Ex Parte Selinger

Patent Trial and Appeal Board

Aug 31, 2016

11823824 (P.T.A.B. Aug. 31, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111823,824 06/28/2007
118610 7590 09/02/2016
DuPont Pioneer
c/o Ballard Spahr LLP
999 Peachtree Street, Suite 1000
Atlanta, GA 30309
FIRST NAMED INVENTOR
David Selinger
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.
36446.0023Ul/2270USE 1797
EXAMINER
LIN, JERRY
ART UNIT PAPER NUMBER
1631
NOTIFICATION DATE DELIVERY MODE
09/02/2016 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):
uspatentmail@ballardspahr.com
PTO-Legal.PRC@dupont.com
IPSupport@pioneer.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID SELINGER1
Appeal2015-001400
Application 11/823,824
Technology Center 1600
Before JOHN G. NEW, RICHARD J. SMITH, and KRISTI L. R. SA WERT,
Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1Appellant states the real party-in-interest is Pioneer Hi-Bred International,
Inc. App. Br. 1.
Appeal2015-001400
Application 11/823,824
SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 1, 6-10, 12, 13, 16, and 18-25.2
Specifically, claims 1, 6-10, 12, 13, 16, 18, 19, 21, 22, and 23, stand rejected
as unpatentable under 35 U.S.C. § 103(a) as being obvious over the
combination of Seul et al. (US 2006/0127916 Al, June 15, 2006) ("Seul"),
Dieter Heusken et al., Design of a genome-wide siRNA library using an
artificial neural network, 23(8) NATURE BIOTECHNOLOGY 995-1001 (2005)
("Heusken"), David Baulcombe, RNA Silencing in Plants, 431 NATURE 356-
63 (2004) ("Baulcombe"), and Gramatikova et al. (US 7 ,226,771 B2, June 5,
2007) ("Gramatikova").
Claims 19, 20, 24, and 25 stand rejected as unpatentable under 35
U.S.C. § 103(a) as being obvious over Seul, Heusken, Baulcombe,
Gramatikova, and Alistair M. Chalk et al., siRNAdb: a database of siRNA
sequences, 33 NUCLEIC ACIDS RESEARCH, Database issue Dl31-D134
("2005") ("Chalk").
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellant's invention is directed to a method for identifying
subsequences in a polynucleotide sequence for specifically silencing a target
gene. The method identifies sequences effective in silencing a target gene or
a series of genes, but not others. Subsequences can be identified and scored
2Claims 3, 5, and 17 are cancelled, and claims 2, 4, 11, 14, 15, and 26-28 are
withdrawn. App. Br. 1.
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using comparisons based on percent sequence identity with respect to a
target reference sequence and siRNA algorithm analysis. The resulting
subsequences may be ranked based on scored percent sequence identity.
The identification of subsequences may be performed using a sliding
window to identify all subsequences of a set length within the sequence. A
user interface may be provided for displaying the results to a user. Abstract.
REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A method of identifying one or more polynucleotide
sequences for specifically silencing a target gene
compnsmg:
providing a target gene to be silenced, wherein the target gene to
be silenced is a gene in a plant;
using a sliding window analysis of the provided target gene by
specifying a series of window sizes; and
processing a polynucleotide sequence of the target gene into a
series of polynucleotide subsequences wherein each
subsequence has a length that is equal to a respective
window size of the series of window sizes;
comparing each polynucleotide subsequence to a reference
sequence to obtain a percent identity for each
subsequence;
comparing said percent identity of each subsequence to a
threshold percent identity value;
selecting, via a processor, each polynucleotide subsequence that
meets or exceeds the threshold percent identity value;
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scoring each polynucleotide subsequence for potential silencing
efficacy of the target gene to obtain a score, wherein
scoring takes into consideration one or more physical
characteristics of the subsequence selected from the group
consisting of, melting temperature, nucleotide content of
3' overhangs, length of subsequence, nucleotide end-
composition of a target site and presence and location of
mismatches with respect to a reference sequence, base
composition at the 5' end of an RNA molecule, helix
stability, base composition numbers at a 3' end, and the
free energy of a molecule; and
reporting the subsequences that meet or exceed the threshold
percent identity value and the score for each
polynucleotide subsequence that meets or exceeds the
threshold percent identity value to thereby assist in
identifying one or more polynucleotide subsequences for
specifically silencing a target gene.
App. Br. 17-18.
ISSUES AND ANALYSES
We agree with, and adopt, the Examiner's findings and conclusion
that the appealed claims are obvious over the cited prior art references. We
address the arguments raised by Appellant on appeal below.
A. Rejection of independent claims 1, 16, and 22
Issue 1
Appellant argues the Examiner erred in finding the combined cited
prior art teaches or suggests scoring subsequences by taking into
consideration free energy or melting temperature, as required by the claims.
App. Br. 9.
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Analysis
Appellant argues that paragraph [ 0013] of Seul, upon which the
Examiner in part relies, teaches algorithms that invoke NN-interaction
parameters to compute the free energy of a hybridization complex of a
known sequence. App. Br. 9. According to Appellant, the same paragraph
teaches that thermodynamic stability of the known sequence can be
expressed in the form of a melting temperature. Id.
Appellant also argues that paragraph [0077] of Seul constitutes a
single sentence that introduces several steps but does not mention free
energy or melting temperature. App. Br. 9. Appellant contends the
Examiner has failed to show how the cited paragraphs teach scoring
subsequences by taking into consideration free energy or melting
temperature, relying instead upon conclusory statements. Id. Appellant
asserts the passages cited by the Examiner fail to describe how the melting
temperature or free energy might be used in Seul, but that other teachings of
Seul, such as paragraph [0015], explain that the free energy referred to is
used in contexts different than scoring, e.g., in the context of a constraint
threshold. Id. Appellant also argues the remaining references fail to cure
the alleged deficiencies of Seul. Id.
The Examiner responds that paragraph [ 0013] of Seul teaches using
melting temperature and free energy to predict the stability of (i.e., score)
hybridization. Ans. 7. The Examiner finds the prediction of the stability of
a given complex "scores" a structure: an siRNA with greater stability in
hybridizing with a target gene would have a higher potential silencing
efficacy of a target gene and thus a higher "score". Id. Therefore, the
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Examiner finds, Seul teaches scoring a sequence using melting temperature
or free energy. Id.
We are not persuaded by Appellant's arguments. Seul teaches:
The iterative method disclosed herein for the concurrent
optimization of primer and probe selection invokes fast logical
string matching functions to perform a complete cross-
correlation of probe sequences and target sequences. The score
function assigns to each probe-target alignment a "degree of
matching" score on the basis of position-weighted Hamming
distance functions introduced herein.
Seul Abstr. (emphasis added). Seul thus explicitly teaches scoring a degree
of matching between hybridized probe and target sequences. In this context,
Seul further teaches:
Several available algorithms for primer and probe design have
been described which invoke NN-interaction parameters to
compute the free energy of a hybridization complex of known
sequence whose thermodynamic stability is expressed in the
form of a "melting temperature", Tm; at T=T m, half of the
complex has denatured into its constituent strands. Several
commercially available software packages focus on the detailed
modeling of probe-target interaction under a wide range of
relevant experimental parameters to predict the stability of the
complex [i.e., scoring the degree of matching between probe and
target sequences] as well as competing structures such as folded
target or probe strands ....
Seul i-f 13. Seul thus teaches that it was well known in the art that
determining the free energy (expressed as a melting temperature Tm) of a
hybridization complex between probe and target sequences was a way of
scoring the stability of the subsequent target-probe complex. We
consequently agree with the Examiner that Seul teaches the disputed
limitation.
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Issue 2
Appellant argues the Examiner erred because Seul teaches away from
the use of mathematical models that are based on calculations of free energy
or melting point. App. Br. 10.
Analysis
Appellant argues Seul teaches cross-reactivity in primer design for
multiplexed assays, and specifically teaches that models based on
calculation of free energy do not address the critical problems of multiplexed
assays raised by Seul. App. Br. 10 (citing Seul i-f 13). Appellant points to
the passage of Seul stating: "In the majority of commercial primer or probe
design tools, the issue of cross-reactivity, critical to the design of
multiplexed assays, remains substantially unaddressed." Id. (quoting Seul i-f
13). Appellant interprets this to mean that the mathematical models referred
to by Seul as calculating free energy or melting points do not address the
issue of cross-reactivity, an issue which is "critical" to the design of the
multiplexed assays taught by Seul. Id. Appellant asserts this point is raised
in the background section of Seul to specifically disparage the use of use
such models and demonstrates why the teachings of Seul are preferable. Id.
Appellant argues further that Seul teaches that the mathematical
models that calculate free energy or melting temperature do not provide an
appropriate representation of priming and are inefficient in evaluating cross-
correlations. App. Br. 10. Appellant points to paragraph [0072] of Seul,
which teaches: "The resulting similarity score is preferable ... to the NN
models for the evaluation of the free energy of probe-target complex
formation which does not provide an appropriate representation of priming
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while requiring detailed inspection to identify each base, thereby
unnecessarily reducing the efficiency of evaluating cross-correlations." Id.
Appellant asserts Seul thus teaches that its approach of calculating a
similarity score is preferable because the mathematical models (NN-models)
that calculate free energy do not appropriately represent priming and require
inefficient processes in the context of cross-correlations. Id. Appellant
asserts Seul raises this point to disparage the use of the mathematical models
that calculate free energy, thereby indicating that such approaches are not
appropriate for tools for dealing with the cross-correlations and multiplexed
assays. Id.
The Examiner responds that, although Seul exhibits a preference for
using a similarity score in paragraph [0072], Seul does not teach away from
using mathematical models that calculate free energy. Ans. 7. The
Examiner also points to paragraph [0072], in which the Examiner finds Seul
infers that mathematical models used for scoring should take into
consideration free energy as well as an appropriate representation of
priming. Id. The Examiner also finds Seul teaches the importance of free
energy calculations in paragraphs [0077]-[0086].
We are not persuaded by Appellant's arguments that the teachings of
Seul rise to the level of a "teaching away" from Appellant's claimed
invention. Seul teaches:
The resulting similarity score is preferable to the
Hamming distance commonly used in the construction of DNA
codes in which free energy considerations are ignored, and also
is preferable to the NN models for the evaluation of the free
energy of probe-target complex formation which does not
provide an appropriate representation of priming while
requiring detailed inspection to identify each base, thereby
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unnecessarily reducing the efficiency of evaluating cross-
correlations.
Seul i-f 72 (emphases added). We interpret this passage to mean that the
method of Seul is superior to the method employing Hamming distance
without considering free energy and also superior to NN models used for the
evaluation of the free energy of probe-target complex formation, rather than
meaning simply discouraging the general use of mathematical models used
to calculate the free energy. Indeed, Seul explicitly teaches the
mathematical calculation of the probe-target complex in Step 4 of an
embodiment of Seul's method: "4-Depending on sequence uniqueness,
identify a position near each transcript's 5' terminus for placement of the
corresponding capture probe; as desirable, a free energy profile may be
calculated to identify particularly stable positions of the probe." Seul i-f 81.
Seul thus explicitly teaches determining the free energy of the complex as a
part of its disclosed method.
A reference teaches away when "a person of ordinary skill, upon
reading the reference, would be discouraged from following the path set out
in the reference, or would be led in a direction divergent from the path that
was taken by the applicant." In re Gurley, 27 F.3d 551, 553 (Fed.Cir.1994).
Furthermore, a reference teaches away from a combination when using it in
that combination would produce an inoperative result. McGinley v. Franklin
Sports, Inc., 262 F.3d 1339, 1354 (Fed. Cir. 2001). In the instant appeal,
although Seul teaches what it claims is a superior method to those that
discount free energy, or which rely upon NN models to determine the free
energy, it also explicitly teaches calculation of the free energy of a portion of
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the target-probe complex. We are therefore not persuaded by Appellant's
argument that Seul teaches away from the claimed invention.
Issue 3
Appellant argues the Examiner erred because the combined cited prior
art neither teaches nor suggests scoring each polynucleotide subsequence for
potential silencing efficacy by taking into account length of subsequences.
App. Br. 11.
Analysis
Appellant points to paragraph [0015] of Seul, upon which the
Examiner relies in part, as teaching selecting unique probe sequences of
equi-length words. App. Br. 11. Appellant argues the Examiner failed to
demonstrate how selecting unique sequence of equi-length words relates to
scoring subsequences by taking into account length of subsequences. Id.
Furthermore, argues Appellant, paragraph [0015] does not teach scoring
subsequences by taking into account length of subsequence. Id. According
to Appellant, the cited passage teaches finding N-letter words based on
Hamming distance, rather than length of a subsequence. Id.
Appellant next points to paragraph [0044] of Seul as teaching:
"optimization in selecting sequence-specific primers for multiplexed reverse
transcription (RT) of a given set of mRNA molecules so as to produce a
desired set of cDNAs of specified length." App. Br. 11. Appellant contends
the Examiner failed to show how optimizing the selection of primers to
produce a set of cDNAs of a specified length relates to scoring
subsequences. Id. Appellant alleges the paragraph merely teaches the
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selection of subsequences to produce a desired set of cDNAs of a specified
length. Id. However, Appellant argues, the paragraph does not mention that
subsequences are scored by taking into account the length of the
subsequence. Id.
Finally, Appellant argues that paragraph [0089] of Seul teaches
generally the use of non-linear regression methods and measures of
convergence to iteratively optimize a selection of probes. App. Br. 12.
Appellant alleges the Examiner failed to show how the user of non-linear
regression methods and measures of convergence to iteratively optimize a
selection of probes is related to scoring. Id. Appellant contends paragraph
[0089] does not teach anything about lengths of subsequences or scoring
subsequences by taking into account length of the subsequences. Id.
The Examiner responds that Seul teaches selecting subsequences of a
particular length. Ans. 7-8. The Examiner finds selection of these
subsequences in accordance to a criteria of length may be interpreted as
scoring the subsequences in accordance with a particular length. Id. at 8.
The Examiner also finds Heusken teaches scoring and reporting
subsequences for potential silencing efficacy, and therefore concludes that
the combination of at least Seul and Heusken teach the argued limitation.
We are not persuaded by Appellant's arguments. Even assuming,
arguendo, that Appellant is correct, claim 1, for example recites, in relevant
part:
scoring each polynucleotide subsequence for potential silencing
efficacy of the target gene to obtain a score, wherein scoring
takes into consideration one or more physical characteristics of
the subsequence selected from the group consisting of, melting
temperature, nucleotide content of 3' overhangs, length of
subsequence, nucleotide end-composition of a target site and
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presence and location of mismatches with respect to a reference
sequence, base composition at the 5' end of an RNA molecule,
helix stability, base composition numbers at a 3' end, and the free
energy of a molecule[.]
(Emphasis added).
Independent claims 16 and 22 recite substantially identical language.
Consequently, claim 1 recites that subsequence length is one of the
alternative considerations by which scoring is conducted.
We have related supra why we find the combined cited prior art
teaches scoring subsequences by taking into consideration free energy or
melting temperature, as recited in claim 1. Because we find the prior art
teaches one of the alternative means of scoring, and because Appellant's
claimed invention could be practiced without scoring based on subsequence
length, we need not address the remainder of Appellant's argument with
respect to this limitation. See Ex parte Katz, 2010-006083, 2011 WL
514314, at *4 (BP ii,I 2011) (non-precedential) (citing Jn re Am. Acad. of Sci.
Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004)) (stating that conditional
steps in a method claim need not be found in the prior art if, under the
broadest scenario, the method need not invoke the steps).
Issue 4
Appellant next argues the Examiner erred by failing to articulate the
reasons why a person of ordinary skill in the art would be motivated to
combine the references. App. Br. 12.
Analysis
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Appellant contends the Examiner summarized the teachings of the
cited references, and then stated:
"Thus, one of ordinary skill in the art at the time of the invention
would have been motivated to use Seu! et al.' s method of creating
subsequences and selecting a subsequence by Gramatikova et
al.' s method and H eus ken et al.' s method of identifying effective
and specific siRNA for a target provided by Baulcombe to
identify the best siRNA to silence."
App. Br. at 13 (quoting Final Act. 4--5). Appellant argues the Examiner's
finding provides no justification for why a person of ordinary skill in the art
would combine the references but is merely a conclusory statement
insufficient to meet the standard set forth in KSR Int 'l Co. v. Teleflex Inc.,
550 U.S. 398, 418 (2007).
Appellant argues further that the Examiner's findings and conclusions
are based on impermissible hindsight analysis. App. Br. 12. According to
Appellant, the Examiner improperly used Appellant's claims as a road map
to justify combining the references. Id. Appellant bases this argument on
the contention that the Office Action allegedly failed to make any finding
regarding the level of skill of the person of ordinary skill or provide any
explanation as to why the as person of ordinary skill would be motivated to
combine the teachings of at least four different references that each are
solving different problems. Id.
The Examiner responds that each of the references contain teachings
that allow one of ordinary skill in the art at the time of the invention to select
siRNAs for plants. Ans. 8. The Examiner finds the prior art references
allow one of ordinary skill in the art to identify and/ or create subsequences,
as in Seul, select a subsequence, as in Gramatikova, identify effective and
specific siRNAs, as in Heusken, and to apply to a plant target, as provided
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by Baulcombe. Id. The Examiner finds that, because all of the references
cited are directed to identifying short nucleic sequences, one of ordinary
skill in the art would have reasonably expected success in combining their
teachings. Id. The Examiner further finds one of skill in the art would have
been motivated to combine the references to identify effective and specific
siRNAs as taught by Heusken. Id.
We are not persuaded by Appellant's arguments. In the Final
Rejection, the Examiner states:
It would have been obvious to one of ordinary skill in the art at
the time of the invention to combine the methods of Seul et al.,
Heusken et al., Baulcombe and Gramatikova et al. to gain the
benefit of being able to select siRNAs for plants. Heusken et al.
teach that siRNA are superior for sequence-specific gene
knockdown, however selecting effective and specific siRNAs is
difficult. Heusken et al. provides guidelines that allow one of
ordinary skill in the art to identify effective and specific siRNAs.
In addition, Baulcombe teaches potential plant gene targets.
Furthermore, Gramatikova et al. provides a method of comparing
a series of subsequences to a reference sequence to aid the
selection of complementary sequences. Thus, one of ordinary
skill in the art at the time of the invention would have been
motivated to use Seul et al.' s method of creating subsequences
and selecting a subsequence by Gramatikova et al.' s method and
Heusken et al.' s method of identifying effective and specific
siRNA for a target provided by Baulcombe to identify the best
siRNA to silence a gene.
Final Act. 4--5. We find the Examiner has thus "some articulated reasoning
with some rational underpinning to support the legal conclusion of
obviousness," viz., to optimize methods for obtaining siRNAs to silence a
targeted gene in a plant. See KSR, 550 U.S. at 418. Moreover, Appellant
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adduces no evidence beyond a conclusory assertion to show that the
Examiner relied upon impermissible hindsight analysis.
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of
ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant's
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). Appellant adduces
no evidence that the Examiner improperly relied upon knowledge that would
have been outside the scope of the knowledge of a person or ordinary skill in
the art or could only have been gleaned from the disclosures of Appellant's
Specification. In the absence of any such evidence, we are not persuaded by
Appellant's arguments.
Issue 5
Appellant argues the Examiner erred because the combined cited prior
art fails to teach or suggest scoring each polynucleotide subsequence for
potential silencing efficacy. App. Br. 14.
Analysis
Appellant argues that Heusken, upon which the Examiner relies,
teaches the use of a program called Biopredsi to score siRNAs for the
potential of the siRNA for silencing a target gene. App. Br. 14. However,
Appellant argues, claim 1 recites "scoring a subsequence of a target gene for
potential silencing efficacy of the target gene." Id. Appellant contends that
Heusken teaches scoring of siRNA against target genes rather than scoring
of subsequences of a target gene for silencing efficacy. Id. Furthermore,
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Appellant argues Heusken teaches scoring siRNAs in regards to entire target
genes, rather than scoring subsequences of target genes for silencing
efficacy. Id. Appellant therefore contends a person of ordinary skill in the
art would not be motivated to practice scoring subsequences of a target gene
for silencing efficacy when Heusken only teaches scoring siRNAs against
target genes. Id.
The Examiner responds that Heusken teaches scoring sequences for
potential silencing efficacy. Ans. 9 (citing Heusken abstract, 998). The
Examiner finds this teaching, combined with teachings of Seul with respect
to subsequences, would allow one of ordinary skill in the art at the time of
the invention to score subsequences for potential silencing efficacy. Id.
(citing Seul i-fi-175; 78).
We agree with the Examiner. Heusken teaches: "The algorithms'
ability to rank [i.e., score] siRNAs targeted to endogenously expressed
mRNAs was assessed using the three previously used data sets (TCJ 0,
UBE2I, CDC34)." Heusken 998. Heusken thus teaches using an algorithm
to score the binding of siRNAs targeted to expressed mRNAs as a means of
scoring the efficacy of silencing targeted genes with siRNAs. We agree with
the Examiner that a person of ordinary skill in the art would recognize that
the ability of an siRNA to bind to mRNA is directly related to its efficacy in
silencing expression of the target gene, because the polynucleotide sequence
of the mRNA is the antisense transcription of the target gene and,
consequently, the siRNA binding to it constitutes a complementary
polynucleotide sequence of the gene, particularly when viewed in
combination with the teachings of Seul with respect to targeting
subsequences of target genes cited by the Examiner and related supra with
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respect to Issue 1. We consequently atlirm the Examiner's rejection of
independent claims 1, 16, and 22. Furthermore, Appellant relies upon the
same arguments presented supra for claims 6-10, 12, 13, 18, 19, 21, and 23,
which depend from claims 1, 16, and 22. See App. Br. 8. For the same
reasons, we affirm the Examiner's rejection of those claims.
B. Claims 19, 20, 24, and 25
Appellant relies upon the same arguments presented supra, arguing
that Chalk fails to cure the deficiencies of the other cited prior art references.
App. Br. 15. For the same reasons related supra, we affirm the Examiner's
rejection of claims 19, 20, 24, and 25.
DECISION
The Examiner's rejection of claims 1, 6-10, 12, 13, 16, and 18-25 as
unpatentable as obvious under 35 U.S.C. § 103 is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l). See 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
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