Ex Parte SULLENGER

Patent Trial and Appeal Board

Jul 20, 2015

12610330 (P.T.A.B. Jul. 20, 2015)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/610,330 11/01/2009 Bruce A. SULLENGER 5667-00157 1218
26753 7590 07/20/2015
Andrus Intellectual Property Law, LLP
100 EAST WISCONSIN AVENUE, SUITE 1100
MILWAUKEE, WI 53202
EXAMINER
SHIN, DANA H
ART UNIT PAPER NUMBER
1674
MAIL DATE DELIVERY MODE
07/20/2015 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte BRUCE A. SULLENGER
__________

Appeal 2012-010469
Application 12/610,330
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, ROBERT A. POLLOCK, and
JACQUELINE T. HARLOW, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a method
for making a Dicer substrate. The Examiner rejected the claims as
anticipated and as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 Appellant identifies the Real Party in Interest as Duke University (see App.
Br. 3).
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Statement of the Case
Background
In “RNA interference (RNAi), endogenously formed (e.g., naturally
produced intracellularly) or exogenously introduced (e.g., transfected, or
introduced by a microorganism, into a cell) double-stranded RNA
(‘dsRNA’) is processed by Dicer (an RNAse III family enzyme) into
discrete, small RNA duplexes of between 21–25 basepairs” (Spec. 1).
“[D]uplexes will be referred to as small interfering RNA (siRNA) if the
strands of the duplexes are perfectly complementary, or as microRNAs
(miRNAs) if the strands of the duplexes are imperfectly base paired” (id.).
The Claims
Claims 6–10 are on appeal. Claim 6 is representative and read as
follows:
6. A method for making a Dicer substrate, comprising:
(a) synthesizing a nucleic acid molecule comprising
(i) a targeting moiety comprising an aptamer, and
(ii) a first single stranded RNA, wherein the
targeting moiety and the first single stranded RNA are a
contiguous nucleic acid molecule; and
(b) hybridizing a second single stranded RNA with the
first single stranded RNA in forming an RNA silencing moiety
that is dsRNA which can act as a Dicer substrate, and wherein
the two strands of dsRNA have full complementarity or partial
complementarity;
wherein the targeting moiety is capable of binding to a
receptor on the surface of a cell and, upon binding, the nucleic
acid molecule is subsequently internalized into the cell and
transported inside the cell to the cytoplasm for accessing Dicer.

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The Issues
A. The Examiner rejected claims 6–9 under 35 U.S.C. §§ 102(a)/102(e)
as anticipated by Davis2 (Ans. 4–5).
B. The Examiner rejected claim 10 under 35 U.S.C. § 103(a) as obvious
over Davis and Lee3 (Ans. 5–7).
A. 35 U.S.C. §§ 102(a)/102(e) over Davis
The Examiner finds that:
Davis teaches that one can make an aptamer-RNAi
construct, wherein aptamer binds to a cell surface protein and a
dsRNA/shRNA (comprising a sense strand and an antisense
strand) is targeted to a desired target sequence for RNAi-
mediated target sequence inhibition. Davis teaches that the
aptamer conjugated to the dsRNA/shRNA enhances cellular
uptake of the dsRNA/shRNA, which is a substrate of Dicer that
generates siRNAs from dsRNA/shRNA. Davis teaches that the
aptamer-RNAi construct is delivered to the cytoplasm of the
targeted cells, wherein aptamer is attached to the 3’ or 5’ end of
either the sense or antisense strand.

(Ans. 5).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Davis anticipates claim 6?
Findings of Fact
1. Davis teaches “an RNAi construct may comprise one or more
aptamers . . . . An aptamer is a nucleic acid that interacts with a target of
interest to form an aptamer:target complex” (Davis ¶ 9).

2 Davis, M., US 2005/0256071 A1, published Nov. 17, 2005.
3 Yoontae Lee et al., MicroRNA Maturation: Stepwise Processing and
Subcellular Localization, 21 EMBO J. 4663–4670 (2002).
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2. Davis teaches that “[i]ncorporation or attachment of the
aptamer to the sense or antisense strand allows each component to retain its
activity; that is, the aptamer component retains the ability to interact with a
specific target, and the sense and/or antisense strands retain their ability to
inhibit target gene expression by an RNAi mechanism” (id.).
3. Davis teaches that “[a]ptamers of the present invention may be
selected and/or optimized for interaction (e.g. binding) with the internalizing
peptides discussed above. Such an interaction may facilitate cellular uptake
of the aptamer and/or RNAi construct” (id. ¶ 100).
4. Davis teaches that the “sense strand should retain the ability to
hybridize with the antisense strand, and, in the case of longer nucleic acids,
should not interfere with the activity of RNAses, such as Dicer, that
participate in cleaving longer double-stranded constructs to yield smaller,
active siRNAs” (id. ¶ 68). Davis teaches that “the siRNA constructs can be
generated by processing of longer double-stranded RNAs, for example, in
the presence of the enzyme dicer” (id. ¶ 87). Davis teaches that “any duplex
portion should be susceptible to processing by nucleases such as Dicer” (id.
¶ 91).
5. Davis teaches that “it is possible to design an RNA molecule
targeted by an aptamer sequence at the 5’ end and containing an siRNA
duplex at the 3’ end . . . . Luciferase downregulation will only be seen if the
siGL3 duplex can reach the cytoplasm of the cells and still function despite
the presence of the aptamer on the 5’ end of the sense strand” (id. ¶ 189).
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6. Davis teaches that “[p]roduction of RNAi constructs can be
carried out by chemical synthetic methods or by recombinant nucleic acid
techniques” (id. ¶ 67).
7. Davis teaches that the “aptamer may occur on either the sense
or antisense strand and may occur at either the 3’ or 5’ end of either strand
. . . typically an aptamer will be incorporated into a linear nucleic acid
backbone of the RNAi construct” (id. ¶ 69).
8. Davis teaches that “double-stranded structure may be formed by
a single self-complementary nucleic acid strand or two complementary
nucleic acid strands. Duplex formation may be initiated either inside or
outside the cell” (id. ¶ 84).
9. Davis teaches that the “aptamer and/or polynucleotide may be
internalized by a cell, and binding of the aptamer to a target molecule, such
as a peptide, polypeptide, or protein, may facilitate internalization of the
polynucleotide into the cell” (id. ¶ 69).
10. Davis teaches an xPSM-A10-3 aptamer sequence that “targets
the prostate-specific membrane antigen (PSMA) that is overexpressed on
prostate acinar epithelial cells” (id. ¶¶ 179, 181).
11. Davis teaches an siGL3 siRNA sequence that “will likely still
be able to function when attached to the 3’ end of the aptamer sequence” (id.
¶¶ 183, 188).
12. Davis teaches that the “combination of the xPSM-A10-3 and
siGL3 sequences yielded the following for the sense strand of this aptamer-
siRNA conjugate . . . . The aptamer sequence is at the 5’ end and the siGL3
sense strand is located at the 3’ end” (id. ¶¶ 184–185).
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13. Davis teaches that the “single-stranded molecule will need to be
annealed to the antisense strand of the siGL3 duplex . . . . This will lead to a
duplex region from nucleotides 60-77 on the xPSM-A10-3-siGL3 sequence
given previously” (id. ¶ 186).
Principles of Law
A prior art reference can only anticipate a claim if it discloses all the
claimed limitations “arranged or combined in the same way as in the claim.”
Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1361
(Fed. Cir. 2012).
The “question for the purposes of anticipation is ‘whether the number
of categories and components’ disclosed in [the prior art] is so large that the
combination . . . ‘would not be immediately apparent to one of ordinary skill
in the art.’ Wrigley, 683 F.3d at 1361.” Kennametal, Inc. v. Ingersoll
Cutting Tool Co., 780 F.3d 1376, 1382 (Fed. Cir. 2015).
Analysis
Davis teaches a Dicer substrate, specifically “an RNAi construct [that]
may comprise one or more aptamers . . . . An aptamer is a nucleic acid that
interacts with a target of interest to form an aptamer:target complex” (FF 1).
Davis teaches that the aptamer functions as a targeting moiety (FF 2–3).
Davis teaches “to design an RNA molecule targeted by an aptamer sequence
at the 5’ end and containing an siRNA duplex at the 3’ end” (FF 5) where
the aptamer and first single stranded RNA form a contiguous nucleic acid
molecule (FF 7). Davis teaches a first step of chemical synthesis of the
RNAi construct (FF 6) followed by a step of duplex formation by
hybridization (FF 8). Davis teaches that “binding of the aptamer to a target
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molecule . . . may facilitate internalization of the polynucleotide into the
cell” (FF 9).
Davis teaches a specific example, Example 4, where a contiguous
nucleic acid molecule is composed of an xPSM-A10-3 aptamer and siGL3
siRNA sequence and the “aptamer sequence is at the 5’ end and the siGL3
sense strand is located at the 3’ end” (FF 12). Davis teaches hybridizing the
antisense strand of the siGL3 siRNA to the nucleic acid molecule to form a
duplex siRNA (FF 13). Davis teaches that the xPSM-A10-3 aptamer is
capable of binding a receptor on a cell (FF 10).
Appellant contends that
nowhere in Davis is a specific embodiment taught that includes
all of the limitations of the present claims. That is, nowhere in
Davis is it taught to synthesize a nucleic acid molecule that
comprises an aptamer and a first single stranded RNA and to
hybridize a second single stranded RNA with the first to form a
dsRNA silencing moiety that acts as a Dicer substrate.

(App. Br. 11).
We find this argument unpersuasive. Davis directly teaches aptamer-
siRNA constructs (FF 1) in which a single stranded RNA comprising both
an aptamer and siRNA sequence (FF 5) are hybridized to a second single
stranded siRNA sequence (FF 8) to form a dsRNA silencing moiety (FF 2)
cleavable by the Dicer enzyme (FF 4).
Further, as already discussed above, Example 4 of Davis teaches
formation of a specific aptamer-siRNA molecule capable of binding a cell
receptor (FF 10–13) and “which is a long dsRNA that serves as a Dicer
substrate. Note that it is art-accepted scientific knowledge that long dsRNAs
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serve as a substrate of Dicer enzyme, which cleaves long dsRNAs into short
siRNAs of about 21 base pairs” (Ans. 12).
Appellant contends that “[w]hile the Examiner picks and chooses
from the various teachings of Davis to arrive at the conclusion that the
reference teaches the invention claimed in claims 6-9, the Examiner does not
explain why one skilled in the art would have made those selections” (App.
Br. 13). Appellant contends that it “is only by picking and choosing from
Davis, using the claimed invention as a blueprint, that one could even
contend otherwise” (id. at 14).
We are not persuaded. In Example 4 of Davis, no picking and
choosing is required to anticipate claim 6 (FF 10–13). The scope of Davis’
disclosure is substantially limited and focused on either stabilized siRNA
constructs or aptamer-siRNA constructs (FF 1). Moreover, it would be
immediately apparent from Davis to form aptamer-siRNA constructs (FF 1)
in which a single stranded RNA comprising both an aptamer and siRNA
sequence (FF 5) are hybridized to a second single stranded siRNA sequence
(FF 8) to form a dsRNA silencing moiety (FF 2) cleavable by the Dicer
enzyme (FF 4).
Appellant contends that “Example 4 of Davis clearly does not teach
that the chimeric RNA described necessarily serves as a Dicer substrate”
(Reply Br. 6).
We are not persuaded. The Examiner finds that long RNAs serve as
Dicer substrates (Ans. 12) and Davis teaches that “the siRNA constructs can
be generated by processing of longer double-stranded RNAs, for example, in
the presence of the enzyme dicer” (Davis ¶ 87; FF 4). Davis teaches that
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“any duplex portion should be susceptible to processing by nucleases such as
Dicer” (Davis ¶ 91; FF 4). Thus, Davis teaches that the chimeric DNA
described in example should function as a Dicer substrate (FF 4). See In re
Antor Media Corp., 689 F.3d 1282, 1289 (Fed. Cir. 2012) (“[W]e therefore
hold that, during patent prosecution, an examiner is entitled to reject claims
as anticipated by a prior art publication or patent without conducting an
inquiry into whether or not that prior art reference is enabling. As long as an
examiner makes a proper prima facie case of anticipation by giving adequate
notice under § 132, the burden shifts to the applicant to submit rebuttal
evidence of nonenablement.”) Appellants fail to provide any evidence
rebutting the presumption that Davis is enabled.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that Davis
anticipates claim 6.
B. 35 U.S.C. § 103(a) over Davis and Lee
Appellant does not argue separately the claims in the obviousness
rejection. Having affirmed the anticipation rejection of claim 6 over Davis
for the reasons given above, we also find that the combination with Lee
renders claim 10 obvious for the reasons given by the Examiner (see Ans. 5–
7).
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SUMMARY
In summary, we affirm the rejection of claim 6 under 35 U.S.C.
§§ 102(a)/102(e) as anticipated by Davis. Pursuant to 37 C.F.R.
§ 41.37(c)(1), we also affirm the rejection of claims 7–9, as these claims
were not argued separately.
We affirm the rejection of claim 10 under 35 U.S.C. § 103(a) as
obvious over Davis and Lee.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED
bar