Ex Parte Mcgonigle

Patent Trial and Appeal Board

Sep 28, 2016

12809324 (P.T.A.B. Sep. 28, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/809,324 06/18/2010
23906 7590 09/30/2016
EIDUPONTDENEMOURSANDCOMPANY
LEGAL PATENT RECORDS CENTER
CHESTNUT RUN PLAZA 721/2340
974 CENTRE ROAD, P.O. BOX 2915
WILMINGTON, DE 19805
Brian Mcgonigle
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
BB1640 USPCT 8133
EXAMINER
ZHOU,SHUBO
ART UNIT PAPER NUMBER
1662
NOTIFICATION DATE DELIVERY MODE
09/30/2016 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
PTO-Legal.PRC@dupont.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte BRIAN MCGONIGLE
Appeal2015-003391
Application 12/809,3241
Technology Center 1600
Before ELIZABETH A. LA VIER, RICHARD J. SMITH, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
LA VIER, Administrative Patent Judge.
Pursuant to 35 U.S.C. § 134(a), Appellant seeks reversal of the
Examiner's rejection of claims 7-9 and 11. We have jurisdiction under 3 5
U.S.C. § 6(b). For the reasons set forth below, we AFFIRM.
BACKGROUND
The Specification relates to "constructs and methods to down-regulate
expression of targeted sequences" in plants, using microRNAs (miRNAs ).
1 Appellant states the real party in interest is E.I. du Pont de Nemours and
Company. Appeal Br. 3.
Appeal2015-003391
Application 12/809,324
Spec. 1: 11-16. The Examiner provides a helpful overview of miRNA
processing and function:
Mature miRNAs are approximately 21 nucleotides in length
and are processed from a pri-miRNA (primary miRNA)
transcript encoding a hairpin loop that comprises a sense
sequence, loop sequence, and antisense sequence. The sense
and antisense regions bind to create a double-stranded RNA
( dsRNA) region of the hairpin. The mature miRNA
corresponds with sense or antisense segment of dsRNA in the
hairpin. The miRNA sequence is complementary to a region of
a target gene. The region of the hairpin which is
complementary to the miRNA is commonly referred to in the
art as a miRNA * or "microRNA star" sequence. The mature
microRNA sequence then binds to an mRNA transcript region
having a high degree of complementarity (i.e. the target mRNA
or target gene), and initiates a process that degrades the mRNA
before it is translated into a protein, thus down-regulating gene
express10n.
Ans. 2-3.
Artificial miRNA (amiRNA) constructs "can be expressed under
different promoters in order to change the spatial pattern of silencing," and
are generated by replacing the miRNA and its complimentary miRNA *
sequence in the precursor miRNA with "substitute sequences that target an
mRNA to be silenced." Spec. 2:9-14. The claims are directed to such
amiRNAs, utilizing the "Glycine max (soybean) miR159 precursor backbone
represented by SEQ ID NO: 14 in which the native miRNA subsequence is
replaced with a variable nucleotide subsequence designed to silence an
endogenous soybean target sequence," and the native miRNA * sequence is
also replaced with a complementary sequence, such that the hybridization of
the two subsequence allows for "formation of the same stem loop secondary
structure as the endogenous pri-miR159." Appeal Br. 13-14.
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Appeal2015-003391
Application 12/809,324
Claim 7 is illustrative:
7. An isolated nucleic acid fragment comprising the
deoxyribonucleotide sequence set forth in SEQ ID NO: 14
wherein:
(i) nucleotides 275 to 295 of SEQ ID NO: 14 are replaced
by a first variable nucleotide subsequence ranging in size
from 19 to 24 nucleotides depending upon an
endogenous soybean target sequence whose expression is
to be reduced;
(ii) nucleotides 121to141 of SEQ ID N0:14 are
replaced by a second variable nucleotide subsequence
ranging in size from 19 to 24 nucleotides, said second
variable nucleotide subsequence being capable of
hybridizing to the first variable subsequence of the
precursor miRN A;
and
(iii) the precursor miRNA produced by said isolated
nucleic acid fragment has the same stem structure as the
precursor miRNA produced by endogenous SEQ ID
N0:14;
wherein the precursor miRNA produced by said isolated
nucleic acid fragment is capable of being processed in a
soybean plant to produce an miRNA that reduces the level of
expression of the endogenous soybean target sequence.
Appeal Br. 23 (Claims Appendix).
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Appeal2015-003391
Application 12/809,324
REJECTION MAINTAINED ON APPEAL
Claims 7-9 and 11 stand rejected under 35 U.S.C. § 103, as
unpatentable over Allen,2 Jover-Gil,3 Schwab,4 and Zuker. 5 Ans. 2.
FINDINGS OF FACT
We adopt the Examiner's findings and conclusions as set forth in the
Final Rejection and as further explained in the Answer. We provide the
following for explanation and emphasis.
Allen describes various circadian miRNA genes in plants, including
miR159. Allen i-f 25. Allen provides the precursor sequence (SEQ ID NO.
10) as well as the mature miRNA sequence (SEQ ID NO. 3) for miR159 in
soybeans (Glycine max). See Allen i-f 131; Sequence Listing. Allen's SEQ
ID NO. 10 "corresponds to SEQ ID NO: 14 of the instant application with
100% identity from nucleotide 1-356 of SEQ ID NO: 14 (see alignment
attached to the office action mailed 12/15/2011 ). The remaining
602 nucleotides of SEQ ID NO: 14 comprise 7 nucleotide mismatches and a
single insertion." Final Action 3. Allen's SEQ ID NO. 10 and the present
application's SEQ ID NO. 14 "contain the same exact sequence in the 5'
region of the pri-miRNA, including the regions which encode the miRNA,
loop structure, and miRNA*." Id. at 4. Allen reports isolation ofmiRNAs
2 Allen et al., US 2007/0300329 Al, published Dec. 27, 2007.
3 Jover-Gil et al., Plant microRNAs and development, 49 INT. J. DEV. BIOL.
733--44 (2005).
4 Schwab et al., Highly Specific Gene Silencing by Artificial MicroRNAs in
Arabidopsis, 18 THE PLANT CELL 1121-33 (May 2006).
5 Michael Zucker, Mfold web server for nucleic acid folding and
hybridization prediction, 31 NUCLEIC ACIDS RESEARCH, 3406-15 (2003).
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Appeal2015-003391
Application 12/809,324
from soybeans and identification of mature miR159 miRNAs. Ans. 13
(citing Allen i-fi-f 127-131). The Examiner finds that SEQ ID NO: 14 is an
obvious, same-species variant of Allen's SEQ ID NO: 10, given the degree
of identity. See Final Action 4--5. Allen also teaches that native miRNA
and miRNA * sequences can be replaced with nucleotides complementary to
a target sequence, forming dsRNA after transcription. Id. at 3 (citing Allen
i-fi-125, 35-37, 49---61); see also Allen i-f 133.
Schwab teaches generation of amiRNAs in Arabidopsis thaliana using
MIR319a and MIRl 72a "backbones" to target down-regulation of various
genes. Final Action 4 (citing Schwab Abstract, 1122, 1130, Table 1).
Furthermore, Schwab teaches specific parameters for designing amiRNAs to
optimize the stem-loop structure. Id. (citing Schwab Fig. 2 and 1124).
Jover-Gil summarizes research in plant miRNAs, particularly
Arabidopsis. See e.g., Jover-Gil Abstract and 734. Jover-Gil describes the
imperfect stem-loop hairpin structures formed from pri-miRNAs, which are
subsequently cleaved by RNase-III to form the active miRNA sequence.
Final Action 3--4 (citing Jover-Gil 734).
Finally, Zucker discusses "Mfold" software for prediction of nucleic
acid folding. Final Action 4 (citing Zucker Abstract). Zucker states Mfold
can be used to predict miRNA sequences. Id. (citing Zucker 3414).
DISCUSSION
Appellant first argues that, although Allen generally discloses that
"miRNA could be altered to silence gene targets other than its native target,"
Allen's only functional data focus on altering target genes, not miRNA, and
Allen does not show that its SEQ ID NO: 10 "is even processed correctly in
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Appeal2015-003391
Application 12/809,324
soybean." Appeal Br. 15. See also Reply Br. 5, 8-10, 14. As the Examiner
points out, however, it is unnecessary for Allen to "reduce the invention to
practice ... to make [it] obvious." Ans. 12. Nor does Allen's reduction to
practice of the alteration of target genes teach away from altering miRNAs.
See id. at 13. The Examiner further explains:
Allen et al actually isolated miRNAs from soybean plants and
were able to identify mature miR159 miRNAs in the plant
(page 18, paragraphs [0127]-[0131]. Given this, there would be
a clear expectation of success that the backbone sequence in
SEQ ID NO: 10 of Allen et al is capable of producing a mature
miRNA. The activity of the mature miRNA is largely
irrelevant given that no specific miRNA sequences are claimed.
The only relevant functionality is to the miRNA backbone,
which is claimed.
Id. Indeed, Allen makes it very clear that miRNAs could be altered, and that
designing such alterations can be "simple":
Any of the circadian plant miRNAs disclosed herein is also
useful as a starting or scaffold sequence for use in designing
novel engineered miRNAs for silencing a target gene, e.g.,
wherein the starting miRNA precursor is modified to yield
engineered miRNA precursors that are processed to engineered
mature miRNAs designed to silence a specific target gene or
genes. Designing an engineered miRNA sequence can be as
simple as substituting sequence that is complementary to the
intended target for nucleotides in the miRNA stem region of the
miRN A precursor ....
Allen i-f 133. Allen then goes on to provide specific steps for accomplishing
such alterations. For purposes of the obviousness analysis, it does not matter
that Allen does not reduce this aspect of the invention to practice, as "a
reference is not limited to the disclosure of specific working examples," and
"[a]ll the disclosures in a reference must be evaluated, including
nonpreferred embodiments," In re Mills, 470 F.2d 649, 652 (CCPA 1972).
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Application 12/809,324
Next, Appellant turns to Schwab, noting that Schwab discloses
Arabidopsis amiRNAs, not soybean, and does not disclose an Arabidopsis
ortholog of the soybean pri-miR159 precursor. Appeal Br. 16; see also
Reply Br. 11. According to Appellant, combining Schwab (and the other
references) with Allen "would entirely alter the focus of the method in
Allen, in which the target is modified to match the native miRNA," instead
of the miRNA itself as in Schwab. Id. The Examiner responds with a
thorough and persuasive rationale for looking to Arabidopsis data as in
Schwab:
miRNAs are a highly conserved functional pathway in
eukaryotic organisms. Given this, the teachings of Schwab et al
would clearly be understood by one of skill in the art to be
broadly applicable to more than just Arabidopsis plants. It is
further noted, that Arabidopsis and soybean are both eudicots
and even in the same subclass of plants, the Rosids. AS
previously discussed, Allen et al also isolate and identify
miRNAs from soybean plant, thus providing evidence that the
miPJ'.Jii:\. path\'l1ay is present in soybean, just as is the case in
Arabidopsis. The Appellants do not provide any examples of
unpredictability specific to soybean miRNA backbones. Given
this, Appellants' argument is not persuasive.
Ans. 14. We agree with the Examiner. As for Appellant's "alter the focus"
argument, it is unpersuasive for the reasons described above, as it ignores
that Allen also teaches miRNAs themselves can be modified.
Appellants then argue that Schwab, Jover-Gil, and Zucker are
insufficient to predict accurately the in vivo secondary structure of miRNAs,
and that Schwab "clearly demonstrates large variabilitv in expression of
the various amiRNAs engineered therein." Appeal Br. 16 (citing Schwab
1124 and Fig. 2). Appellant maintains that "due to the high level of
unpredictability of the technology, the skilled artisan would have no
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Application 12/809,324
reasonable expectation of success at producing a functional soybean
amiR159 in view of the cited references." Id. at 17; see also Reply Br. 12-
13. Appellant states that Schwab's data suggest differences in efficacy for
any given miRNA backbone depending on the target gene, as well as
differences in efficacy between backbones. Appeal Br. 17-18. However, as
the Examiner points out, Allen "already identif1ies] the mature miR159
miRNA sequence in SEQ ID NO: 10 ... [t]he use of predictive software
would merely be needed to find the fold-back region which would bind to
the miRNA sequence," such that Zucker's Mfold program would be needed
to assess only a "very limited number of possibilities," and would be "a
common optimization of the invention," for which one of ordinary skill in
the art would have a reasonable expectation of success. Ans. 15. As for the
varying efficacy of different backbones and target gene combinations, we
disagree with Appellant's unpredictability argument, especially given that
the claims do not include any structural limitations on the variable
sequences. As the Examiner explains:
all of the backbones tested by Schwab et al had functionality.
Some backbones may function better with certain miRNA
sequences, but there is no indication of broad unpredictability
that would lead one of ordinary skill in the art to believe that an
amiRNA backbone would have a likelihood of non-operability
with any particular miRNA subsequences, as the claims are
broadly drawn.
Ans. 17.
We also disagree with Appellant's related argument that the data in
the Specification "show high unpredictability in the efficacy of different
soybean miRNA backbones in amiRNA-mediated silencing," Appeal Br. 18,
or alternatively that the Specification shows unexpected results for SEQ ID
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Appeal2015-003391
Application 12/809,324
NO: 14. According to Appellant, SEQ ID NO: 14 demonstrates "surprising
and superior efficacy" because of the backbones tested, only SEQ ID NO: 14
"exhibit[ ed] amiRNA-mediated silencing of all of the genes tested (with the
exception thatfatb was not silenced by any amiRNA tested)." Id. at 19. The
Specification's data are not robust enough to support such a conclusion. As
the Examiner notes, the Specification only tests a genus of three miRNA
subsequences, one ofwhich,fatb, was not silenced by SEQ ID NO: 14 (i.e.,
the miR159 backbone) or any other backbone tested. Ans. 19. As the
Examiner observes, the Specification shows variability in silencing efficacy
depending on the particular backbone and on the particular subsequence
when used within the same backbone. See id. at 18. Accordingly, the
Examiner concludes, and we agree, that:
The claims as broadly drawn allow for miRNA subsequences to
any soybean gene of choice. Given this, the invention only
needs have an expectation of success for use broadly with
miRNA subsequences drawn to any number of different target
genes. The success of Schwab et al clearly indicates that one of
ordinary skill would be able to optimize the invention for use as
an amiRNA construct capable of down-regulating a target gene,
wherein one would be able to select those miRNA and
miRNA *subsequences which provide optimal results.
Ans. 18 (emphasis added).
Finally, Appellant takes issue with the Examiner's position that
Appellant has failed to show nonobviousness for the invention as broadly
claimed. Appeal Br. 20. Appellant states that the claims are drawn to "only
Q!!!}_ miRNA backbone, the SEQ ID NO: 14 backbone from soybean
miR159," and avers that the "breadth around the amiRNA sequence and its
corresponding star sequence ... is necessary to effectuate the invention,
which relates to using the miR159 backbone as a tool for amiRNA-mediated
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Application 12/809,324
gene silencing." Id. at 21. Again, this is not persuasive. Although the
claims are limited to a single backbone, "the claimed isolated nucleic acid is
in fact a genus of billions of possible miRNA precursors, which merely
happen to share a backbone structure." Ans. 20-21. Thus, we discern no
error in the Examiner's finding that "demonstrating performance of the
backbone with only a few miRNA subsequences is not commensurate in
scope with the claims." Id. at 21.
Having considered all of Appellant's arguments, we are unpersuaded
that the Examiner erred in rejecting claim 7. Claims 8, 9, and 11 are not
argued separately, and fall with claim 7. See 37 C.F.R. § 41.37(c)(l)(iv).
CONCLUSION
The rejection of claims 7-9 and 11 under 35 U.S.C. § 103(a) is
affirmed for the reasons of record and as explained herein.
TIME PERIOD FOR RESPONSE
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
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