IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
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`Applicants:
`
`Hannon eta/.
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`Confmnation No.:
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`9352
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`Application No:
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`10/997,086
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`Ali Unit:
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`1635
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`Filed:
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`Title:
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`November 23, 2004
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`Examiner:
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`K. CHONG
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`METHODS AND COMPOSITIONS FOR RNA INTERFERENCE
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`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`AMENDMENT AND RESPONSE TO JULY 2, 2010 OFFICE ACTION
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`This paper is filed in response to the July 2, 1010 Final Office Action. A reply was
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`originally due on October 2, 2010. Applicants request a three-month extension of time to
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`January 2, 2011, which is a Sunday. Therefore a response is due Monday, January 3, 2011 and
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`this paper is being timely filed. The required fee for the extension accompanies this paper. The
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`Commissioner is authorized to charge any other fees due, or to credit any overpayment in fees, to
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`Deposit Account No. 08-0219.
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`Amendments to the Claims begin on page 2.
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`Remarks begin on page 4.
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`1
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`Benitec - Exhibit 1023 - page 1
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`

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`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
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`AMENDMENT
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`In the Claims
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`Please amend the claims as fol.lows, without prejudice. This listing of the claims will
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`replace all prior versions and listings of claims in the application:
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`1-37.
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`(Cancelled)
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`38.
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`(Previously presented) A method for attenuating expression of a target gene in a
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`mammalian cell, the method comprising:
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`introducing into a mammalian cell an expression vector comprising:
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`(i) an RNA polymerase promoter, and
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`(ii) a sequence encoding a short hairpin RNA molecule comprising a double-stranded
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`region, wherein the double-stranded region consists of at least 20 nucleotides but not more than
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`29 nucleotides, [such that the saort hairpin RNA does not trigger a protein kiflase Rl'JA activated
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`(PK..I(.) response in the mammalian cell,]
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`wherein the shmt hairpin RNA molecule is a substrate for Dicer-dependent cleavage and
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`does not trigger a protein kinase RNA-activated CPK) response in the mammalian cell,
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`wherein the double-stranded region of the short hairpin RNA molecule comprises a
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`sequence that is complementary to a portion of the target gene, and
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`wherein the short hairpin RNA molecule is stably expressed in the mammalian cell in an
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`amount sufficient to attenuate expression of the target gene in a sequence specific manner, and is
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`expressed in the cell without use of a PK inhibitor, whereby expression of the target gene is
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`inhibited.
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`39.
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`40.
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`(Cancelled)
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`(Previously presented) The method of claim 38, wherein the expression vector
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`further comprises LTR sequences located 5' and 3' of the sequence encoding the short hairpin
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`RNA molecule.
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`41.
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`42.
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`(Cancelled)
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`(Previously presented) The method of claim 38, wherein the short hairpin RNA
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`molecule comprises a double-stranded region consisting_ of at least 21 nucleotides.
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`Benitec - Exhibit 1023 - page 2
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`Application No. 10/997,086
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`43.
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`(Previously presented) The method of claim 38, wherein the short hairpin RNA
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`molecule comprises a double-stranded region consisting_ of at least 22 nucleotides.
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`44.
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`(Previously presented) The method of claim 38, wherein the short hairpin RNA
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`molecule comprises a double-stranded region consisting_ of at least 25 nucleotides.
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`45.
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`(Previously presented) The method of claim 38, wherein the short hairpin RNA
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`molecule comprises a double-stranded region consisting_of29 nucleotides.
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`46.
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`(Previously presented) The method of claim 38, wherein the short hairpin RNA
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`molecule has a total length of about 70 nucleotides.
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`47.
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`(Previously presented) The method of claim 38, wherein the RNA polymerase
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`promoter comprises a polll promoter or a pol III promoter.
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`48.
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`(Withdrawn) The method of claim 47, wherein the pol III promoter comprises a
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`U6, an H 1, or an SRP promoter.
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`49.
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`(Previously presented) The method of claim 47, wherein the pol II promoter
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`comprises a Ul or a CMV promoter.
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`50.
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`(Currently Amended) The method of claim 38, wherein the short hairpin RNA
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`molecule attenuates expression of the target gene in the mammalian cell by at least about 60% as
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`compared to a control cell consisting of an expression construct encoding a short hairpin RNA
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`that does not target the target gene.
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`51.
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`(Currently Amended) The method of claim 38, wherein the short hairpin RNA
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`molecule attenuates expression of the target gene in the mammalian cell by about 60% to about
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`90% as compared to a control cell consisting of an expression construct encoding a short hairpin
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`RNA that does not target the target gene.
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`Benitec - Exhibit 1023 - page 3
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`

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`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
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`REMARKS
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`I.
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`STATUS OF THE CLAIMS
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`Claims 38, 40, and 42-51 are pending in this application. Claim 48 has been withdrawn.
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`Claim 38 is amended to more particularly point out the presently claimed invention. The
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`amendment to claim 38 raises no issue of new matter. Support for the amendments to claim 38
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`("wherein the short hairpin RNA molecule is a substrate for Dicer-dependent cleavage and does
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`not trigger a protein kinase RNA-activated (PKR) response in the mammalian cells") may be
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`found throughout the application, for example, support may be found, inter alia, at Example 8 of
`the application entitled "dsRNA Suppression in the Absence of a PKR Response." See mf 0349-
`0354 ofUS 20080213861. Support may also be found in the originally published claims, and~
`0044. Support for "is expressed in the cell without use of a PK inhibitor" can be found, inter
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`alia, at Example 8 and Figure 50 and ~~120 and 141, showing MEF cells with the PK response
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`suppressed. This is contrasted with dsRNA in MEF cells without use of a PK inhibitor. Support
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`for these amendments can be found throughout the present specification and in the parent
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`application, U.S.S.N. 10/055,797. These amendments raise no issue of new matter.
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`II.
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`REJECTIONS UNDER 35 U .S.C. § 112, SECOND PARAGRAPH
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`Claims 50 and 51 are rejected as being allegedly indefinite.
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`In response, applicants traverse the rejection. Without conceding the correctness of the
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`Examiner's position, applicants have amended claims 50 and 51. In view of these amendments,
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`applicants request that the Examiner reconsider and withdraw this ground of rejection.
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`111.
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`DOUBLE PATENTING
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`The Examiner rejected the pending claims over co-pending application U.S. Serial No.
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`11/894,676.
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`In reply, applicants request that the Examiner hold this rejection in abeyance since the
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`'676 application is not yet allowed.
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`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
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`IV.
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`OBVIOUSNESS
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`A.
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`Rejections
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`Claims 38, 40,42-47 and 49-51 were rejected under 35 U.S.C. § 103(a) as allegedly
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`being obvious over Kreutzer eta/., Dietz eta/., and Kingsman eta/.
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`Claims 38, 40, 42-47 and 49-51 were rejected under 35 U.S.C. § l 03(a) as allegedly
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`being obvious over Fire eta/., Dietz et al., and Kingsman et al.
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`In reply, applicants traverse the rejection. Before addressing the Examiner's two
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`rejections, applicants have set out below a discussion of the state of the art as of the priority date
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`of this application and how the inventors' claimed invention was an advance over that that art.
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`B.
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`The State of the Art Prior to January 22, 20021
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`In order to provide background to the views of a person of ordinary skill in the art, and
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`background against which the present invention was made, Applicants provide below a brief
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`summary of the state of the ati regarding gene silencing using RNA molecules. This summary is
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`not to be considered an admission that any reference set out below is proper prior art as to the
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`presently claimed invention.
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`1. Dr. Hannon's Goal: Exploiting RNAi to Study Gene Function in Mammalian
`Cells
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`By the invention of the short hairpin technology described in the Hannon application, Dr.
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`Hannon and his co-inventors successfully achieved an ambitious goal of exploiting RNAi. as a
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`powerful and widely applicable genetic tool to study gene function in mammalian cells. In
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`particular, this novel approach allowed one to use RNAi to stably attenuate expression of the
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`target gene in a sequence specific manner in a mammalian cell, without activating a non(cid:173)
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`sequence specific PK response. To achieve this goal, Dr. Hannon and his co-inventors focused
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`on identifying and understanding the cellular machinery that mediated RNAi in the cell. A key
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`part of their work involved identifying and characterizing the components of the RNAi pathway.
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`Among other things, Dr. Hannon and his co-inventors isolated and described two critical
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`Application No. 10/997,086
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`components of the RNAi machinery: the enzyme Dicer, which the inventors named and
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`demonstrated as mediating the processing of dsRNA (Bernstein et al. Nature, 2001), and
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`"RJSC", the nuclease complex responsible for degradation of target mRNAs. Dr. Hannon
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`concisely summarized his overall strategy in a grant proposal for the work he subsequently
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`carried out:
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`My laboratory has devoted a number of years to creating improved
`tools for probing gene function in cultured mammalian cells;
`however, our experience indicates that a facile loss-of-function
`tool is lacking. Unfortunately, dsRNA induces somewhat generic
`responses in mammalian cells. It is our hope that by understanding
`the mechanistic basis of dsRNA-iuduced silencing, we may not
`only unravel a mysterious and important piece of biology but also
`provide the means to create improved tools for analyzing gene
`function in diverse organisms in which traditional genetic methods
`are either cumbersome or unavailable. This notion that has
`contributed to the decision to focus substantial effort in my
`laboratory toward elucidating the mechanism of RNA
`interference ...
`
`. . .In this application, we propose a biochemical approach to
`deciphering the mechanisms that underlie dsRNA-induced gene
`silencing. RNA-interference allows an adaptive defense against
`both exogenous and endogenous dsRNAs, providing something
`akin to a dsRNA immune response. The primary goal of the work
`proposed in this application is to understand the mechanisms by
`which a cell can raise this response. We have presented evidence
`that RNA interference is accomplished, at least in part, through the
`action of a sequence-specific nuclease that is generated in response
`to dsRNA. Our data, and that of others (Hamilton and Baulcombe,
`1999), is consistent with a model in which dsRNAs present in a
`cell are converted, in a manner analogous to antigen processing,
`into discrete, small RNAs that guide the nuclease in the choice of
`substrate. We propose to purify and characterize the nuclease and
`to clone the protein and RNA components of the enzyme. In
`addition, we propose to develop approaches that may atlow the use
`of cultured Drosophila cells as a general tool for probing gene
`function. The combination of these studies may lead eventually to
`an ability to harness RNA interference as a genetic tool in other
`organisms, particularly mammals, in which analogous tools are
`presently lacking.
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`1 January 22,2002 is the tiling date oftbe parent USSN 10/055,797 to wbicb tbe present application claims priority.
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`Application No. 10/997,086
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`2. Dicer Cleaves Long dsRNA to Make Guide RNAs or siRNAs
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`Hannon and his co-inventors demonstrated that Dicer processes long dsRNAs into short
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`(approximately 21-25 nt) RNAs, which are referred to as short interfering RNAs (siRNAs) or
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`"guide" RNAs, the tetm coined by Dr. Hannon. Bernstein et al. Nature 409: 363-366 (2001).
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`The siRNAs are then incorporated into a protein (nuclease) complex called the RNA-induced
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`silencing complex (RJSC) Hammond et at., Nature 404:293-296 (2000). The siRNAs function
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`to guide the RJSC/siRNA complex to specific mRNAs, which are recognized through base
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`pairing interactions by having a complementary sequence to the siRNA, and are then destroyed
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`by RISC. Through this process, guide RNAs or siRNAs can inhibit gene expression by
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`targeting destruction of specific mRNAs in the cell. Notably, the ability of long dsRNAs to
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`trigger RNAi, therefore, requires Dicer to first cleave or process the long dsRNA into guide or
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`siRNAs. Bernstein et aL Nature 409: 363-366 (2001); Hammond et al., Nature Rev. Genetics
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`2:110-119.
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`3. Pre-Dicer and Post-Dicer Strategies to Achieve RNAi
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`Dr. Hannon's work in discoveting Dicer and the mechanism ofDicer processing
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`demonstrated that one could potentially intervene in the RNAi pathway in two places.
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`Benitec - Exhibit 1023 - page 7
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`

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`I Pre-Dicer
`Long dsRNA
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`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
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`j Post-Dicer I
`SiRNA
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`(I) A Pre-Dicer strategy (see Pre-Dicer Pathway in above diagram) starts with long
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`dsRNA triggers (see "Long dsRNA" in diagram above). Fire et al. demonstrated that long
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`dsRNAs (for example, 300-500 bp) could effect gene silencing. Once introduced into a cell,
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`these long dsRNA triggers are cleaved into siRNAs by Dicer. The siRNAs then combine with
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`RISC to mediate specific gene silencing.
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`(ll) A Post-Dicer strategy (see Post-Dicer Pathway above) uses short RNAs that mimic
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`the siRNA products ofDicer cleavage (i.e., 21-25 nucleotide long short RNAs with 3'
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`overhangs). Once introduced into a cell, the siRNAs bypass the Dicer enzyme altogether. The
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`siRNAs directly combine with RISC to effect gene silencing. Elbashir SM, Lendeckel W,
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`Tuschl T (200 I) RNA interference is mediated by 2 1- and 22-nucleotide RNAs. Genes Dev
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`15(2): 188-200. Elbashir et al. has been discussed by Dr. Hernandez in her Declaration filed in
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`Application No. 10/997,086
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`this case. In this regard, Elbashir et al. included data showing that dsRNAs of30 nucleotides in
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`length or shorter were ineffective in mediating RNAi and would not work as Pre-Dicer triggers.
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`Short RNAs would work only if they were designed to bypass Dicer processing.
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`4. Fire and Elbashir and Caplen Fail to Show Stable, Long Term Silencing
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`Fire's approach of using long dsRNA as a pre-Dicer trigger failed to show how one could
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`use this strategy in mammalian cells. Of course, it was known that introducing or expressing
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`long dsRNA in most mammalian cells would ki.ll them by activating the anti-viral!PKR response.
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`(Williams, B. R. Role of the double-stranded RNA-activated protein kinase (PKR) in cell
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`regulation. Biochern. Soc. Trans. 25, 509-513 (1997).) This innate anti-viral pathway would
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`have taught away from using dsRNA for silencing expression of a particular gene in a
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`mammalian cell.
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`Another approach was taken by both Elbashir and Caplen --using post-Dicer triggers,
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`that is, siRNAs to achieve inhibition of gene expression. One primary drawback of this approach
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`is that the effect is only transient. The application of siRNAs (see the post-Dicer pathway in the
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`above diagram) is transitory. Once the siRNAs are applied exogenously i.nto the cell, processed
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`by Dicer and then complexed with RJSC, there is no additional effect. This Post-Dicer approach
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`using siRNAs will only temporarily silence genes.
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`These two approaches (Pre-Dicer and Post-Dicer) did not provide for stable, long term
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`silencing in mammalian cells. Therefore, the pre-Dicer and post-Dicer approaches were of
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`limited benefit in mammalian cells. Stable, long term silencing was necessary to carry out
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`studies in mammalian cells to understand the genetic basis of human disease that Dr. Hannon
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`envisioned. Before RNAi could be harnessed as a tool for silencing specific genes in
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`mammalian systems, such as in methods claimed in the present invention, a considerable hurdle
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`had to be overcome. The problem was how to nigger RNAi in a gene-specific manner in
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`mammalian cells without invoking non-specific anti-viral responses to the RNAi trigger.
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`Application No. 10/997,086
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`5.
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`Invention ofHannon et al. Using Expressed shRNA in Mammalian Cells
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`Hannon demonstrated that one could actually engineer a pre-Dicer trigger that would not
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`activate the anti-viral!PKR response, that could be stably expressed in the mammalian cell and
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`surprisingly, would function as a potent trigger to specifically silence gene expression in
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`mammalian cells. The presently claimed invention solves the problems of stable expression,
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`avoidance of the PK response and sequence-specific inhibition of gene expression in mammalian
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`cells. The diagram below illustrates the shRNA expression vector approach, which is claimed by
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`the applicants.
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`The above diagram shows the introduction of shRNA expression vectors into the
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`mammalian cell. These vectors can be stably expressed in a mammalian cell and don't activate
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`the PKR response. The vectors express a short hairpin RNA molecule which is a substrate for
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`Dicer-dependent cleavage and does not activate the PKR response. The double-stranded region
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`Benitec - Exhibit 1023 - page 10
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`

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`Application No. 10/997,086
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`of the short hairpin RNA molecule comprises a sequence that is complementary to a portion of
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`the target gene.
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`Thus, the entirely different approach ofElbashir and Caplen- that of using post-Dicer
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`triggers which could act to silence gene expression without being processed by Dicer taught
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`away from Hannon's invention of using stable expression of shmi hairpin RNAs as pre-Dicer
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`triggers to suppress mammalian gene expression.
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`6.
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`lndust1y Acclairn
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`As evidenced by numerous awards and by the adoption of his short hairpin technology as
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`a fundamental biomedical research tool, Dr. Hannon's pioneering work in the RNAi field has
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`received widespread acclaim. In 2005, Dr. Hannon received the Award for Outstanding
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`Achievement in Cancer Research from the American Association for Cancer Research (AACR),
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`which honored Dr. Hannon" ... for his work uncovering the biochemical mechanism ofRNA
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`interference of gene expression (RNAi) and his contributions to the discovery and development
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`of short hairpin RNAs as tools for genetic manipulation of mammalian cells. (See Exhibit A).
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`In 2007, Dr. Hannon received two more prestigious awards, the Award in Molecular Biology
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`from the National Academy of Sciences, and the Paul Marks prize for the valuable contribution
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`his RNAi work to cancer research from Memorial Sloan-Kettering Cancer Center. (See Exhibits
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`B and C.) In granting that award, MSKCC noted how Dr. Hannon had applied his research in
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`understanding the RNAi pathway to develop this valuable new technology, and his recognition
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`as a leader in the field:
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`Dr. Hannon is a leader in the relatively new field of RNA
`interference (RNAi). RNAi is a naturally occurring mechanism for
`regulating the expression of genes (controlling which genes are
`turned on and turned off in cells). In the laboratory, it is used as a
`tool to study the function of specific genes, and it's being
`investigated as a therapeutic approach for treating many different
`diseases, including cancer.
`
`Dr. Hannon's laboratory has elucidated key biochemical details of
`the components of the pathways involved in RNAi and is using
`these fmdings to develop molecular tools that can be used for gene
`discovety, the evaluation of gene function, and the generation of
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`animal models. He has developed new techniques for using RNAi
`to study cancer development and is investigating possible cancer
`therapies that make use of small. interfering RNAs (siRNAs).
`
`Dr. Hannon discovered several proteins and enzymes that are an
`essential part of the RNAi mechanism, including Dicer, which
`cleaves double-stranded RNA into siRNAs; the RISC complex,
`which helps regulate protein translation and is involved in the
`body's defense against viral infections; and Argonaute2, which
`cleaves messenger RNA.
`
`He also has been at the forefront of adapting RNAi techniques to
`study genes in mammals, and using these techniques to understand
`the variety ofpathways that can lead to the formation of tumors.
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`The presently claimed invention described in the Hannon application was the basis for
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`various shRNA libraries, which have become widely used tools for genetic analysis in
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`mammalian cells. Reflecting the valuable contribution of this technology to biomedical research,
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`during 2002-2006, Dr. Hannon was among the top five most highly cited scientists with the
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`highest number of high impact papers in the field of molecular biology and genetics. The 2002
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`Genes & Development paper, "Short hairpin RNAs (shRNAs) induce sequence-specific
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`silencing in mammalian cells," in which Dr. Hannon reported much of the work underlying the
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`presently claimed invention, was cited more than 500 times, including more than 100 papers in
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`the biotechnology field.
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`As further evidence of the non-obviousness of the claimed invention, Applicants
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`previously submitted a Declaration under 37 C.F.R. § 1.132 from Professor Nouria Hernandez.
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`(Another courtesy copy is attached as Exhibit D.) As Prof. Hernandez states, it would not have
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`been obvious to one of ordinary skill in the art at the time of the invention that one could
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`attenuate target gene expression in a mammalian cell by introducing an expression construct
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`encoding a short hairpin RNA molecule having a double-stranded region of20-29 nucleotides.
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`Indeed, according to Prof Hernandez it was unexpected that the claimed method would result in
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`effective target gene attenuation, and one of ordinary skill at the time of the invention would
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`have had no reasonable expectation that it would do so.
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`

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`C.
`
`The Claimed Invention
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`The claimed invention is directed to:
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`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
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`Claim 38. A method for attenuating expression of a target gene in a
`mammalian cell, the method comprising:
`
`introducing into a mammalian cell an expression vector
`comprising:
`
`(i) an RNA polymerase promoter, and
`
`(ii) a sequence encoding a short hairpin RNA molecule comprising
`a double-stranded region, wherein the double-stranded region
`consists of at least 20 nucleotides but not more than 29
`nucleotides,
`
`wherein the short ha.irpin RNA molecule is a substrate for
`Dicer-dependent cleavage and does not trigger a protein kinase
`RNA-activated (PK) response in the mammalian cell,
`
`wherein the double-stranded region of the short hairpin RNA
`molecule comptises a sequence that is complementary to a p01tion
`of the target gene, and
`
`wherein the short hairpin RNA molecule is stably expressed in the
`mammalian cell in an amount sufficient to attenuate expression of
`the target gene in a sequence specific manner, and is expressed in
`the cell without use of a PK inhibitor, whereby expression of the
`target gene is inhibited.
`
`Applicants note that this claim is presented as an example of the claimed invention and in
`
`order to facilitate the discussion below of certain claimed features of the invention.
`
`D.
`
`Examiner's Comments Regarding Declaration of Professor Hernandez
`Under 37 C.F.R. §1.132 Are Incorrect Legally and Factually
`
`The Examiner has taken the position the Hernandez Declaration does not provide
`
`sufficient evidence that a person of ordinary skill in the art would not have had a reasonable
`
`expectation of success at using a shRNA with a double stranded region of between 20 and 29
`
`nucleotides in length. The Examiner takes the position that Kreutzer et al. (of record) provides
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`evidence that a dsRNA having a double stranded region of at least 21 bp was capable of
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`mediating RNAi in cells which is direct evidence against the data in Elbashir.
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`Application No. 10/997,086
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`In reply, applicants respectfully traverse the Examiner's position. Applicants have
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`identified several legal and factual errors with regard to the Examiner's discussion of the
`
`Hernandez Declaration which are important to point out. First, the Examiner erroneously
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`discounted the "opinion" evidence provided by Professor Hernandez. The Examiner mistakenly
`
`believes Professor Hernandez is providing "expert opinion." In fact, Professor Hernandez is
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`providing the opinion of a person of ordinary skill in the art, which is different than an expert
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`opinions. The opinion of a person of ordinary skill in the art at the critical time is actually a fact
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`to be considered in an obviousness analysis. Prof. Hernandez was an Investigator at the Howard
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`Hughes Medical Institute at the time working in the area of RNA and studying RNA polymerase
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`Ill. She was aware ofElbashir et al. at the time. Unlike a retrospective expert opinion, the
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`Declaration is based on the personal knowledge of Prof. Hernandez testifying as a person of
`
`ordinary skill in the art at that time. The statement of Professor Hemandez is therefore factual
`
`evidence that must be taken into account, and not expert opinion as discussed in the passage
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`from the MPEP relied upon by the Examiner, MPEP 716.0l(c).
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`Second, it appears that the Examiner has impermissibly heightened the standard when
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`catTying out a patentability assessment under 35 U.S. C.§ 103. The Examiner ctiticizes the
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`Hemandez Declaration because "the Declaration by Dr. Hernandez does not conclusively prove
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`that one of ordinary skill in the art would not have expected to be able to use a dsRNA of20-29
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`bps in an expression vector to mediate RNAi." (Emphasis added.) There is no requirement
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`under the patent law that a rebuttal to obviousness "conclusively prove" that a person of ordinary
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`skill in the art would not have an expectation. Dr. Hernandez has provided evidence that a
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`person of ordinary skill in the art would have believed that Elbashir teaches away from the
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`invention and that there would have been no reasonable expectation of success in carrying out
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`the claimed invention. There is no requirement for conclusive proof, and applicants request that
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`the Examine reconsider the evidence of the Hemandez Declaration.
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`Third, the Examiner has misapprehended the contents ofElbashir in her statement that
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`"Elbashir et al. teach double stranded RNAs of30 bp are not efficiently processed to 21 to 23 bp
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`dsRNAs is not a true teaching of teaching away from using dsRNAs of30 bp or less given it
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`appeared some of the dsRNAs of less than 30 bps worked., See Office Action sentence
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`spanning pages 9-10. Applicants direct the Examiner to the data expressed in Figure 1 b of
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`US !DOCS 7804991 vl
`
`14
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`Benitec - Exhibit 1023 - page 14
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`

`
`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
`
`Elbashir showing that dsRNAs of 29 bp and 30 bp in length failed to mediate RNAi (bars
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`indicating effect of both 29bp and 30bp was equivalent to controls). The factual evidence in
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`Elbashir et al. therefore teaches away from the claimed invention. This is conclusive evidence
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`supporting the statements made by Prof. Hernandez that Elbashir teaches away from using
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`dsRNAs of29 or 30 bps, and teaches away by discouraging one of skill from pursuing the
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`claimed invention. Moreover, there is no evidence whatsoever in Elbashir that dsRNAs shorter
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`than 29 bp were effective as pre-Dicer triggers. Such an inference would have no scientific
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`support.
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`Elbashir taught that to overcome the inability of the cellular RNAi machinery to process
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`short dsRNA molecules into the 21-23nt (guide) siRNA mediating target gene suppression, one
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`instead could directly introduce an RNA molecule mimicking an siRNAs into the cell. (See
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`Figure 5 ofElbashir.) In view ofElbashir, one of skill would have expected that a 21 nucleotide
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`long RNA could therefore serve as an RNAi trigger without the need for processing. To one of
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`ski.ll in the art, such a result, however, would have provided no evidence or expectation that a
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`hairpin RNA molecule with a 21 bp double-stranded region could mediate RNAi, in particular
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`because to mediate RNAi, the hairpin RNA would first have to be processed into an siRNA. In
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`view ofElbashir, that a short hairpin RNA (having a double-stranded region of less than 29 bp or
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`at least 20 base pairs) could be used as an RNAi trigger was, in fact, surprising and unexpected.
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`Fourth, rebuttal evidence can be submitted by way of a declaration and the entire
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`situation regarding patentability must be reviewed in view of the new evidence. See 37 C.P.R.
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`§ 1.132 and M.P .E.P. § 2141. In particular, whenever an applicant submits additional evidence,
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`the Examiner must reconsider patentability of the claimed invention, and any decision to
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`maintain a rejection must show it was based on the totality of the evidence. !d. "Facts
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`established by the rebuttal evidence must be evaluated along with the facts on which the
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`conclusion of obviousness was reached, not against the conclusion itself." M.P.E.P. 2142
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`(citing In re Eli Lilly & Co., 902 F.2d 943 (Fed. Cir. 1990))(emphasis added). "Consideration of
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`rebuttal evidence and arguments requires Office personnel to weigh the proffered evidence and
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`arguments. Office personnel should avoid giving evidence no weight, except in rare
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`circumstances." See In re Alton, 76 F.3d 1168, 1174-75, 37 USPQ2d 1578, 1582-83 (Fed. Cir.
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`1996).
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`US !DOCS 7804991 vl
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`15
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`Benitec - Exhibit 1023 - page 15
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`

`
`Application No. 10/997,086
`Attorney Docket No. 0287000.130.US1
`
`Here, applicants have met their burden by providing rebuttal evidence via the teachings
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`of Elbashir and the Hernandez Declaration. Instead of taking the factual evidence contained in
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`the Hernandez Declaration into account, the Examiner characterizes the statements made by
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`Prof Hernandez in her Declaration and data cited therein as "opinion." Prof. Hernandez is not
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`offering an expert opinion, but is offering the opinion of a person who was a person of ordinary
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`skill in the art, and thus the opinion ofProf. Hernandez is a fact that must be considered in
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`carrying out a patentability assessment as to obviousness. Indeed, Prof. Hernandez is not
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`"arguing" but is rather presenting evidence as a person of ordinary skill in the art at that time for
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`the Examiner to consider. It is en-or to consider the content of the Hernandez Declaration as
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`"opinion." The statements therein are facts that must be taken into account.
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`E.
`
`The Claimed Invention Is Not Obvious In View Of the Combination of
`Kreutzer, Dietz and Kingsman
`
`Claims 38, 40,42-47 and 49-51 were rejected under 35 U.S.C. § 103(a) as aUegedly
`
`being obvious over Kreutzer et al., Dietz et al., and Kingsman eta!.
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`1.
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`Kreutzer et at. Discloses "Chemically Modified" Structures that Do Not
`Make Obvious the Claimed Invention
`
`Applicants traverse the rejection. First, applicants note that the claims have been
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`amended and now require that the "short hairpin RNA molecule is a substrate for Dicer(cid:173)
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`dependent cleavage." Kreutzer provides no evidence that the chemicaUy modified RNA
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`structures are even processed through the RNAi pathway. The claimed invention requires that
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`the short hairpin RNA molecule be a substrate for Dicer and the structures described by
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`Kreutzer, with the chemical modifications, would not be such a substrate.
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`The "dsRNA" that Kreutzer describes (see [0069]) is a synthetic and chemically altered
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`RNA molecule (synthons modified by disulfide bridges) comprised of single strands linked by a
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`disulfide bridge. Such a chemically altered species cannot be expressed within in a cell.
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`Kreutzer would not have provided any reasonable expectation of success with regard to how an
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`unmodified dsRNA, or a hairpin RNA molecule that is expressed within a cell, would have
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`affected gene expression.
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`US !DOCS 7804991 vl
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`16
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`Benitec - Exhibit 102