Ex Parte Wolber

Board of Patent Appeals and Interferences

Jun 27, 2008

10271074 (B.P.A.I. Jun. 27, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte
PAUL K. WOLBER
__________

Appeal 2007-3265
Application 10/271,074
Technology Center 1600
__________

Decided: June 27, 2008
__________

Before TONI R. SCHEINER, LORA M. GREEN, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL

Appellant appeals under 35 U.S.C. § 134 from a final rejection of
claims 26-38,1 as anticipated by, and obvious over the prior art. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse.

1 Claims 39-44 are also pending, but have been withdrawn from
consideration.
Appeal 2007-3265
Application 10/271,074

BACKGROUND
“[P]olynucleotide arrays . . . are useful in diagnostic, screening, gene
expression analysis, and other applications” (Spec. 1: 5-7). “The arrays,
when exposed to a sample, will exhibit a pattern of binding which is
indicative of the presence and/or concentration of one or more [target]
components of the sample” (Spec. 1: 14-16). One way to increase the
sensitivity of polynucleotide array based assays is “multidentate binding”
(Spec. 4: 29). That is, using “two or more probes . . . which together bind
with respective regions of a target at two or more regions” (Spec. 4: 21-23).
The present invention is directed to “a method of evaluating
polynucleotide target probes on their ability to form simultaneous hybrids
with respective regions of a same target polynucleotide molecule” (Spec. 7:
25-27); in other words, a method of selecting probes “suitable to provide . . .
‘multidentate’ binding” (Spec. 4: 28-29).
“[F]or any given target polynucleotide there can be a large number of
potential sequences which can individually bind with all possible sub-
sequences of a target polynucleotide” (Spec. 17: 11-14), and “finding a good
set of target probes is not necessarily a matter of simply selecting probe
sequences complementary to . . . the target polynucleotide” (Spec. 4: 25-27).
According to Appellant, pre-selecting combinations of probes based on their
ability to hybridize individually to the target with at predetermined
efficiency, before testing them in combination (Spec. 21: 1-17), “is much
more efficient than testing all probe combinations” (Spec. 23: 17-18).
2
Appeal 2007-3265
Application 10/271,074

STATEMENT OF THE CASE
The claims stand rejected as follows:
I. Claims 26-36 under 35 U.S.C. § 102(b) as anticipated by Urdea.2
II. Claims 26-38 under 35 U.S.C. § 102(b) as anticipated by Palva.3
III. Claims 37 and 38 under 35 U.S.C. § 103(a) as unpatentable over
Urdea and Dehlinger.4
Claim 26 is representative and reads as follows:
26. A method of evaluating polynucleotide target probes on their ability to
form simultaneous hybrids with respective regions of a same target
polynucleotide molecule, the method comprising:
(a) selecting candidate probes which can potentially hybridize with
selected respective candidate target regions of the target polynucleotide,
based on the sequence of the selected candidate target regions;
(b) testing candidate probes on their ability to actually hybridize
individually with respective candidate target regions;
(c) further selecting at least two of the candidate probes which
actually hybridized individually with at least a predetermined efficiency with
respective candidate target regions; and
(d) testing the selected candidate probes on their ability to form
simultaneous hybrids with the respective candidate target regions.

FINDINGS OF FACT (FF)
The Invention
1. Claim 26, which represents the claimed invention in its broadest
aspect, is directed to a method of evaluating polynucleotide probes for their
ability to form simultaneous hybrids with different regions of the same target
polynucleotide. The method comprises four basic steps:

2 U.S. Patent 4,868,105 to Urdea, issued September 19, 1989.
3 U.S. Patent 4,731,325 to Palva, issued March 15, 1988.
4 U.S. Patent 5,723,320 to Dehlinger, issued March 3, 1998.
3
Appeal 2007-3265
Application 10/271,074

(a) selecting candidate probes based on the sequence of different
regions of the target polynucleotide;
(b) testing the candidate probes for the ability to actually hybridize
individually with the target;
(c) selecting at least two of the candidate probes which actually
hybridized to the target with at least a predetermined efficiency; and
(d) testing the selected candidate probes for the ability to form
simultaneous hybrids with the target.
2. “‘Binding efficiency’ refers to the productivity of a binding reaction,
measured as either the absolute or relative yield of binding product formed
under a given set of conditions in a given amount of time. ‘Hybridization
efficiency’ . . . refers to binding efficiency in the case where the binding
components are polynucleotides” (Spec. 11: 28-32).
3. “‘[P]redetermined efficiency’ can, for example, be some preselected
lower limit, or alternatively a preselected number of the strongest
hybridizing successful individually hybridizing candidate probes” (Spec. 19:
28-30).
4. “[F]orming ‘simultaneous hybrids’ . . . does not imply any particular
order of formation, but only that the hybrids exist at the same time” (Spec.
13: 16-17).
Urdea
5. Urdea describes “[m]ethods and compositions . . . for detecting a
nucleic acid sequence . . . [b]y using combinations of nucleic acid sequences
complementary to a nucleic acid analyte” (Urdea, col. 2, ll. 17-20) as probes
4
Appeal 2007-3265
Application 10/271,074

included in “[t]wo sets of reagents . . . referred to as the capturing set and the
labelling set” (Urdea, col. 1, ll. 41-60).
6. “The set of sequences which are complementary to the analyte may be
selected based on a variety of considerations. Depending upon the nature of
the analyte, one may be interested in a consensus sequence, a sequence
associated with polymorphisms, a particular phenotype or genotype, a
particular strain, or the like” (Urdea, col. 3, ll. 12-17). For example, in an
assay where “[t]he analyte is an HBV [DNA] fragment . . . 12 different
sequences complementary to different sequences present in HBV are
provided” (Urdea, col. 11, ll. 21-27).
7. Tables 1-3 of Urdea (cols. 13-14) show the quantitative results of
assays for HBV DNA using the sets of complementary probes as labeling
and capture reagents. No results are provided for any of the individual
probes.
Palva
8. Palva describes “sensitive nucleic acid reagents, comprising at least
two series of alternating arrays of nucleic acid fragments prepared from
either one or several segments homologous to . . . [a] nucleic acid to be
identified” (Palva, col. 2, ll. 1-5). “The higher sensitivity of the nucleic acid
reagents . . . is in part based on the fact that the use of several probes
increases the quantity of labeled hybrids on the solid carrier” (Palva, col. 2,
ll. 14-18).
9. Palva’s “arrays of nucleic acid reagents comprise at least two, but
preferably several, alternating nucleic acid fragments, up to 20 fragments,
which are derived from one or several nucleic acids sufficiently homologous
5
Appeal 2007-3265
Application 10/271,074

to the nucleic acid which is to be identified. Thereby there are obtained at
least two series of alternating arrays of nucleic acid fragments, which must
not be homologous to one another” (Palva, col. 3, ll. 34-42).
10. Palva teaches that the nucleic acid reagents must be “sufficiently
homologous [to the nucleic acid to be identified], so that a stable hybrid is
formed between the reagent and the nucleic acid to be identified” (Palva,
col. 4, ll. 4-7).
11. Palva compares the quantitative results of sandwich hybridization
assays “in which an individual probe reagent is used (b1, b2 or b3)” with
assays using “a reagent of b1, b2 or b1, b2, b3 . . . The results show that the
array of nucleic acid reagents . . . [is] four times as sensitive as individual
nucleic acid reagents (Palva, col. 13, ll. 19-26; Table 5).
DISCUSSION
Anticipation
I. The Examiner rejected claims 26-36 under 35 U.S.C. § 102(b) as
anticipated by Urdea.
Appellant contends, among other things, that “there is no disclosure in
Urdea . . . of (1) formation of simultaneous hybrids after testing candidate
probes on their ability actually to hybridize individually with respective
candidate target regions and then (2) selection of at least two candidate
probes which actually hybridize individually with at least a predetermined
efficiency with respective target regions” (App. Br. 9). In other words,
Appellant contends that Urdea does not disclose steps (b) and (c) of claim
26, the broadest claim on appeal.
6
Appeal 2007-3265
Application 10/271,074

Appellant emphasizes that Urdea’s “[s]election of the probes is based
on a variety of considerations . . . none of which involves actual
hybridization individually with at least a predetermined [binding] efficiency
with respective candidate target regions” (App. Br. 13), where binding
efficiency, as defined in Appellant’s Specification, “refers to the
productivity of a binding reaction, measured as either the absolute or relative
yield of binding product formed under a given set of conditions in a given
amount of time” (id.).
The Examiner contends that Urdea “teaches a method of probe
selection and individual testing for hybridization by first determining
complementarity . . . and then optimizing conditions for denaturing and
hybridization of each probe . . . [and] then teaches methods of hybridizing
multiple probes to the analyte sequence” (Ans. 16). Thus, the Examiner
contends, “when considered as a whole, Urdea teaches all the limitations of
the claims” (Ans. 15).
With respect to selection based on a predetermined binding efficiency,
the Examiner contends that “the results of [Urdea’s] Tables 1-3 represent[ ]
a measurement of the binding efficiency of the probe and labeling system of
Urdea” (Ans. 17). The Examiner acknowledges that the results shown in
Tables 1-3 “represent the overall binding efficiency of multiple probes”
(id.), but contends that “it is clear that Urdea has first optimized the
annealing conditions for each probe” (id.).
Anticipation under § 102 requires a showing that each limitation of a
claim is found in a single reference, either expressly or inherently.
Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1369 (Fed. Cir. 2005).
7
Appeal 2007-3265
Application 10/271,074

However, “[i]nherency . . . may not be established by probabilities or
possibilities. The mere fact that a certain thing may result from a given set
of circumstances is not sufficient.” Continental Can Co. v. Monsanto Co.,
948 F.2d 1264, 1269 (Fed. Cir. 1991).
The principal issue raised by this rejection on appeal, then, is whether
the evidence relied on by the Examiner establishes that Urdea necessarily
performed the disputed method steps in selecting combinations of nucleic
acid sequences suitable for his method of detecting a target nucleic acid
sequence.
We agree with Appellant that the Examiner has not established that
“all the method steps of present Claim 26 are . . . disclosed by Urdea” (App.
Br. 13), or that “steps (b) and (c) [would] be inherently present” (id.). The
Examiner has not identified any objective evidence that Urdea’s probes were
selected on the basis of anything other than sequence (FF 6), or that the
probes were ever tested individually (FF 7), much less that their individual
binding efficiencies, measured as either the absolute or relative yield of
binding product formed under a given set of conditions in a given amount of
time (FF 2, 3), were ever determined as part of the selection process for sets
of simultaneously hybridizing probes.
Accordingly, the rejection of claims 26-36 as anticipated by Urdea is
reversed.
II. The Examiner also rejected claims 26-38 under 35 U.S.C. § 102(b) as
anticipated by Palva.
The Examiner contends that “Palva teaches each and every limitation
of [the] claims” (Ans. 19), including steps in which “the probes are selected
8
Appeal 2007-3265
Application 10/271,074

and tested both by determination of complementarity as well as actual
testing” (Ans. 20). In addition, the Examiner “asserts that the results of
Tables 2 and 5 represent a measurement of the binding efficiency of the
probe array system of Palva . . . [and] represent the overall binding
efficiency of both individual and combinations of probes” (Ans. 21).
Appellant contends that Palva “is concerned with increasing the
sensitivity of sandwich hybridization assays, based on the use of several
probes . . . [and] is not concerned with evaluating target probes” (App. Br.
16). Appellant contends that in Palva’s method, “the probe sets have already
been found” (id.), and “[t]here is nothing in Palva . . . that would indicate
that probes are selected based on testing followed by selection based on
hybridization efficiency” (id.). In other words, Appellant contends that
Palva does not disclose step (c) of claim 26, the broadest claim on appeal.
The principal issue raised by this rejection on appeal, then, is whether
the evidence relied on by the Examiner establishes that Palva necessarily
selected the members of the probes sets (i.e., probe arrays) based, at least in
part, on measurements of their individual hybridization efficiencies.
It is true that Palva measures the hybridization efficiencies of
individual probes in order to compare them to the hybridization efficiencies
of combinations of those same probes (FF 11), but the Examiner has not
identified any objective evidence that Palva’s probes were selected in the
first instance on the basis of anything other than sequence (FF 8, 9, 10), and
alignment with alternating positions on the target nucleic acid (FF 8, 9).
While it is possible that Palva also determined the binding efficiencies of the
individual probes (measured as either the absolute or relative yield of
9
Appeal 2007-3265
Application 10/271,074

binding product formed under a given set of conditions in a given amount of
time (FF 2, 3)), as part of the selection process for the alternating sets of
simultaneously hybridizing probes, “[i]nherency . . . may not be established
by probabilities or possibilities. The mere fact that a certain thing may result
from a given set of circumstances is not sufficient” (Continental Can, 948
F.2d at 1269).
Accordingly, the rejection of claims 26-38 as anticipated by Palva is
reversed.
Obviousness
III. The Examiner rejected claims 37 and 38 under 35 U.S.C. § 103(a) as
unpatentable over Urdea in view of Dehlinger.
Dehlinger is cited as evidence that “producing position-addressable
arrays comprising oligonucleotides having different sequences” was known
in the art (Ans. 24), but the reference does not cure the underlying
deficiencies of Urdea.
The rejection of claims 37 and 38 as unpatentable over Urdea and
Dehlinger is reversed.
10
Appeal 2007-3265
Application 10/271,074

CONCLUSION
The rejection of claims 26-36 under 35 U.S.C. § 102(b) as anticipated
by Urdea is reversed.
The rejection of claims 26-38 under 35 U.S.C. § 102(b) as anticipated
by Palva is reversed.
The rejection of claims 37 and 38 under 35 U.S.C. § 103(a) as
unpatentable over Urdea and Dehlinger is reversed.

REVERSED

cdc

AGILENT TECHNOLOGIES, INC.
Intellectual Property Administration
Legal Department, DL429
P.O. Box 7599
Loveland CO 80537-0599
11