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`CASE 4-31671A
`(167-62)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`IN RE PCT NATIONAL STAGE APPLICATION OF
`
`LANE ET AL.
`
`INTERNATIONAL APPLICATION NO: PCT/EP02/01714
`
`FILED: 18 FEBRUARY 2002
`
`U.S. Serial NO: 10/468,520
`
`35 USC §371 DATE: January 27, 2004
`
`FOR: TREATMENT OF SOLID TUMOURS WITH RAPAMYCIN
`
`DERIVATIVES
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`AMENDMENT
`
`In response to the Office Action of November 2, 2005, please amend the above-
`
`identified application as follows:
`
`Amendments to the specification begin on page 2 of this paper.
`
`Amendments to the Claims are reflected in the listing of the claims which begins on
`
`page 3 of this paper.
`
`Remarks/Arguments begin on page 9 of this paper.
`
`CERTIFICATE OF MAILING UNDER 37 C.F.R. §1.S(a)
`I hereby certify that this correspondence is being deposited with the United States Postal Service as
`first class mail, postpaid in an envelope, addressed to the: MAIL STOP AMENDMENT, Commissioner of Patents,
`U.S. Patent and Trademark Office, P.O. Box 1450, Aexandria, V
`2311-14 0 on May 2, 2006.
`
`Dated: May 2, 2006
`
`i......12. a. J
`
`Ann R. Pokalsky
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0024
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`

`

`Amendments to the Specification:
`
`Please replace paragraph 3 on page 1, beginning with "Compounds of formula I are" with the
`
`following amended paragraph:
`
`Compounds of formula I are disclosed e.g. in WO 94/0901 O[[,]] WO 95/16691 or 'PIO 90/41807
`
`[[,]] U.S. Patent Nos: 5.665,772: 6.440.990; 5.985.890; and 6.200.985. which are incorporated
`
`herein by reference. They may be prepared as disclosed or by analogy to the procedures
`
`described in these references.
`
`Please replace paragraph 4 on page 1, beginning with "Preferred compounds are" with the
`
`following amended paragraph:
`
`Preferred compounds are 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-
`
`2-ynyloxy-32( S )-dihydro-rapamyci n, 16-pent-2-ynyloxy-32( S )-dihydro-40-0-(2-hydroxyethyl )(cid:173)
`
`rapamyci n and, more preferably, 40-[[0]]-0-(2-hydroxyethyl)-rapamycin (referred thereafter as
`
`Compound A), disclosed as Example 8 in 'NO 94/09010 U.S. Patent Nos: 5.665.772 and
`
`6.440.990.
`
`- 2 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0025
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`

`

`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the application:
`
`Listing of Claims:
`
`Claim 1 (currently amended): A method for treating solid tumors in a subject in need thereof,
`
`comprising administering to said subject a therapeutically effective amount of a compound of
`
`formula I
`
`41
`
`5~4 3 ,,...... ~ 34
`
`2 1 0
`7
`6 N
`
`8
`
`0 0
`
`24
`
`19
`
`21
`
`wherein
`
`R1 is CH3 or C3-aalkynyl,
`
`Xis =O, (H,H) or (H,OH)
`
`provided that R2 is other than H when X is =O and R, is CH3i
`
`wherein said compound of formula I is administered concomitantly or sequentially with a co-
`
`agent which is a chemotherapeutic agent selected from the group consisting of:
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`an aromatase inhibitor.
`
`an antiestrogen. an anti-androgen or a gonadorelin agonist.
`
`a topoisomerase I inhibitor.
`
`a microtubule active agent, an alkylating agent. an antineoplastic antimetabolite or a
`
`platin compound.
`
`v.
`
`a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid
`
`phosphatase activitv. a further anti-angioqenic compound or a compound which induces cell
`
`differentiation processes.
`
`vi.
`
`a bradykinin 1 receptor or an anqiotensin 11 antagonist.
`- 3 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0026
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`vii.
`
`a cyclooxvgenase inhibitor. a bisphosphonate. a histone deacetvlase inhibitor. a
`
`heparanase inhibitor. a biological response modifier. an ubiguitination inhibitor. or an inhibitor
`
`which blocks anti-apoptotic pathways.
`
`viii.
`
`an inhibitor of Ras oncogenic isoforms,
`
`ix.
`
`x.
`
`a telomerase inhibitor. and
`
`a protease inhibitor. a matrix metalloproteinase inhibitor. a methionine aminopeptidase
`
`inhibitor. or a proteosome inhibitor.
`
`Claims 2-12 (cancelled)
`
`Claim 13 (currently amended): A method for treating solid tumor invasiveness or symptoms
`
`associated with such solid tumor §fGWtR invasiveness in a subject in need thereof comprising
`
`administering to said subject a therapeutically effective amount of a compound of formula I
`
`24
`
`13
`
`15
`
`19
`
`21
`
`wherein
`
`R1 is CH3 or C3-ealkynyl,
`
`R2 is H or-CHrCHrOH, and
`
`Xis =O, (H,H) or (H,OH)
`
`provided that R2 is other than H when X is =O and R, is CH3 ..
`
`wherein said compound of formula I is administered concomitantly or sequentially with a co(cid:173)
`
`agent which is a chemotherapeutic agent selected from the group consisting of:
`
`i.
`
`an aromatase inhibitor,
`
`- 4 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
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`ii.
`
`iii.
`
`iv.
`
`an antiestrogen. an anti-androgen or a gonadorelin agonist.
`
`a topoisomerase I inhibitor.
`
`a microtubule active agent. an alkylating agent. an antineoplastic antimetabolite or a
`
`platin compound,
`
`v.
`
`a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid
`
`phosphatase activity, a further anti-angiogenic compound or a compound which induces cell
`
`differentiation processes.
`
`vi.
`
`vii.
`
`a bradykinin 1 receptor or an anqiotensin II antagonist.
`
`a cyclooxvaenase inhibitor. a bisphosphonate. a histone deacetvlase inhibitor. a
`
`heparanase inhibitor. a biological response modifier. an ubiquitination inhibitor. or an inhibitor
`
`which blocks anti-apoptotic pathways.
`
`viii.
`
`an inhibitor of Ras oncogenic isoforms.
`
`ix.
`
`x.
`
`a telomerase inhibitor. and
`
`a protease inhibitor. a matrix metalloproteinase inhibitor. a methionine aminopeptidase
`
`inhibitor. or a proteosome inhibitor.
`
`Claims 14-15 (cancelled)
`
`Claim 16 (currently amended): A method for inhibiting or controlling deregulated angiogenesis
`
`in a subject in need thereof, comprising administering to said subject a therapeutically
`
`[[a]]~ffective amount of r:apamycin er a r:aparnycin derivati'w<e a compound of formula I
`
`24
`
`- 5 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0028
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`

`wherein
`
`R1 is CH3 or C3-aalkynyl.
`
`fu is H or -CH,-CH;r:.oH. and
`
`Xis =0. (H.H) or (H.OH)
`
`provided that R? is other than H when X is =O and R1 is CH~.
`
`Claim 17 (currently amended): The method of claim 16, wherein said r:apaFRycin or rapaFRycin
`
`derivative compound of formula I is administered concomitantly or sequentially with a co-agent
`
`which is a chemotherapeutic agent.
`
`Claim 18 (previously presented): The method of claim 17, wherein the co-agent is selected
`
`from the group consisting of
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`an aromatase inhibitor,
`
`an antiestrogen, an anti-androgen or a gonadorelin agonist,
`
`a topoisomerase I inhibitor or a topoisomerase II inhibitor,
`
`a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a
`
`platin compound,
`
`v.
`
`a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid
`
`phosphatase activity, a further anti-angiogenic compound or a compound which induces cell
`
`differentiation processes,
`
`vi.
`
`vii.
`
`a bradykinin 1 receptor or an angiotensin 11 antagonist,
`
`a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a
`
`heparanase inhibitor, a biological response modifier, an ubiquitination inhibitor, or an inhibitor
`
`which blocks anti-apoptotic pathways,
`
`viii.
`
`an inhibitor of Ras oncogenic isoforms,
`
`ix.
`
`x.
`
`a telomerase inhibitor, and
`
`a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase
`
`inhibitor, or a proteosome inhibitor.
`
`- 6 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0029
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`

`

`Claim 19 (cancelled)
`
`Claim 20 (currently amended): A pharmaceutical combination comprising a) a compound of
`
`Formula I
`
`24
`
`wherein
`
`R1 is CH;i or C3-ealkynyl.
`
`R2 is Hor -CH,-CH?-OH. and
`
`Xis =O. (H.H) or (H.OH)
`
`provided that R2 is other than H when X is =O and R1 is CH;i
`
`and b) a co-agent which is a chemotherapeutic agent selected from the group consisting of:
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`an aromatase inhibitor.
`
`an antiestroqen. an anti-androgen or a gonadorelin agonist.
`
`a topoisomerase I inhibitor.
`
`a microtubule active agent. an alkylating agent. an antineoplastic antimetabolite or a
`
`platin compound.
`
`v.
`
`a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid
`
`phosphatase activity, a further anti-angioqenic compound or a compound which induces cell
`
`differentiation processes.
`
`vi.
`
`a bradykinin 1 receptor or an anqiotensin II antagonist.
`
`- 7 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0030
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`

`

`vii.
`
`a cyclooxygenase inhibitor. a bisphosphonate. a histone deacetvlase inhibitor. a
`
`heparanase inhibitor. a biological response modifier. an ubiquitination inhibitor. or an inhibitor
`
`which blocks anti-apoptotic pathways.
`
`viii.
`
`an inhibitor of Ras oncogenic isoforms.
`
`ix.
`
`x.
`
`a telomerase inhibitor. and
`
`a protease inhibitor. a matrix metalloproteinase inhibitor. a methionine aminopeptidase
`
`inhibitor. or a proteosome inhibitor.
`
`Claims 21-23 (cancelled)
`
`- 8 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0031
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`

`

`REMARKS/ARGUMENTS
`
`In response to the Office Action of November 2, 2005, Applicants have amended the
`
`specification and claims, which when considered with the following remarks, is deemed to place
`
`the present application in condition for allowance. Favorable consideration of all pending claims
`
`is respectfully requested.
`
`The specification has been objected to for an alleged improper incorporation by
`
`reference. In response to this objection, Applicants have amended the specification at page 1 to
`
`include the equivalent U.S. patent equivalents to the WO publications listed therein. As
`
`presently amended, the specification is in compliance with 37 C.F.R.§1.57(f). Withdrawal of the
`
`objection to the specification is therefore respectfully requested.
`
`Claims 19 and 20 have been objected to as failing to specifically list the R 1, R2 and X
`
`substituents. As presently amended, claim 20 specifically recite the R1, R2 and X substituents.
`
`Claim 19 has been canceled without prejudice. Withdrawal of the objection to claims 19 and 20
`
`is therefore respectfully requested.
`
`Claims 13-15, 16-18, and 22-23 have been rejected under 35 U.S.C. §112, second
`
`paragraph, as allegedly indefinite for failing to particularly point out and distinctly claim the
`
`subject matter which applicant regards as the invention. Specifically, claim 13 is rejected for
`
`reciting "such tumor growth" which allegedly has no antecedent basis in the claim. In order to
`
`advance prosecution of this case, claim 13 has been amended to recite in relevant part: ""a
`
`method for treating solid tumor invasiveness or symptoms associated with such sold tumor
`
`invasiveness." Claims 16-17 and 22-23 have been rejected since the limitation "rapamycin
`
`derivative" is allegedly not clearly set forth explicitly and with reasonable clarity in the
`
`specification. As presently amended, claims 13 and 16 have been amended to recite "a
`
`compound of formula I" having a specific structural formula and a specific definition of the R1, R2
`
`and X substituents. Claims 14, 15, 22, and 23 have been canceled without prejudice.
`
`Withdrawal of the rejection of claims 13, 16-18 and 22-23 under 35 U.S.C.§ 112, second
`
`paragraph, is therefore respectfully requested.
`
`- 9 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0032
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`

`

`Claims 16-18 and 22-23 have been rejected under 35 U.S.C.§ 102(b) as allegedly
`
`anticipated by Surendra et al. (U.S. Patent No. 4,885, 171 ). Surendra et al. has been cited for
`
`teaching a method for treating certain tumors such as lymphatic leukemia, colon, mammary,
`
`melanocarcinoma and ependymoblastoma tumors with rapamycin alone or with other
`
`conventional chemotherapeutic drugs.
`
`As presently amended, claims 16-18 recite specific rapamycin derivatives. Claims 22-23
`
`have been canceled without prejudice. None of the rapamycin derivatives recited in presently
`
`amended claims 16-18 are disclosed in Surendra et al. Nor does Surendra et al. disclose a
`
`pharmaceutical composition comprising such rapamycin derivatives for use in a method for
`
`inhibiting or controlling deregulated angiogenesis. The subject matter of claims 16-18 is
`
`therefore distinguished from Surendra et al. Withdrawal of the rejection of claims 16-18 and 22-
`
`23 is therefore respectfully requested.
`
`Claims 16 and 22 have been rejected under 35 U.S.C.§ 102(b) as allegedly anticipated
`
`by Kao (U.S. Patent No. 5, 194,447). Kao has been cited for disclosing pharmaceutical
`
`compositions containing rapamycin derivatives, wherein the pharmaceutical compositions may
`
`be used in methods of treating solid tumors or inflammation. The rapamycin derivatives
`
`disclosed in Kao are sulfonylcarbamates of rapamycin. As presently amended, claim 16 does
`
`not encompass sulfonylcarbamates of rapamycin. Claim 16 is therefore distinguished from Kao.
`
`Claim 22 has been canceled without prejudice. Withdrawal of the rejection of claim 16 under 35
`
`U.S.C.§ 102(b) is therefore warranted.
`
`Claims 1, 11-15 and 19-21 have been rejected under 35 U.S.C § 102(b) as allegedly
`
`anticipated by WO 94/09010 ('010). WO '010 has been cited for allegedly teaching a method of
`
`treating tumors by administering pharmaceutical compositions comprising the rapamycin
`
`derivatives of formula (I) in combination with another anti-neoplastic agent such as etoposide.
`
`The Examiner notes that WO '010 indicates that a preferred compound is 40-0-(2-
`
`Hydroxy)ethyl-rapamycin, and directs Applicants to page 3, pages 6-8, page 12, and example 8
`
`for this teaching.
`
`Applicants respectfully traverse the rejection for the following reasons. Page 3 of WO
`
`'010 indicates that 40-0-(2-Hydroxy)ethyl-rapamycin is a preferred compound. Page 6 of WO
`- 10 -
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0033
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`

`

`'010 indicates that the compounds disclosed therein, which are of a much larger genus than that
`
`claimed in the present application, may be used in the "treatment of proliferative disorders, e.g.,
`
`tumors, hyperproliferative skin disorder and the like." Page 8 of the '01 O application discloses
`
`that compounds disclosed therein may be administered as the sole active ingredient or together
`
`with other drugs. Applicants respectfully submit however, that the "other drugs" mentioned on
`
`page 8 are included only in immunosuppressive and anti-inflammatory applications:
`
`The Novel Compounds may be administered as the sole
`active ingredient or together with other drugs. For example, in
`immunosuppressive applications such as prevention and treatment
`of graft vs. host disease, transplant rejection or autoimmune
`disease, the Novel Compounds may be used in combination with
`Ciclosporin, DK-506, or their immunosuppressive derivatives,
`corticosteroids, azathioprene; immunosuppressive monoclonal
`antibodies, e.g., monoclonal antibodies to CD3, CD4, CD25,
`CD28, or CD 45; and/or other immunomodulatory compounds.
`For anti-inflammatory applications, the Novel Compounds can be
`used together with anti-inflammatory agents, e.g., corticosteroids.
`For anti-infective agents, e.g., anti-viral drugs or antibiotics.
`
`Page 12 to which the Examiner refers, is not directed to a method for treating solid
`
`tumors or inhibiting or controlling deregulated angiogenesis in a subject in need thereof. Rather,
`
`as the heading on page 9 indicates, "The pharmacological activity of the Novel Compounds are
`
`demonstrated in e.g., the following tests." Subheading "8. Antitumor and MOR activity"
`
`discloses various tests where the antitumor activity of the compounds disclosed in WO '01 O and
`
`the ability to enhance performance of anticancer agents such as colchicine or etoposide, and
`
`performed in multidrug resistant cells and drug sensitive cells in vitro or in animals having
`
`multidrug resistant or drug sensitive tumors or infections. As page 13 of WO '01 O describes,
`
`equivalent results may be obtained using the compounds described therein "using test animals
`
`infected with drug-resistant and drug sensitive viral strains, antibiotic (e.g., penicillin) resistant
`
`and sensitive bacterial strains, anti-mycotic resistant and sensitive fungal strains as well as drug
`
`resistant protozoa! strains, e.g. ,Plasmodial strains, for example naturally occurring sub-strains
`
`of Plasmodium falciparum exhibiting acquired chemotherapeutic, anti-malarial drug resistance. "
`
`In order to advance prosecution of this application, the presently amended claims do not
`
`recite a topoisomerase II inhibitor. As described on page 7 of the application, etoposide is a
`
`topoisomerase II inhibitor.
`
`It is axiomatic that anticipation under section 102 requires that the
`
`- 11 -
`
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`Selected Prosecution History Documents
`Page 0034
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`

`

`prior art reference disclose every element of the claims. In re King, 801 F.2d 1324, 1326, 231
`
`USPQ 136, 138 (Fed. Cir. 1986). Thus, there must be no differences between the subject matter
`
`of the claim and the disclosure of the prior art reference. The corollary of this rule is equally
`
`applicable. The absence from the reference of any claimed element negates anticipation.
`
`Kloster Speedsteel AB v. Crucible Inc., 793 F.2d 1565, 1571, 230 USPQ 81, 84 (Fed. Cir. 1986).
`
`Applicants' invention is distinguished from WO '010 since the reference does not teach a
`
`method for treating solid tumors in a subject by administrating a therapeutically effective amount
`
`of a compound of formula I (wherein R1 is CH3 or C3-ealkynyl,
`
`R2 is H or-CH2-CHrOH, and Xis =O, (H,H) or (H,OH) provided that R2 is other than H when X
`
`is =O and R1 is CH3) concomitantly or sequentially with a chemotherapeutic co-agent as
`
`specifically claimed. Nor does WO '010 teach the specific pharmaceutical combination of claim
`
`20. Withdrawal of the rejection under 35 U.S.C. § 102(b) as pertains to presently amended
`
`claims 1, 13 and 20 is therefore warranted.
`
`Claims 1, 11-15 and 19-21 have been rejected under 35 U.S.C. §103(a) as allegedly
`
`unpatentable over Cottens et al. 5,985,890 and WO 95/16691 ('691 ). Cottens et al. has been
`
`cited for teaching rapamycin derivatives and pharmaceutical compositions comprising such
`
`rapamycin derivatives, of a much broader genus than that claimed by Applicants. For example,
`
`based on the substituents listed in columns 2 and 3 of '890 patent, and pages 3-7 of the '691
`
`application, the rapamycin derivatives described by Cottens et al. encompass many more
`
`compounds than recited in the presently amended claims. Cottens et al. has also been cited for
`
`teaching "that the anti-tumor activity of the compounds of the invention and their ability to
`
`enhance the performance of anti-tumor agents by alleviating multi-drug resistance is
`
`demonstrated by administration of an anti-cancer agent such as colchicines or etoposide to
`
`animals suffering from drug sensitive or multi-drug resistant tumors." Office Action, page 6, lines
`
`13-17, citing '980 column 14, lines 28-38., and '691, page 15. According to the Examiner, it
`
`would have been obvious to one skilled in the art at the time the invention was made, to select
`
`any of the species of the genus taught by Cottens and WO '691, including those that make up
`
`the subgenus of the claims because one of ordinary skill in the art would reasonably expect that
`
`West-Ward Exhibit 1027
`Selected Prosecution History Documents
`Page 0035
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`

`

`any of the species of the genus would have similar properties and thus the same use as the
`
`genus as a whole.
`
`Applicants respectfully traverse the rejection of claims 1, 11-15 and 19-21 under 35
`
`U.S.C. §103(a) for the following reasons. Cottons and WO '691 teach an enormous class of
`
`compounds allegedly having anti-tumor activity. As presently amended, claims 1, 13, and 20
`
`recite a much smaller class of compounds which when combined with a specific
`
`chemotherapeutic agent, may be used in a method for treating solid tumors or in a method for
`
`treating solid tumor invasiveness. None of the chemotherapeutic agents presently recited by the
`
`claims are taught by Cottons or WO '691. Indeed, Cottens and WO '691 only disclose
`
`colchicine or etoposide as anticancer agents to be used in an in vitro or in vivo test to
`
`demonstrate anti-tumor activity of the compounds described therein.
`
`Applicants respectfully submit therefore, that there is nothing in the combined teachings
`
`of Cottens and WO '691 that would suggest a method for treating solid tumors or solid tumor
`
`invasiveness in a subject using the compounds of formula I with the substituents R1, R2 and X
`
`as specifically defined in the presently amended claims, in combination with a
`
`chemotherapeutic agent as specifically recited in the presently amended claims. Nor is there a
`
`suggestion for the pharmaceutical combination of presently amended claim 20 in the combined
`
`teachings of Cottens and WO '691. Absent a suggestion in the teachings of Cottens and WO
`
`'691 taken as a whole, for the different combinations presently claimed, the subject matter of
`
`claims 1, 13 and 20 is not obvious. Withdrawal of the rejection as it applies to presently
`
`amended claims 1, 13 and 20, is therefore respectfully requested.
`
`In view of the foregoing remarks and amendments, it is firmly believed that the subject
`
`case is in condition for allowance, which action is earnestly solicited.
`
`Novartis
`Corporate Intellectual Property
`One Health Plaza, Building 430
`East Hanover, NJ 07936-1080
`(862) 778-7909
`
`- 13 -
`
`Respectfully submitted,
`
`Ann R. Pokalsky
`Attorney for Applicants
`Reg. No. 34,697
`
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`\P E
`
`O
`
`~.('I
`~
`\iO~· l\_.11\\m ~
`~- IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CASE 4-31671A
`(167-62)
`
`- - - - - - #
`
`-
`
`IN RE PCT NATIONAL STAGE APPLICATION OF
`LANE ET AL.
`
`ART UNIT:1614
`
`INTERNATIONAL APPLICATION NO: PCT/EP02/01714
`
`EXAMINER: RAE, C.E.
`
`FILED: 18 FEBRUARY 2002
`
`U.S. SERIAL NO: 10/468,520
`
`35 USC §371 DATE: January 27, 2004
`
`FOR: TREATMENT OF SOLID TUMOURS WITH
`RAPAMYCIN DERIVATIVES
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`AMENDMENT
`
`In response to the Office Action of May 4, 2007, please amend the above-identified
`
`application as follows:
`
`Amendments to the Claims are reflected in the listing of the claims which begins on
`
`page 2 of this paper.
`
`Remarks/Arguments begin on page 12 of this paper.
`
`CERTIFICATE OF MAILING UNDER 37 C.F.R. §1.S(a)
`
`I hereby certify that this correspondence is being deposited with the United States Postal Service as first class mail,
`postpaid in an envelope, addressed to the: MAIL STOP AMENDMENT, Commissioner of Patents, U.S. Patent and
`Trademark Office, P.O. Box 1450, Alexandria, V 22313-14
`on November 5, 2007.
`
`Dated: November 5, 2007
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`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the application:
`
`Listing of Claims:
`
`Claim 1 (currently amended): A method for treating solid tumors in a subject in need thereof,
`
`comprising administering to said subject a therapeutically effective amount of a compound of
`
`formula I
`
`24
`
`wherein
`
`R2 is M-eF -CHrCHrOH, and
`
`Xis =O, (l=l,l=l) er (l=l,Ol=l)
`
`13rei,tiEleEf tl=aat ~ is etl=aer tl=laR l=I wl=leR X is -Q aRG R+--i&-GWarr•JJ
`
`wherein said compound of formula I is administered concomitantly or sequentially with a co-
`
`agent which is a chemotherapeutic agent selected from the group consisting of:
`
`i.
`
`an aromatase inhibitor selected from the group consisting of steroids and the group
`
`consisting of the non-steroids aminogluethimide. roglethimide. pyridoglutethimide. trilostane.
`
`testolactone. ketokonazole. vorozole. fadrozole. anastrozole and letrozole ,
`
`ii.
`
`an antiestrogen selected from the group consisting of tamoxifen. fulvestrant. raloxifene.
`
`and raloxifene hydrochloride, aA the anti-androgen bicalutamide or a gonadorelin agonist
`
`selected from the group consisting of abarelix. goserelin and goserelin acetate,
`
`iii.
`
`a topoisomerase I inhibitor selected from the group consisting of topotecan. irinotecan. 9-
`
`nitrocamptothecin and the camptothecin conjugate PNU-166148. or a topoisomerase II inhibitor
`
`selected from the group consisting of an anthracylcline and an antraguinone,
`- 2 -
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`iv.
`
`a microtubule active agent selected from the group consisting of taxanes. vinca
`
`alkaloids. discodermolides. and epothilones, an alkylating agent selected from the group
`
`consisting of cyclophosphamide. ifosfamide. melphalan and nitrosourea, an antineoplastic
`
`antimetabolite selected from the group consisting of 5-fluorouracil. capecitabine. gemcitabine.
`
`methotrexate and edatrexate. or a platin compound,
`
`v.
`
`a compound targeting/decreasing a pFeteiR eF lipid kiAase the activity of a vascular
`
`endothelial growth factor (VEGF) selected from the group consisting of 1-(4-chloroanilino)-4-(4-
`
`pyridyl methyl)phthalazine or a pharmaceutically acceptable salt thereof. an anthranilic acid
`
`amide an anti-VEGF antibody. and an anti-VEGF receptor antibody: a compound which targets.
`
`decreases or inhibits the activitv of the epidermal growth factor receptor selected from the
`
`group consisting of compound CP 358774. compound ZD 1839. compound ZM105180.
`
`trastuzumab. cetuximab. lressa. 081-774. CL-1033. EKB-569. GW-2016. E1.1. E2.4. E2.5.
`
`E6.2. E6.4. E2.11. E6.3. and E7.6.3. or a compound which targets. decreases or inhibits the
`
`activitv of PDGF. c-Abl family members and their gene fusion products. or lipid phosphatase
`
`selected from the group consisting of N-phenyl-2-pyrimidine-amine derivatives. imatinib.
`
`PD180970. AG957 and NSC 680410: a compound which targets. decreases or inhibits the
`
`activitv of protein kinase C selected from the group consisting of the staurosporine derivatives
`
`midostaurin. UCN-01. safingol. BAY 43-9006. Brvostatin 1. Perifosine. limofosine. RO 318220.
`
`RO 320432. GO 6976. Isis 3521. l Y333531 and l Y379196: okadaic acid. pFeteiA eF lipia
`
`pl:lespl=latase aGtivity, a f1:1Ftt:\eF the anti-angiogenic compounds thalidomide or TNP-470. or a
`
`compound which induces cell differentiation processes selected from the group consisting of
`
`retinoic acid. a-. y- or a-tocopherol or a-. y- and a-tocotrienol,
`
`vi.
`
`a 13FadykiAiR 1 FeGepteF eF aA aRgieteAsiA II aAtageAist[[,]]
`
`vi[[i]}. a cyclooxygenase inhibitor selected from the group consisting of celecoxib. refecoxib.
`
`etoricoxib. valdecoxib or a 5-alkyl-2arvlaminophenylacetic acid, a bisphosphonate selected from
`
`the group consisting of etridonic acid. clodronic acid. tiludronic acid. pamidronic acid. alendronic
`
`acid. ibandronic acid. risedronic acid and zoledronic acid, a histone deacetylase inhibitor
`
`selected from the group consisting of MS-27-275. SAHA. pyroxamide. FR-901228 and valproic
`
`acid. a t:\epaFaAase iAl:tieiteF, a biological response modifier selected from the group consisting
`-3-
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`of a lymphone and an interferon, aR 1:1l3iei1:1itiRatioR iRl:lil3itor, or aA iRl:lil3iter 'NRisl:l 131osks aRti
`
`a13013totis 13atl:lways[[,]]
`
`vii[[i]]. aA iRl:lil3itor of Ras OAGO€J0AiG
`
`iseforms[[,]] a farnesyl transferase inhibitor selected from
`
`the group consisting of L-744.832 and DK8G557.
`
`viii[[x]]. a the telomerase inhibitor telomestatin, and
`
`!x.
`
`a 13rotease iRl:lil3itor[[,]] a matrix metalloproteinase inhibitor selected from the group
`
`consisting of batimastat. marimastat. prinomastat. BMS-279251, BAY 12-9566. TAA211 or
`
`AAJ996, a the methionine aminopeptidase inhibitor bengamide or a derivative thereof, or a the
`
`proteosome inhibitor PS-341.
`
`Claims 2-12 (cancelled)
`
`Claim 13 (currently amended): A method for treating solid tumor invasiveness or symptems
`
`assosiatoe with s1:1cl:l selie t1:1mer irv.iasiveAess in a subject in need thereof comprising
`
`administering to said subject a therapeutically effective amount of a compound of formula I
`
`24
`
`wherein
`
`R1 is CH3 Gf-GualkyAyl,
`
`R2 i&-l=f....aF-CH2-CHrOH, and
`
`Xis =O, (1=1,1=1) or (1=1,01=1)
`13rovidod tl:lat ~ is etl:lor tl:laA l=I wl:leA X is -o aRd ~-i&GMa[l.JJ
`
`-4-
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`wherein said compound of formula I is administered concomitantly or sequentially with a co-
`
`agent which is a chemotherapeutic agent selected from the group consisting of:
`
`i.
`
`an aromatase inhibitor selected from the group consisting of steroids and the group
`
`consisting of the non-steroids aminogluethimide. roglethimide. pyridoglutethimide. trilostane.
`
`testolactone. ketokonazole. vorozole. fadrozole. anastrozole and letrozole,
`
`ii.
`
`an antiestrogen selected from the group consisting of tamoxifen. fulvestrant. raloxifene.
`
`and raloxifene hydrochloride, aR the anti-androgen bicalutamide or a gonadorelin agonist
`
`selected from the group consisting of abarelix. goserelin and goserelin acetate,
`
`iii.
`
`a topoisomerase I inhibitor selected from the group consisting of topotecan. irinotecan. 9-
`
`nitrocamptothecin and the camptothecin conjugate PNU-166148. or a topoisomerase II inhibitor
`
`selected from the group consisting of an anthracylcline and an antraquinone,
`
`iv.
`
`a microtubule active agent selected from the group consisting of taxanes. vinca
`
`alkaloids. discodermolides. and epothilones, an alkylating agent selected from the group
`
`consisting of cyclophosphamide. ifosfamide. melphalan and nitrosourea,