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`PHIGENIX
`PHIGENIX
`Exhibit 1027
`Exhibit 1027
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`

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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant:
`Serial No.:
`
`Sharon Erickson, et al.
`11/949,351
`
`Docket No.:
`Group Art Unit:
`
`GNE-0073R2C2
`1643
`
`Filing Date:
`
`12/03/2007
`
`Examiner:
`
`Nataraj an, Meera
`
`Customer No.
`
`35489
`
`Confirmation No.
`
`4598
`
`For:
`
`METHODS OF TREATMENT USING ANTI-ErbB ANTIBODY-
`MAYTANSINOID CONJUGATES
`
`FILED VIA EFS — JULY 6, 2010
`
`AMENDMENT AND RESPONSE TO OFFICE ACTION
`
`MS: AMENDMENT
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`Dear Sir:
`
`This is in response to the Office Action mailed on June 8th, 2010 (Paper No./Mail Date
`
`20100604) in connection with the above-identified patent application, which vacates the earlier
`
`Office Action mailed on April 1“, 2010. The present Amendment and Response is timely filed
`
`within the three month shortened statutory period set in the Office Action, and is accompanied
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`by Declarations of Barbara Klencke, MD. and Mark X. Sliwkowski, Ph.D., respectively, the
`
`entry and consideration of which is respectfully requested.
`
`Amendments to the Specification begin on page 2 of this paper.
`
`Claims begin on page 4 of this paper.
`
`Remarks/Arguments begin on page g of this paper.
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`LA: 639078v3
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`PHIGENIX
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`Exhibit 1027-01
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`

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`Amendment to the Specification:
`
`The title of the application has been amended as follows:
`
`WhuMAb4DS-S ANTI-ErbB2
`
`ANTIBODY-MAYTANSINOID CONJUGATES
`
`Paragraph [0217] has been amended as follows:
`
`[0217] HERCEPTIN® (huMAb4D5—8, rhuMAb HER2, US. Pat. No. 5,821,337) (1 vial
`
`containing 440 mg antibody) was dissolved in 50 mL MES buffer (25 mM MES, 50 mM NaCl,
`
`pH 5.6). The sample was loaded on a cation exchange column (Sepharose S, -15 cm x 1.7 cm)
`
`that had been equilibrated in the same buffer. The column was then washed with the same
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`buffer (5 column volumes). HERCEPTIN® was eluted by raising the NaCl concentration of the
`
`buffer to 200 mM. Fractions containing the antibody were pooled, diluted to 10 mg/mL, and
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`dialyzed into a buffer containing 50 mam—w potassium phosphate, 50 mM NaCl, 2 mM
`
`EDTA, pH 6.5.
`
`Paragraph [0229] has been amended as follows:
`
`[0229] Despite its effectiveness at shrinking tumors and suppressing tumor growth,
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`HERCEPTIN®-DM1 does not kill normal human cells, indicating a selective activity. The
`
`effect of various concentrations of HERCEPTIN®-DM1 on lawman—human mammary
`
`epithelial cells, human hepatocytes and human small airway epithelial cells was investigated.
`
`At antibody concentrations of up to 10 ug/ml, the conjugate had no significant effect on cell
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`number.
`
`Paragraph [0233] has been amended as follows:
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`[0233] The results of a similar experiment are depicted in Figure 13. The results of
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`three different dosing regimens of HERCEPT1N®-DM1 conjugate on tumor size are shown
`
`compared to matching dosing regimens of RITUXAN®-DM1. Tumor size was reduced and
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`tumor growth was suppressed for at least about 50 days by treatment with 5 doses of
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`HERCEPTTN®-DM1 at a concentration of 300 pg DMl/kg. This was true both when the
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`2
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`PHIGENIX
`
`Exhibit 1027-02
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`

`

`HERCEPTIN®-DM1 was administered once a week and when it wsa—w_as administered twice a
`
`week. By contrast, administration of 5 doses of HERCEPTIN®-DM1 twice a week at a
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`concentration of 100 ug DMl/kg did not shrink tumor size and suppressed tumor growth for
`
`somewhat less time. Matched RITUXAN®-DM1 treatment showed little effect on tumor size,
`
`indicating that the observed effect is specific to HERCEPTIN®-DM1. Similarly, unconjugated
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`RITUXAN® (control MAb E25) showed no efficacy.
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`PHIGENIX
`
`Exhibit 1027-03
`
`

`

`
`Claims:
`
`This listing of claims will replace all prior listings and versions of claims in this
`
`application.
`
`1—39.
`
`(canceled)
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`40.
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`(previously presented) An immunoconjugate comprising an anti-ErbB2
`
`antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5-8.
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`41.
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`(previously presented) The immunoconj ugate of claim 40, wherein the
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`maytansinoid is DMl having the structure:
`
`CH3O
`
`and wherein the antibody is chemically linked to the maytansinoid via a disulfide or
`
`thioether group at “R” shown in the structure.
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`42.
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`(previously presented) The immunoconjugate of claim 40, wherein the
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`immunoconjugate comprises from 3 to 5 maytansinoid molecules per antibody molecule.
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`PHIGENIX
`
`Exhibit 1027-04
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`

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`43.
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`(currently amended) The immunoconjugate of claim 40 or—4—lr, wherein the
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`antibody and the maytansinoid are conjugated by a chemical linker selected from N—
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`succinimidyl-3-(2-pyridyldithio)propionate (3111911), N—succinimidyl-4-(2-
`
`pyridylthi0)pentanoate (SPP) and succinimidyl—4-(N-maleimidomethyl)cyclohexane-1-
`
`carboxylatefSMGQ.
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`44.
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`(currently amended) A pharmaceutical composition comprising an
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`immunoconjugate of any of claims 40 to 42 fl, and a pharmaceutically acceptable carrier.
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`45.
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`(new) The immunoconjugate of claim 43, wherein the antibody and the
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`maytansinoid are conjugated by succinimidyl—4-(N-maleimidomethyl)cyclohexane-1-
`
`carboxylate.
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`46.
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`(new) The immunoconjugate of claim 41 , wherein the antibody and the
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`maytansinoid are conjugated by a chemical linker selected from N—succinimidyl-3 —(2-
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`pyridyldithio)propionate, N—succinimidyl-4-(2-pyridylthio)pentanoate (SPP) and succinimidyl-
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`4-(N-maleimidomethyl)cyclohexane— 1 —carboxylate.
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`47.
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`(new) The immunoconjugate of claim 46, wherein the antibody and the
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`maytansinoid are conjugated by succinimidyl-4—(N-maleimidomethyl)cyclohexane—1—
`
`carboxylate.
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`48.
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`(new) A pharmaceutical composition comprising an immunoconjugate of claim
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`46 or 47 and humanized monoclonal antibody 2C4 (ATCC HB-12697).
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`PHIGENIX
`
`Exhibit 1027-05
`
`

`

`REMARKS/ARGUMENTS
`
`The title has been amended to better reflect the invention claimed in the present
`application, and certain minor obvious typographical errors have been corrected in the
`
`specification. Claim 43 has been amended, and new claims 45 to 48 have been added. All
`
`amendments are of formal nature and do not add new matter. Support for the new claims is, at
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`least, in original claim 10, in paragraph [0177], and in Example 2. Support for new claim 48,
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`in particular, may be found, for example, at page 55, lines 5-9.
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`Upon entry of the present amendment, claims 40-48 will be pending. Claims 40—44 are
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`rejected.
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`Claim Rejections - 35 USC § 103
`
`Claims 40—44 are rejected under 35 U.S.C. 103(a) as allegedly being unpatentable over
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`Chari (US. Patent 5,208,020) in View of Carter (US. Patent 6,054,297).
`
`Chari et al. is cited as allegedly teaching a composition comprising one or more
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`maytansinoids linked to a monoclonal antibody or an antibody fragment (e. g. Fab, Fab’,
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`F(ab)2), where the monoclonal antibody is selective for tumor cell antigens. The Examiner
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`acknowledges that Chari et al. does not teach an anti-ErbB2 antibody conjugated to
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`maytansinoid but asserts that these “deficiencies are made up for in the teachings of Carter et
`
`al. and Lewis et al.” (Office Action, page 3, paragraph 7.) Since “Lewis et a1” is not listed as a
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`secondary reference in the rejection, it is assumed that the reference to Lewis et al. is a
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`typographical error.
`
`Carter et al. is cited for its teaching of humanized 4D5 antibodies that bind ErbB2,
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`including huMAb4D5-8, and disclosing that “the humanized 4D5 antibodies may be used as
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`immunotoxins, where they are conjugated with a cytotoxic moiety.” (Office Action, page 3,
`
`paragraph 8.)
`
`According to the rejection, it would have been primafacz’e obvious to one of ordinary
`
`skill in the art at the time the invention was made to have used the teachings of Chari et al. and
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`PHIGENIX
`
`Exhibit 1027-06
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`

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`of Carter et al. to make an immunotoxin, such as a humanized anti-ErbB2 antibody conjugated
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`to maytansinoid for treating breast cancer patients. The Examiner further asserts that one
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`“would have been motivated to use the antibodies of Carter et al. to make the maytansinoid
`
`conjugates of the instant claims, because Carter ct al. teach that ErbB2 (Her-2) is amplified or
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`overexpressed in many human malignancies.” (Office Action, pages 3-4, paragraph 9.)
`
`Applicants disagree and respectfully traverse the rejection.
`
`Claim 40 of the present application is drawn to an immunoconjugate comprising a
`
`particular anti-ErbB2 antibody, huMAb4D5—8 (also known as trastuzumab, HERCBPTIN®)
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`conjugated to a maytansinoid.
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`The re "ection disre ards im ortant
`
`rior art teachin awa
`
`am the claimed invention
`
`A rejection under 35 U.S.C. 103 must be based on a fair assessment of all relevant art
`
`that would have been known to one of ordinary skill in the art at a given time point, such as at
`
`the time the invention was made or when a patent application was filed. The present rejection
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`reviews certain information that was known to one of ordinary skill about antibody-
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`maytansinoid conjugates, huMAb4D5-8, and ErbB2 expression in cancer, but overlooks
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`important information about the respective mechanisms of action of MAb4D5 and
`
`maytansinoids, information that would have counselled against making conjugates between
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`huMAb4D5-8 and maytansinoids.
`
`The combination of Chari et al. and Carter et al. does not provide motivation to
`conz'ugate hu.MAb4D5-8 and a maytansinoid.
`
`Based on the disclosures of Chari et al. and Carter et al., and general knowledge in the
`
`art, one of ordinary skill at the time the present invention was made would not have been
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`motivated to conjugate huMAb4D5-8 with a maytansinoid.
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`Enclosed is a Declaration of Dr. Mark Sliwkowski which provides evidence and solid
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`scientific reasoning why, based on the seemingly incompatible mechanisms of action of
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`huMAb4D5—8 and maytansinoids, at the time the present invention was made one skilled in the
`
`art would not have been motivated to make a conjugate of huMAb4D5-8 with a maytansinoid.
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`PHIGENIX
`
`Exhibit 1027-07
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`

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`Dr. Sliwkowski has extensive experience in the field of drug development, and in
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`particular, in developing various therapeutic approaches targeting members of the ErbB
`
`receptor family, including ErbB2. During his employment at Genentech, Dr. Sliwkowski has
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`worked on a number of programs involving drugs directed against the human epidermal growth
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`factor receptor family (the ErbB family), including study of the ErbB receptor activation
`
`process. Dr. Sliwkowski has participated in the development of HERCEPTIN® (trastuzumab,
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`huMAb4D5-8), which first received US. Food and Drug Administration (FDA) approval in
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`1998. Dr. Sliwkowski has also been involved in the development of T-DMI , a therapeutic
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`immunoconjugate in which HERCEPTIN® (trastuzumab, huMAb4D5-8) is conjugated to the
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`cytotoxic maytansinoid “DMl” for the treatment of ErbB2 expressing tumors.
`
`As explained in paragraph 11 of the Sliwkowski Declaration, before the earliest priority
`
`date of the present application (March 16, 2000) studies into the mechanism of action of 4D5
`
`(the “parent” of humanized huMAb4D5-8) revealed that 4D5 has a cytostatz'c (not cytotoxic)
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`effect on tumor cells that overexpress ErbB2, meaning that the action on tumors expressing
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`ErbB2 receptor is via arrest of the cell cycle. Specifically, it was known that 4D5 acts by
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`arresting breast cancer cells in the G0/G1 phase of the cell cycle, which precedes the
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`subsequent S, G2 and M (mitosis) phases of the cell cycle. In particular, Lewis et a1. (1996)
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`(Exhibit E to the Sliwkowski Declaration) shows that 4D5 has a cytostatic effect, and in
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`particular, it reduces the number of S-phase cells, thus suggesting a GO-Gl block. See Lewis,
`
`et al. e.g., at page 1460, column 2, lines 11-13; page 1461, column 1, to 1462, column 2, 1st
`
`paragraph; Figure 5; and page 1464, column 1, lines 32-33. Indeed, this cytostatic effect was
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`decisively confirmed in a post-filing date reference, see enclosed article by Lane et a1. (2000)
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`(Exhibit G to the Sliwkowski Declaration). See Lane et al. e. g., at page 3214, column 1, line
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`12 — page 3215, column 1, line 23; page 3218, column 2, lines 12—15; and abstract. Thus, it
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`was known at the time the invention was made that 4D5 reduced or blocked tumor cell
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`proliferation.
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`It was also known before the earliest priority date of the present application that
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`maytansine and maytansinoids, such as DMl, exert their cytotoxic effects during M phase by
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`inhibiting microtubule polymerization (see, e. g., US. Patent No. 5,208,020, column 3, lines
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`13-25), and cells synchronized in G1 have been shown to be most resistant to maytansine (see,
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`8
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`PHIGENIX
`
`Exhibit 1027-08
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`

`

`e.g, Sliwkowski Declaration, Exhibit C, e.g., abstract and page 3155, col. 1, last para). Thus,
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`cells treated with 4D5 would be expected to arrest in GO/Gl and therefore be resistant to
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`maytansinoids, which act later in the cell cycle. Accordingly, it would have been expected
`
`before the priority date of the present application that the mechanism for the 4D5 antibody (and
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`therefore humanized huMab4D5-8) works in opposition to the mechanism of maytansinoids,
`
`which reguire cells to be proliferating in order to act.
`
`Thus, at the time the invention was made, it was known that 4D5 and maytansinoids
`
`acted by opposing and mutually exclusive mechanisms. Based on the opposing mechanisms of
`
`action of huMAb4D5-8 and maytansinoids, before the priority date, one of ordinary skill in the
`
`art would not have been motivated to conjugate huMAb4D5-8 with a maytansinoid. For the
`
`same reasons, one of ordinary skill would not have had a reasonable expectation that such
`
`conjugates, even if prepared, would be effective in the treatment of ErbB2-expressing cancer.
`
`There is nothing is Chari et al. or Carter et al. that would contradict this conclusion.
`
`Thus, at the earliest priority date of the present application the combined disclosures of Chari
`
`et al. and Carter et al. did not create a motivation to make a conjugate of huMAb4D5-8 with a
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`maytansinoid, and did not create a reasonable expectation that such a conjugate would be
`
`effective in the treatment of ErbB2-expressing cancer. Indeed, one of ordinary skill, familiar
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`not only with Chari et al. and Carter et al., but also with information about the opposing
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`mechanisms of action of huMAb4D5-8 and maytansinoids, would have been discouraged from
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`conjugating huMAb4D5-8 with a maytansinoid, since huMAb4D5—8 would have been
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`expected to oppose and possibly prevent the effects of a maytansinoid, if those two agents were
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`linked together in an immunoconjugate. Thus, the prior art, as a whole, teaches away from the
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`invention claimed herein.
`
`The disclosure of the present application includes experimental support [or unexpected,
`non-obvious properties of the huMb4D5-8-maytansinoid conz'ugates claimed, that are
`not suggested by the combination 07: Chart et al. and Carter et al.
`
`At the priority date of the present application it was known that HER2 (ErbB2) is
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`expressed on normal cells in addition to being overexpressed on certain cancer cells. For
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`example, Press et al. (Exhibit B to the Sliwkowski Declaration) describes the distribution of
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`PHIGENIX
`
`Exhibit 1027-09
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`

`

`HER2 (ErbB2) expression in normal adult and fetal tissues and characterizes the expression
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`levels (see e.g., Table 1 and Figures 1 and 2). As Dr. Sliwkowski explains in paragraphs 13
`
`and 14 of his Declaration, before the priority date of this application the use of
`
`immunoconjugates was often limited due to the expression of the target antigen both on normal
`
`and on cancerous cells, even where the target antigen was expressed at higher levels on
`
`cancerous cells relative to normal cells. See e. g., Trail and Bianchi (Exhibit H to the
`
`Sliwkowski Declaration) at page 585, col. 1. In view of this knowledge, even if huMAb4D5-8
`
`had not counteracted or negated the cytotoxicity of the maytansinoid to which it is conjugated,
`
`at the priority date of the present application it would have been unpredictable whether a
`
`huMAb4D5-8-maytansinoid immunoconjugate would have been unacceptably toxic due to
`
`delivery of the maytansinoid component to normal HER2 expressing cells. It was, therefore,
`
`unexpected that, despite its effectiveness at shrinking tumors and suppressing tumor growth,
`
`HERCEPTlN®—DM1 did not kill normal human cells, but rather showed a selective activity, as
`
`reported in Example 4 (paragraph [0229]) of the present application. It was further
`
`unexpected, as reported in the same Example (paragraph [0237]), that in preclinical studies the
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`HERCEPTlN®-DM1 conjugate showed dose-dependent efficacy. These two findings, when
`
`taken together, enhanced the likelihood that a therapeutic window could be achieved, striking
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`an appropriate balance between potency and selectivity in a clinical setting. There is nothing
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`in the combination of Chari et al. and Carter et al. that would teach or suggest these beneficial
`
`results, which were highly unexpected at the priority date.
`
`Clinical trials of unprecedented successz wholly unpredictable fiom the combination of
`Chari et al. and Carter et al., Zurther support the unobviousness of the invention
`claimed.
`
`Unexpected results, “demonstrating that the claimed invention exhibits some superior
`
`property or advantage that a person of ordinary skill in the relevant art would have found
`
`surprising or unexpected” are highly relevant and suitable for the rebuttal of a primafacie
`
`showing of obviousness. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). This was recently
`
`confirmed in Procter & Gamble Co. v. Teva Pharmaceuticals USA Inc. 566 F.3d 989, 989-99
`
`(Fed. Cir. 2009), where the Federal Circuit approved the district court’s consideration of
`
`evidence showing that the claimed compound (risedronate) possessed unexpected superior
`
`properties in the treatment of osteoporosis, including increased potency and low toxicity. It is
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`10
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`PHIGENIX
`
`Exhibit 1027-10
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`

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`noted that Procter & Gamble ultimately did not have to rely on this evidence to defend its
`
`patent, because the Federal Circuit held that Teva did not establish a primafacie case of
`
`obviousness. See also In re Dillon, 919 F.2d 688 (Fed. Cir. 1990).
`
`Although Applicants believe that, just as in Procter & Gamble, a primafacz’e case of
`
`obviousness has not been established in the present case, and thus Applicants need not rely on
`
`further evidence of unobviousness, it is nonetheless submitted that clinical trials of
`
`unprecedented success further support the non-obviousness of the claimed invention.
`
`It is well established that a patent owner can rebut the holding of obviousness, or an
`
`“obviousness” challenge, by using results of unexpected benefits, even if discovered after the
`
`patent had issued (see, Knoll Pharmaceutical Co., Inc. v. Teva Pharmaceuticals USA, Inc.,
`367F.3d 1381 (Fed. Cir. 2004)). In that case, Teva claimed that Knoll’s patented combination
`
`of hydrocodone (a narcotic) and ibuprofen (a non-steroidal anti-inflammatory drug or
`
`“NSAID”) was invalid on the ground of obviousness in view of similar combinations known in
`
`the art at the time the patent application was filed. Knoll submitted results of three clinical
`
`trials which had shown that the combination of hydrocodone and ibuprofen, when administered
`
`in the ratios specified in the patent, had unexpected synergistic analgesic effect. Overturning
`
`the district court’s refusal to consider this evidence because these unexpected benefits were
`
`discovered after the patent issued, the Federal Circuit held:
`
`Evidence developed after the patent grant is not excluded from consideration,
`for understanding of the full range of an invention is not always achieved at the
`time of filing the patent application. It is not improper to obtain additional
`support consistent with the patented invention, to respond to litigation attacks
`on validity. There is no requirement that the invention’s properties and
`advantages were fully known before the patent application was filed, or that the
`patent application contains all of the work done in studying the invention, in
`order for that work to be introduced into evidence in response to litigation
`attack. Nor is it improper to conduct additional experiments and provide later—
`obtained data in support of patent validity. (Knoll v. Teva, at 1385)
`
`Clearly, the same stande should be applied when assessing the non—obviousness of a
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`claimed invention during patent prosecution.
`
`11
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`PHIGENIX
`
`Exhibit 1027-11
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`

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`Enclosed is a Declaration of Dr. Barbara Klencke, M.D. discussing the results of a
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`single—arm, multi-center Phase II clinical trial (TDM43 74g) that has been undertaken with “T—
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`DMl,” a huMAb4D5-8—maytansinoid conjugate within the scope of the present claims. The
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`unexpectedly superior activity of T-DMl in that trial was wholly unpredictable to those skilled
`
`in the art.
`
`As explained in paragraphs 12 and 13 of the Declaration, patients in the TDM43 74g
`
`trial had progressive disease (metastatic HER2—expressing breast cancer) despite having been
`
`treated with a median of seven different anti—tumor agents, including at least five agents
`
`representing the most commonly used classes of drugs currently available for the treatment of
`
`metastatic breast cancer, HERCEPTIN® being one of them. The patients were terminally ill
`
`and T—DMl represented a last option, a last hope.
`
`Dr. Klencke reports in paragraph 15 of her Declaration that the results of the clinical
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`trial well exceeded all expectations, with an objective response rate (OR) of 32.7%
`
`(percentage of patients whose tumors shrank by at least 30%), and clinical benefit rate of
`
`44.5% (percentage of patients with objective response or stable disease maintained for at least
`
`6 months).
`
`Dr. Klencke further explains the significance of these results and how much better they
`
`are than results seen for other agents currently used in second- and third-line metastatic breast
`
`cancer therapy. Specifically, the OR for the combination of lapatinib and capecitabine as a
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`second-line therapy was 23.7%, and the OR for ixabepilone, the only approved third—line
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`therapy of metastatic breast cancer, was 12.4%. In the TDM43 74g clinical trial, the OR
`
`(32.7%) achieved with T-DM1 in a third—line setting significantly exceeded the ORRs observed
`
`in those current second-line and third-line therapies. (See, paragraphs 15, 16 and 17 of the
`
`Declaration.) Moreover, T—DMl demonstrated not only superior efficacy but also low toxicity.
`
`The clinical significance of this combination of properties is immediately apparent to those of
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`ordinary skill.
`
`12
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`PHIGENIX
`
`Exhibit 1027-12
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`

`

`Secondar considerationso non-obviousness
`
`Secondary considerations, such as failure by others, skepticism by experts, praise by
`
`others and satisfaction of a long-felt unmet need, are highly relevant for obviousness
`
`determination. Graham V. John Deere Co., 383 U.S. 1, 17 (1966). Indeed, secondary
`
`considerations “may often be the most probative and cogent evidence” of non-obviousness.
`
`Stratoflex, Inc. v. Aeroguip Corp, 713 F.2d 1530, 1538 (Fed. Cir. 1983).
`
`The clinical results discussed in the Klencke Declaration address a significant unmet
`
`medical need. In the real world of clinical practice, the ability to treat patients who do not
`
`respond to any other treatment currently available is immensely valuable. HERCEPTIN® itself
`
`has been hailed as a “wonder drug”, and yet there are many patients who do not respond to
`
`treatment with HERCEPTIN®. The present invention provides a new drug successful in the
`
`treatment of such patients and therefore makes a great contribution to the medical field. This
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`result was completely unpredictable from the cited references or from the prior art in general.
`
`The excitement of the medical community over the results of the efficacy of T-DMI in
`
`the terminally ill patient population of the TDM43 74g clinical trial is clearly reflected by the
`
`opinions expressed in Exhibits I and J of the Klencke Declaration. The same Exhibits also
`
`show that T-DMI addresses an unmet medical need, providing clinical benefits to a seriously
`
`ill patient population, which failed to respond to a variety of other standard of care treatments.
`
`As Ian Krop, MD, of the Dana-Farber Cancer Institute in Boston, states: “This is the first study
`
`looking at women who have failed so many other treatments,” adding that “these results are as
`
`good as we’ve ever seen in such a refractory [sick] population.” Edith Perez, MD, a breast
`
`cancer specialist at the Mayo Clinic in Jacksonville, Florida, expressed a similar sentiment
`
`stating that: “These patients. are very sick and right now we have no choices to offer them.”
`
`(See, Exhibit I of the Klencke Declaration.)
`
`Before the priority date, those skilled in the art predicted that utility of
`
`immunoconjugates would lie in “minimal—disease settings” due to difficulty in achieving a
`
`therapeutic window. (See Trail and Bianchi (Exhibit F of the Klencke Declaration), e.g., at
`
`page 585, col. 2, last para, and page 586, col. 2, last para; and see para. 11 of the Klencke
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`13
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`PHIGENIX
`
`Exhibit 1027-13
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`

`

`Declaration.) T—DMl surprisingly excelled in a disease setting that was anything but
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`“minima ”. The unexpected superior results achieved with T-DMl in the clinical setting are
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`highly relevant given that the success of the presently claimed immunoconjugates was
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`surprising and unexpected in view of the prior art, not only in view of the opposing
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`mechanisms of action of the two components of the immunoconjugate, but also in view of the
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`disappointing results of prior immuoconjugates. (See para. 26 of the Klencke Declaration.)
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`In conclusion, the claimed huMb4D5-8-maytansinoid conz'ugates are not rendered
`obvious by Chari ei al. in view 07_‘ Carter et al.
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`The ability of a prototype of the claimed huMAb4D5-8-maytansinoid conjugates to
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`provide clinical benefits to metastatic breast cancer patients who have failed multiple treatment
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`regimens is completely non—obvious from the cited combination of Chari et al. and Carter et al.
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`Indeed, to one of ordinary skill in the art at the time the present invention was made, reading
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`Chari et al. and Carter et al. but also being familiar with other pertinent art, such as the art cited
`
`in the Sliwkowski Declaration, manufacture of the conjugates claimed in the present
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`application would have been counter-intuitive. Given the incompatible mechanisms of action
`
`of the two components, i.e. the huMAb4D5-8 antibody and maytansinoid, known before the
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`earliest priority date of the present application, one of ordinary skill would have expected that
`
`the conjugation of a maytansinoid to the huMAb4D5—8 anti-ErbB2 antibody would not provide
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`any clinical benefit. Thus, at the time the present invention was made, one skilled in the art
`
`would not have been motivated to make a conjugate of huMAb4D5-8 with a maytansinoid.
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`In addition, the present invention addresses a significant unmet clinical need, extending
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`the lives and/or improving the quality of life of terminal cancer patients, who failed prior
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`stande of care treatments for HER2-expressing breast cancer.
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`Accordingly, the Examiner is respectfully requested to reconsider and withdraw the
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`present rejection.
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`Double Patenting
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`Claims 40-44 are provisionally rejected under 35 U.S.C. 101 as allegedly claiming the
`
`same invention as that of claims 20, 21, 22, 24 and 25 of copending Application No.
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`14
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`PHIGENIX
`
`Exhibit 1027-14
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`

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`12/609,737. This is a provisional double patenting rejection since the conflicting claims have
`
`not in fact been patented.
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`Applicants submit that upon consideration of the present arguments, this will be the
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`only rejection remaining in this application. Accordingly, the Examiner is respectfillly
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`requested to withdraw this rejection and permit the present application to issue as a patent.
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`(MPEP 804(I)(B)(2))
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`CONCLUSION
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`All claims pending in this application are believed to be in primafacie condition for
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`allowance, and an early action to that effect is respectfiilly solicited.
`
`Please charge any additional fees, including any fees for additional extension of time,
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`or credit overpayment to Deposit Account No. 50-2387 (referencing Attorney’s Docket No.
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`GNE-00073R2C2 ).
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`Respectfiilly submitted,
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`Date: July 6, 2010
`
`By Electronic Signature: /GINGER R. DREGER/
`Ginger R. Dreger, Reg. No, 33,055
`
`ARNOLD & PORTER LLP
`
`555 Twelfth Street, NW
`
`Washington, DC. 20004-1206
`Telephone: +1 415.356.3000
`Facsimile: +1 415.356.3099
`
`15
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`PHIGENIX
`
`Exhibit 1027-15
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`