PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicants
`
`Application No.
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`Filed
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`For
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`:
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`:
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`:
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`:
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`Sung Hwan Moon et al.
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`12/553,858
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`September 3, 2009
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`REVERSE-TURN MIMETICS AND METHOD RELATING
`
`THERETO
`
`Examiner
`
`Art Unit
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`Docket No.
`
`Date
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`:
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`:
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`:
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`:
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`Kahsay Habte
`
`1624
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`200146.402C9
`
`July 29, 2011
`
`Mail Stop Amendment
`Commissioner for Patents
`
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`Commissioner for Patents:
`
`AMENDMENT
`
`In response to the Office Action dated February 10, 2011, please extend the
`
`response due date 3 months, to expire on August 10, 2011. Enclosed are a Petition for an
`
`Extension of Time and the requisite fee.
`
`Please amend the above-identified application as follows:
`
`Amendments to the Claims are reflected in the listing of claims which begins on
`
`page 2 of this paper.
`
`Remarks begin on page 11 of this paper.
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`Amendments to the Claims:
`
`This listing of claims will replace all prior versions, and listings, of claims in the
`
`application:
`
`Listing of Claims:
`
`1. — 42.
`
`(Canceled)
`
`43.
`
`(Previously Presented) A compound of formula (VI):
`
`ave?
`RC\N/NY\N
`
`KW”
`
`0
`
`X1
`
`X2
`
`RJ
`
`E O
`
`as an isolated stereoisomer or a mixture of stereoisomers or as a pharmaceutically
`
`*3
`
`(VI)
`
`acceptable salt, wherein,
`
`Ra is a bicyclic aryl group haVing 8 to 11 ring members, which may have 1 to 3
`
`heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
`
`Rb is a monocyclic aryl group haVing 5 to 7 ring members, which may have 1 to 2
`
`heteroatoms selected from nitrogen, oxygen or sulfur, and aryl ring in the compound may have
`
`one or more substituents selected from a group consisting of halide, hydroxy, cyano, lower alkyl,
`
`and lower alkoxy groups;
`
`RC is a saturated or unsaturated C1_6alkyl, C1_6alkoxy, perfluoro C1_6alkyl group;
`
`and
`
`X1, X2, and X3 may be the same or different and independently selected from
`
`hydrogen, hydroxyl, and halide.
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`44.
`
`(Previously Presented) The compound of claim 43, wherein the bicyclic
`
`aryl group is not substituted.
`
`45.
`
`(Previously Presented) The compound of claim 43, wherein the bicyclic
`
`aryl group is substituted.
`
`46.
`
`(Previously Presented) The compound of claim 45, wherein the bicyclic
`
`aryl group is substituted indazolyl.
`
`47.
`
`(Previously Presented) The compound of claim 46 selected from the
`
`group consisting of:
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`HN
`
`O
`
`Y
`
`CH
`H’
`\N
`
`OOH
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`N
`
`0 KO
`
`OH
`
`NH
`
`OH
`
`; and
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`48.
`
`(Previously Presented) The compound of claim 45, wherein the bicyclic
`
`aryl group is substituted quinolinyl.
`
`49.
`
`(Previously Presented) The compound of claim 48 selected from the
`
`group consisting of:
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`50.
`
`(Previously Presented) The compound of claim 45, wherein the bicyclic
`
`aryl group is substituted 3,4-dihydrobenzo[1,4]oxazinyl.
`
`51.
`
`(Previously Presented) The compound of claim 50 selected from the
`
`group consisting of:
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`52.
`
`(Previously Presented) The compound of claim 45, wherein the bicyclic
`
`aryl group is substituted naphthyl.
`
`53.
`
`(Previously Presented) The compound of claim 52 being
`
`54.
`
`(Previously Presented) The compound of claim 45, wherein the bicyclic
`
`aryl group is substituted benzotriazolyl.
`
`55.
`
`(Previously Presented) The compound of claim 54 selected from the
`
`group consisting of:
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`56.
`
`(Previously Presented) A pharmaceutical composition comprising a
`
`compound according to claim 43 and a pharmaceutically acceptable carrier.
`
`57.
`
`(Previously Presented) The pharmaceutical composition of claim 56,
`
`wherein the bicyclic aryl group is not substituted.
`
`58.
`
`(Previously Presented) The pharmaceutical composition of claim 56,
`
`wherein the bicyclic aryl group is substituted.
`
`59.-66. (Canceled)
`
`10
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`REMARKS
`
`Reconsideration of the present application in View of the above amendments and
`
`the following remarks is respectfully requested.
`
`Claims 43-66 were pending.
`
`Claims 59-66 have been canceled without
`
`acquiescing to the rejection in the Office Action or prejudice to future prosecution in a
`
`continuation application. Accordingly, claims 43-58 are pending.
`
`Re'ection Under 35 U.S.C. 112 First Para ra h Written Descri tion
`
`Claims 59-66 stand rejected under 35 U.S.C. 112, first paragraph, as containing
`
`new matter with regard to the Rd (C1_7 alkyl) moiety recited in formula (VII) of claim 59.
`
`H
`vaN
`
`O
`
`R
`
`N
`
`\T Rd
`c\N/ j/\N/\Ra
`N\_/§O
`to
`o.
`
`Applicants respectfully disagree with this ground of rejection. Compounds of
`
`formula (VII) are a subgroup of compounds of formula (IV).
`
`(VII)
`
`Rb
`
`H
`N
`
`0
`
`RC\ /N
`
`/\N
`
`Ra
`
`11
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`As discussed below, the present application provides sufficient written description for the Rd
`
`moiety in formula (IV), it thus also provides sufficient support for the Rd moiety in formula
`
`(VII).
`
`The present application exemplifies over 3000 compounds, a significant portion
`
`of which are compounds of Structure (IV) having hydrogen at the 9-position (i.e., at Rd). The
`
`application as originally filed also exemplifies a number of compounds having substituents other
`
`than hydrogen at the 9-position (see Compound Nos. 69, 78, 80, 81, 82, 83, and 111 of Table 4).
`
`Of these, Compound Nos. 69, 78, 80, 83, and 111 exemplify the embodiment wherein the 9-
`
`position substituent is methyl.
`
`The compounds of Structure (IV) may be made by coupling different individual
`
`component pieces in a series of amide bond formations, followed by a ring closure step, and then
`
`conversion to compounds of Structure (IV) by conventional techniques. One embodiment of this
`
`synthetic procedure is illustrated in Figure 1 of the application as originally filed:
`
`(a) DMSU
`(h) HATU/DIEAINMP
`(v) i) Pipaidinc I DMF
`ii) HOBT / [31C I UMP
`(d) HCOOH, mom lamp,
`
`DH
`
`OR
`
`H
`0/7301
`b3/R1 4’ monN/
`
`R.
`Second Component Piece
`
`——~—.—n’.
`mg/
`
`ow
`
`N/Re
`
`P01
`
`R
`
`3
`
`0
`
`M/
`
`<__.____
`
`(a)
`
`W
`
`0/
`
`6/;;"6/R-..
`
`Fin“: Companam Piece
`
`N
`
`/
`
`0R1
`
`N
`
`0
`
`“4
`
`G
`
`R9
`
`Tuner:
`
`NH WM G/NH
`
`1) pipetidine/DMF
`Z:
`0
`
`OH
`
`‘21
`
`(3/
`
`Rs
`
`0
`
`Third Cumponent Hm
`
`Founh Component Piece:
`
`12
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`In more general terms,
`
`the specification teaches that the compounds of this
`
`application (referred to as “reverse-tum mimetics”) “may be synthesized by reacting a first
`
`component piece with a second component piece to yield a combined first-second intermediate,
`
`followed by reacting the first-second intermediate with third component pieces sequentially to
`
`provide a combined first-second-third-fourth intermediate, and then cyclizing this intermediate
`
`to yield the reverse-tum mimetic structure” (see specification at page 24, lines 17-22). The
`
`specification continues by teaching that “[t]he reverse-tum mimetic structures of formula (III)
`
`and (IV) may be made by techniques analogous to the modular component synthesis disclosed
`
`above, but with appropriate modifications to the component pieces” (see specification at
`
`page 25,
`
`lines 3-5) (emphasis added). Further, synthesis of a library of such reverse-tum
`
`mimetic compounds “may be accomplished using known peptide synthesis techniques,
`
`in
`
`combination with first, second and third component pieces of the invention” (see specification at
`
`page 28, line 7 to page 29, line 2).
`
`Referring again to Figure 1, the substituent at the 9-position of Structure (IV) is
`
`introduced via a first component piece having the following general structure:
`
`R0
`
`R2
`
`WAN/H
`
`OR
`
`First Component Piece
`
`This starting material may be prepared by any of a variety of known synthetic
`
`techniques.
`
`In Figure 1,
`
`it
`
`is prepared by a displacement reaction between HzN-Rz and
`
`CH(OR)(OPol)CH2Br (where Pol represents a polymeric support). However, one skilled in this
`
`art can make this starting material by any number of techniques, including preparation from
`
`amino acids which, depending upon the amino acid used, gives first component pieces with
`
`different amino acid side chain groups on the (x-amino acid carbon:
`
`amino acid
`side chain
`
`
`
`amino acid
`side chain
`
`
`
`OH
`
`OR
`
`Amino Acid
`
`First Component Piece
`
`13
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`For example, when made from glycine,
`
`the first component piece has the
`
`following structure:
`
`0
`
`OH
`
`Glycine
`
`NH2 —>
`
`R0
`
`OR
`
`R2
`
`N/H
`
`First Component Piece
`
`Similarly, when made from alanine, valine,
`
`leucine or isoleucine,
`
`the first
`
`component piece has one of the following structures:
`
`CH3
`
`0
`
`OH
`
`Alanine
`
`NH2 —>
`
`CH3
`
`R2
`
`N/H
`
`R0
`
`OR
`
`First Component Piece
`
`H30
`
`CH3
`
`H30
`
`CH3
`
`0
`
`0
`
`NH2 —>
`
`R0
`
`R2
`
`N/H
`
`OH
`
`Valine
`
`OR
`
`First Component Piece
`
`CH3
`
`CH3
`
`NH2 —>
`
`R0
`
`CH3
`
`CH3
`
`R2
`
`N/H
`
`OH
`
`Leucine
`
`OR
`
`First Component Piece
`
`CH3
`
`CH3
`
`H30
`
`0
`
`OH
`
`NH2 —>
`
`14
`
`H30
`
`R0
`
`OR
`
`R2
`
`N/H
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`Isoleucine
`
`First Component Piece
`
`While Figure 1 of the specification illustrates the first component piece as a
`
`glycine equivalent, the specification also teaches that compounds of Structure (IV) may be made
`
`with modification to the component pieces, which necessarily includes use of first component
`
`pieces other than the glycine equivalent shown in Figure 1.
`
`In this regard, Table 1 of the application lists the amino acid side chain groups for
`
`naturally occurring amino acids. Specifically included in this table are the amino acid side chain
`
`groups for glycine, alanine, valine, leucine and isoleucine (see specification at pages 17 and 18).
`
`In the case of the amino acid side chain groups for alanine (methyl), valine (isopropyl), leucine
`
`(isobutyl) and isoleucine (sec-butyl), these amino acid chain groups are classified as “lower
`
`chain alkyl” in the specification as originally filed (see specification at page 18, lines 13-15).
`
`The specification continues by stating that lower chain alkyl specifically includes C1_7alkyl (see
`
`specification at page 18, lines 18-23).
`
`Accordingly, the specification as originally filed:
`
`(1)
`
`illustrates synthesis of the claimed compounds using a first component
`
`piece that is a glycine equivalent (z'.e.,
`
`the amino acid side chain group is hydrogen), and
`
`exemplifies the same with a very large number of compounds having hydrogen at the 9-position;
`
`(2)
`
`teaches that compounds of Structure (IV) may be made with modification
`
`to the component pieces;
`
`(3)
`
`exemplifies such modification with compounds made using a first
`
`component piece other than a glycine equivalent, of which Compounds Nos. 69, 78, 80, 83, 84
`
`and 111 exemplify the embodiment wherein the first component piece is an alanine equivalent
`
`(i.e., the amino acid side chain group — and thus the 9-position substituent of Structure (IV) — is
`
`methyl); and
`
`(4)
`
`teaches that amino acid side chain groups include natural amino acid side
`
`chain groups, specifically hydrogen (glycine), methyl (alanine),
`
`isopropyl (valine),
`
`isobutyl
`
`(leucine) and sec-butyl (isoleucine); and further that a preferred amino acid side chain group is
`
`C 1 -7alkyl .
`
`15
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`This is not a situation where Applicants have failed to make representative
`
`compounds having an alkyl group at
`
`the position in question.
`
`Indeed, Applicants have
`
`specifically exemplified compounds with methyl at this position. Having made and disclosed
`
`methyl derivatives of Structure (IV), and having taught that Structure (IV) compounds are made
`
`by modification to the component pieces, Applicants clearly had possession of “alkyl” at this
`
`position. One need not exemplify multiple alkyl groups in order to have possession of an alkyl
`
`substituent, particularly when other alkyl groups are readily introduced to Structure (IV) by
`
`relatively simple modification of the first component piece (which modification is taught in the
`
`specification as originally filed). As for the specific carbon range (z'.e., C1_7), Applicants teach
`
`that amino acid side chain groups include the alkyl side chains of naturally occurring amino
`
`acids, as well as lower chain alkyls generally and preferably C1_7alkyl. Again, while Figure 1
`
`illustrates synthesis using a glycine equivalent of the first component piece, one skilled in this art
`
`readily appreciates that any of a variety of amino acid side chain groups can be introduced at this
`
`position. Such side chain groups include a C1_7alkyl as specifically disclosed in the specification
`
`as originally filed, and as exemplified by representative compounds having methyl as the amino
`
`acid side chain group (z'.e., an alanine equivalent).
`
`As the Examiner correctly noted in the outstanding Office Action, the written
`
`description requirement
`
`is satisfied when the claimed subject matter is described in the
`
`specification in such a way as to reasonably convey to one skilled in the relevant art that the
`
`inventors, at the time the application was filed, had possession of the claimed invention. This is
`
`clearly the situation at hand. Not only have Applicants disclosed specific representative
`
`compounds of C1_7alkyl at the 9-position of Structure (IV) (i.e., Compounds Nos. 69, 78, 80, 83,
`
`and 111), but have also specifically disclosed that compounds of Structure (IV) are made by
`
`modification of the component pieces — which modification readily includes use of other amino
`
`acid side chain groups in the preparation of the first component piece.
`
`Accordingly, Applicants submit that the claimed subject matter is sufficiently
`
`supported by the specification as originally filed to satisfy the written description requirement of
`
`§1 12, first paragraph.
`
`16
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`However, merely for expediting issuance of claims directed to the embodiment
`
`wherein Rd is hydrogen, Applicants have canceled claims 59-66. This amendment should not be
`
`construed as an acquiescence to this rejection, and Applicants specifically reserve the right to
`
`continue prosecution of embodiments wherein Rd is other than hydrogen in a continuation
`
`application.
`
`Allowable Subject Matter
`
`Claims 43-58 are allowed. Applicants thank the Examiner for allowing these
`
`claims.
`
`Potentially Related Application
`
`Applicants submit that US. Application No. 12/682,881 may be related to the
`
`present application.
`
`The Director is authorized to charge any additional fees due by way of this
`
`Amendment, or credit any overpayment, to our Deposit Account No. 19-1090.
`
`Respectfully submitted,
`
`SEED Intellectual Property Law Group PLLC
`
`/g Qing Lin/
`Qing Lin, Ph.D.
`Registration No. 53,937
`
`17
`
`

`

`Application No. 12/553,858
`Response to Office Action dated February 10, 2011
`
`QXL/kw
`
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`
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`Fax: (206) 682-6031
`
`1944397_1.DOCX
`
`18
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