Ex Parte Kincaid

Board of Patent Appeals and Interferences

Jul 29, 2010

10184501 (B.P.A.I. Jul. 29, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ROBERT KINCAID
__________

Appeal 2010-001053
Application 10/184,501
Technology Center 1600
__________

Before ERIC GRIMES, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

Opinion filed for the Board by Administrative Patent Judge PRATS.

Opinion dissenting filed by Administrative Patent Judge FREDMAN.

PRATS, Administrative Patent Judge.
DECISION ON APPEAL1
This appeal under 35 U.S.C. § 134 involves claims to a method of
identifying candidate probe sequences for use in a nucleic acid array. The
Examiner rejected the claims as anticipated.

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
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We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

STATEMENT OF THE CASE
Claims 32-71 stand rejected and appealed (App. Br. 3).2 Claim 32 is
representative and reads as follows:
32. A method of identifying candidate probe
sequences for a nucleic acid sequence for use as probes in a
nucleic acid array, said method comprising:
(a) providing a set of known, undesirable probe
sequences present in a format representative of the nucleotide
sequences of said known, undesirable probe sequences, wherein
said set of undesirable probe sequences comprises probe
sequences that do not meet a predetermined specificity of
binding affinity for said nucleic acid sequence;
(b) comparing said nucleic acid sequence
present in a format representative of the nucleotide sequence of
said nucleic acid sequence to each member of said set;
(c) marking regions of said nucleic acid
sequence that have no more than 5 mismatches with a sequence
of a member of said set as undesirable regions for candidate
probe sequences for said nucleic acid sequence;
(d) identifying candidate probe sequences for
said nucleic acid sequence for use as probes in a nucleic acid
array from unmarked regions of said nucleic acid sequence; and
(e) synthesizing at least one of said identified
candidate probe sequences.

The sole rejection before us for review is the Examiner’s rejection of
claims 32-71 under 35 U.S.C. § 102(b) as anticipated by Lockhart3 et al.
(Ans. 3-8).

2 Appeal Brief filed January 30, 2009.
3 WO 97/10365 A1 (published March 20, 1997).
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ANTICIPATION
ISSUE
The Examiner finds that Lockhart meets the claimed comparing step
(b) because Lockhart describes a process that includes a step in which the
sequences of candidate probes are compared to known gene sequences to
determine if the probes will hybridize to more than one gene (Ans. 5).
Appellant contends, among other things, that Lockhart’s process does
not meet step (b) because “Lockhart compares the designed probes to genes
other than the gene to which they were designed for purposes of pruning”
(App. Br. 8).
In view of the positions advanced by Appellant and the Examiner, the
issue with respect to this rejection is whether the evidence of record supports
the Examiner’s finding that Lockhart discloses a process that includes step
(b) of the appealed claims.
FINDINGS OF FACT (“FF”)
1. Lockhart discloses
a computer-implemented method for monitoring expression of
genes comprising the steps of: receiving input of a nucleic acid
sequence constituting a gene; generating a set of probes that are
perfectly complementary to the gene; and identifying a subset
of probes, including less than all of the probes in the set, for
monitoring the expression of the gene.

(Lockhart 11.)
2. Lockhart discloses, however, that:
One of the causes of poor signals in expression chips is
that genes other than the ones being monitored have sequences
which are very similar to parts of the sequences which are being
monitored. The easiest way to solve this is to remove probes
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which are similar to more than one gene. Thus, in a preferred
embodiment, it is desirable to remove (prune) probes that
hybridize to transcription products of more than one gene.

(Id. at 42.)
3. Lockhart discloses that the “simplest pruning method is to line up a
proposed probe with all known genes for the organism being monitored,
then count the number of matching bases” (id.).
4. Lockhart provides an example in which the sequence of a probe to
“gene 1” of an organism is aligned alongside “gene 2” of an organism to
determine the degree to which the gene 1 probe contains sequences that
match, and will likely cross-hybridize, to gene 2 (id. at 42-3).
PRINCIPLES OF LAW
“[T]he examiner bears the initial burden . . . of presenting a prima
facie case of unpatentability.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir.
1992). “To anticipate a claim, a prior art reference must disclose every
limitation of the claimed invention, either explicitly or inherently.” In re
Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997).
ANALYSIS
We are not persuaded that the evidence of record supports the
Examiner’s finding that Lockhart discloses a process that includes step (b) of
the appealed claims.
Claim 32 recites a method of identifying candidate probe sequences
for a target nucleic acid sequence, the probes being intended for use on a
nucleic acid array. The first claimed step (a) requires the practitioner to
provide a set of known, undesirable probe sequences in a format
representative of the undesirable sequences, with the set of undesirable
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probe sequences including sequences that do not meet a predetermined
specificity of binding affinity for the target nucleic acid sequence.
The second step in the claimed process is “(b) comparing said nucleic
acid sequence present in a format representative of the nucleotide sequence
of said nucleic acid sequence to each member of said set.” Thus, step (b)
requires the practitioner to compare the target nucleic acid sequence, in a
representative form, to each member of the set of undesirable probe
sequences.
In the instant case, the portion of Lockhart cited by the Examiner as
meeting step (b), pages 42-43 (Ans. 5), does not disclose comparing the
potential probes to the target gene, but instead discloses that the probes are
to be compared to genes other than the target, to assess whether the
potential probes have sequences that would cause them to undesirably cross-
hybridize with the non-target genes, should the non-target genes be present
in the sample (FF 1-4). As the Examiner points to no other disclosures in
Lockhart that meet this limitation, we are not persuaded that the Examiner
has made a prima facie case of anticipation with respect to claim 32.
Claims 46 and 53 recite similar processes to that recited in claim 32,
including the same step (b). Therefore, as we are not persuaded that the
Examiner has adequately explained how or why Lockhart describes a
process that includes all of the steps recited in claims 32, 46, and 53, we
reverse the Examiner’s anticipation rejection of those claims, and their
dependents, over Lockhart.

REVERSED

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DISSENTING OPINION
Fredman,
Administrative Patent Judge
I respectfully dissent from the Majority’s interpretation of the prior art
as it relates to independent claim 32, and therefore dissent from the
anticipation analysis in the instant situation. While in my opinion, the
rejection would have been better framed under obviousness, I would
nonetheless affirm the Examiner’s anticipation rejections under 35 U.S.C. §
102(b).
ADDITIONAL FINDINGS OF FACT
5. The Specification teaches that an undesirable probe sequence
does “not meet a predetermined specificity of binding affinity for its
complement” (Spec. 14 [0055]).
6. The Specification teaches that “[b]y known in [sic ?] meant that
the probes are proven or acknowledged to be undesirable probes for use in a
nucleic acid array” (Spec 15 [0055]).
7. Lockhart teaches that “[a]pparently suitable probes often prove
ineffective for expression monitoring by hybridization. For example, certain
subsequences of a particular target gene may be found in other regions of the
genome and probes directed to these subsequences will cross-hybridize with
the other regions and not provide a signal that is a meaningful measure of
the expression level of the target gene” (Lockhart 21, ll. 6-10).
8. Lockhart teaches that “[b]ecause of the high degree of
redundancy provided by the large number of probes for each target gene, it
is possible to eliminate those probes that function poorly under a given set of
hybridization conditions and still retain enough probes to a particular target
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gene to provide an extremely sensitive and reliable measure of the
expression level” (Lockhart 21, ll. 14-18).
9. Lockhart teaches a particular example in which such pruning
occurs where:
The simplest pruning method is to line up a proposed
probe with all known genes for the organism being
monitored, then count the number of matching bases. For
example, given a probe to gene 1 of an organism and gene 2
of an organism as follows:

More complicated algorithms also exist, which allow the
detection of insertion or deletion mismatches. Such
sequence alignment algorithms are well known to those of
skill in the art and include, but are not limited to BLAST, or
FASTA, or other gene matching programs such as those
described above in the definitions section.
In another variant, where an organism has many
different genes which are very similar, it is difficult to make
a probe set that measures the concentration only one of those
very similar genes. One can then prune out any probes
which are dissimilar, and make the probe set a probe set for
that family of genes.

(Lockhart 42-43.)
10. Lockhart teaches, in claim 74, “a method of selecting probes for
monitoring expression of genes, comprising the steps of receiving input of a
nucleic acid sequence constituting a gene; generating a set of probes that are
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perfectly complementary to the gene, and identifying a subset of probes,
including less than all of the probes in the set, for monitoring the expression
of the gene” (Lockhart 104, claim 74).
11. Lockhart teaches, in claim 75, “wherein the identifying step
includes the step of analyzing each probe of the set by criteria the specify
characteristics indicative of low hybridization or high cross hybridization”
(Lockhart 105, claim 75).
12. Lockhart teaches, in claim 80, “wherein one of the criteria
indicates low hybridization or cross hybridization if occurrences of a
specific nucleotide in a probe crosses a threshold value” (Lockhart 105,
claim 80).
13. Lockhart teaches that pairs of probes, with “each pair including
a perfect match probe that is perfectly complementary to a portion of the
nucleic acids and a mismatch probe that differs from the perfect match probe
by at least one nucleotide” (Lockhart 10, ll. 26-29).
ADDITIONAL PRINCIPLES OF LAW
A reference is anticipatory under § 102(b) when it satisfies particular
requirements. First, the reference must disclose each and every element of
the claimed invention, whether it does so explicitly or inherently. Eli Lilly &
Co. v. Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1375 (Fed. Cir. 2006).
While those elements must be “’arranged or combined in the same way as in
the claim,’” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1370 (Fed.
Cir. 2008), the reference need not satisfy an ipsissimis verbis test, In re
Bond, 910 F.2d 831, 832-33 (Fed. Cir. 1990).
As long as the reference discloses all of the claim limitations and
enables the “subject matter that falls within the scope of the claims at issue,”
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the reference anticipates-no “actual creation or reduction to practice” is
required. Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1380-81
(Fed. Cir. 2003).
ANALYSIS
In my opinion, Lockhart teaches the elements of claim 32. Lockhart
teaches generating a set of probe sequences (FF 10) and teaches identifying
a set of “known, undesirable probe sequences” within that set (FF 7-8).
Lockhart teaches “to eliminate those probes that function poorly under a
given set of hybridization conditions and still retain enough probes to a
particular target gene to prove an extremely sensitive and reliable measure of
the expression level” (Lockhart 21, ll. 14-18; FF 8). In my opinion, this
teaching reasonably satisfies step (a) of claim 32.
Lockhart exemplifies the pruning at page 42, where Lockhart
compares nucleic acid sequences of probes and targets with one another, and
teaches the use of known software to compare sequences and prune out
regions which are undesirable (FF 9). In my opinion, this teaching
reasonably satisfies steps (b) and (c) of claim 32.
Finally, Lockhart teaches identifying and synthesizing the candidate
probe sequences as required by steps (d) and (e) of claim 32 (see FF 10).
Where I particularly disagree with the Majority is in their
interpretation of both claim 32 and of Lockhart. The Majority states that
Lockhart “does not disclose comparing the potential probes to the target
gene, but instead discloses that the probes are to be compared to genes other
than the target, to assess whether the potential probes have sequences that
would cause them to undesirably cross-hybridize with the non-target genes”
(see Maj. Op. Supra).
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I see no requirement in claim 32 which delimits the comparison to
either the target gene or to genes other than the target. That is, when step (b)
of claim 32 states “comparing said nucleic acid sequence present in a format
representative of the nucleotide sequence of said nucleic acid sequence to
each member of said set,” I interpret that comparison as reasonably
encompassing the comparison performed by Lockhart between the target
sequence and undesired target sequences to eliminate undesirable probes “in
the set” as disclosed at page 42 (FF 7-9). I also interpret the pruning step of
Lockhart as clearly requiring a comparison of the probes to the desired target
to ensure 100% identity, as well as comparison to interfering non-target
sequences, to maximize mismatch (FF 7-9). Lockhart teaches criteria for
such comparisons (FF 11-12). I would find that sufficient to teach step (b)
of claim 32.
While Lockhart does not use the same words as the claim, the intent,
process, and purpose are clearly the same, satisfying the requirements for
anticipation, which “is not an ‘ipsissimis verbis’ test.” See In re Bond, 910
F.2d at 832-33.
I am not persuaded by Appellant’s argument that “Lockhart does not
disclose ‘a set of known undesirable probe sequences’ and a method of using
these known undesirable probe sequences to identify candidate probe
sequences” (App. Br. 6).
When Lockhart teaches that “[a]pparently suitable probes often prove
ineffective for expression monitoring by hybridization,” this cannot be any
teaching other than the presence of a set of known, undesirable probe
sequences (Lockhart 21, ll. 6-7; FF 7). Lockhart then teaches the reason
these probes are undesirable is that the may cross hybridize (FF 7) and
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Lockhart teaches to use this cross hybridization as a pruning technique to
“eliminate those probes that function poorly under a given set of
hybridization conditions” (Lockhart 21, ll. 15-16; FF 8).
Appellant also argues that “the cited methods of Lockhart are limited
to discarding probes that cross-hybridize while the rejected methods are not
so limited” (App. Br. 7). In my opinion, this argument concedes the point,
since claim 32 is broadly open to any reason to discard probes, whether due
to cross-hybridization or due to undesirable structural elements.
Appellant argues that even if Lockhart is performing the required
comparison, “Lockhart still fails to disclose step c) of the rejected claims,
i.e., marking regions of the nucleic acid sequence that have no more than 2
mismatches (Claim 31) or no more than 5 mismatches (Claim 46)” (App. Br.
8-9).
I am not persuaded, since Lockhart teaches identification of both
match and mismatch probes, where the mismatch probes can have only a
single mismatch (FF 13). In order for Lockhart to obtain these match and
mismatch probes, Lockhart must identify regions with even a single
mismatch as undesirable, or the match probes would not be perfectly
complementary.
In conclusion, I would affirm the Examiner’s anticipation rejection
over Lockhart.

Appeal 2010-001053
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