROFESSIONAL AFFILIATIONS
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`American So'ciety of Clinical Oncology
`American Associafion for Cancer Research
`American Society for Biochemistry and Molecular Biology
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`INVITED PRESENTATIONS (SINCE. 2006)
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`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
`. FASEB 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 Translafional Medicine, San Francisco, March 2006
`
`'
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`Vanderbflt University, January 2006
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`PEER REVIEW ACTIVITIES
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`Department of Defense Breast Cancer Program
`Nature ad .hoc
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`Oncogene ad hoc
`Cancer Research ad hoc
`Clinical Cancer Research ad hoc
`Cancer Cell ad hoc
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`PHIGENIX
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`Exhibit 1028-11
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`MARK X. SLIWKOWSKI
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`PUBLICATIONS
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`Curriculum Vitae
`Page 4
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`l.
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`9.
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`10.
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`ll.
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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 HERZ/HERB-
`mediated growth ofbreast cancer cells with combinations of GDC-O94l PIBK inhibitor, trastuzumab, and
`pertuzumab. Clin Cancer Res 2009;15:4147-56.
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`Pols‘on AG, Sliwkowski MX. Toward an effective targeted chemotherapy for multiple myeloma. Clin
`Cancer Res 2009;15:3906-7.
`‘
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`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 of pertu'zumab 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-DMI, HERZ Antibody-Drug Conjugate,
`Given Every 3 Weeks to Patients with HER2+ Metastatic Breast Cancer J Clin Oncol 2009; to be
`submitted.
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`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 afilcosylated trastuzumab in the treatment of HER2 amplified breast
`cancer. to be submitted 2009.
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`Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski
`MX. Ligand-independent HERZ/HERB/PIBK complex is disrupted by trastuzumab and is effectively
`inhibited by the PIBK inhibitor GDC-094l. Cancer Cell 2009;15:429-40.
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`Hollmen M, Maatta JA, Bald L, Sliwkowski MX, Elenius K. Suppression of breast cancer cell growth by
`a monoclonal antibody targeting cleavable ErbB4 isoforrns. 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 NIX. Targeting HERZ-positive breast cancer with trastuzumab-DMl, an antibody—cytotoxic
`drug conjugate. Cancer Res 2008;68:9280-90.
`-
`i
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`Lee-Hoeflich ST, 'Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stem HM. A
`central role for HER3 in HERZ—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, McDonnan 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;26:925-312.
`
`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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`Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, SlikaWSki MX.
`Humanization of a recombinant monoclonal antibody to 'produce a therapeutic HER dimerization
`inhibitor, pertuzumab. Cancer Immunol Immunother 2006;55:717-27.
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`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 of pertuzumab, 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 BrbB2 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;52317428.
`
`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. MolBiol Cell 2004; 15: 5268-82.
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`Sliwkowski MX. Ready to partner. Nat Struct Biol 2003;10:158-9.
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`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 Immun012003;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 of EGF/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.
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`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.
`-
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`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;2z127-37.
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`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 beta]
`treatment in wild-type and ErbB gene-targeted mice depend on receptor levels and pregnancy. Am' J
`Path‘012001;158:l871-80.
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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-stirnulated activation of ErbB2, ErbB3, and ErbB4. Cancer Res 2001;61:4467-
`73.
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`Koeppen HK, Wright BD, Burt AD, Quirke P, McNicol AM, Dybdal NO, Sliwkowski MX, Hillan KJ.
`Overexpression of HERZ/neu in solid tumours: an innnunohistochemical survey. Histopathology
`2001;38:96-104.
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`I Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol 2000;27:17-24.
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`Patel NV, Acarregui MJ, Snyder M, Klein JM, Sliwkowski MX, Kern JA. Neuregulin-l 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;22:432—40.
`'
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`Kurokawa H, Lenferink AB, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT, Arteaga CL.
`Inhibition of I-IERZ/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action
`against HERZ-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.
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`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 afier 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;1116-22.
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`Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies
`addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 1999;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 of ErbB2. 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 I-IBR-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-l. 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, Firm 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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`lines correlates with a specific pattern of receptor expression. Endocrinology
`1998;139:4756-64.
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`Jones JT, Ballinger MD, Pisacane PI, Lofgren JA, Fit