Ex Parte Agris et al

Board of Patent Appeals and Interferences

Apr 15, 2010

10190795 (B.P.A.I. Apr. 15, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte PAUL F. AGRIS,
CHRISTOPHER D.J. PEARCE and LLOYD G. MITCHELL
__________

Appeal 2009-012113
Application 10/190,795
Technology Center 1600
__________

Decided: April 15, 2010
__________

Before LORA M. GREEN, MELANIE L. McCOLLUM, and
STEPHEN WALSH, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s final rejection of claims 33-44. We have jurisdiction under
35 U.S.C. § 6(b).
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STATEMENT OF THE CASE
Claims 33, 40, and 44 are the independent claims on appeal, and read
as follows:
33. A method of screening an oligonucleotide array for insufficient
deprotection or insufficient elongation of oligonucleotides therein, said
method comprising the steps of:
(a) providing an oligonucleotide array comprising a substrate having a
plurality of different oligonucleotides immobilized thereon, with said
different oligonucleotides immobilized in different separate and discrete
locations on said substrate;
(b) providing an antibody that specifically binds to a synthetic
oligonucleotide having an organic protecting group covalently bound
thereto, which antibody does not bind to said synthetic oligonucleotide when
said organic protecting group is not covalently bound thereto; and then
(c) contacting said antibody to said oligonucleotide array to thereby
detect the presence or absence of binding of said antibody selected and
discrete locations on said array, the presence of binding to separate and
discrete locations in said array indicating insufficient deprotection or
insufficient elongation of oligonucleotides therein.

40. An oligonucleotide array, comprising, in combination:
(a) a substrate having a plurality of different oligonucleotides
immobilized thereon, with said different oligonucleotides immobilized in
different separate and discrete locations on said substrate; and
(b) a plurality of indicia associated with said array, said indicia
recording the presence of insufficient deprotection or insufficient elongation
of at least one oligonucleotide, each of said at least one oligonucleotide
located in a different separate and discrete location on said array.

44. An oligonucleotide array, comprising, in combination:
(a) a substrate having a plurality of different oligonucleotides
immobilized thereon, with said different oligonucleotides immobilized in
different separate and discrete locations on said substrate;
(b) a plurality of indicia associated with said array, said indicia
recording the presence of insufficient deprotection or insufficient elongation
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of at least one oligonucleotide, each of said at least one oligonucleotide
located in a different separate and discrete location on said array; and
(c) wherein said indicia are contained on a web site, said array further
comprising an identifier associating said substrate and said indicia.

The Examiner relies on the following evidence:
Coolidge US 5,464,759 Nov. 7, 1995
Barany US 6,852,487 B1 Feb. 8, 2005
Cattell US 2003/0059094 A1 Mar. 27, 2003
McClelland US 2003/0224382 A1 Dec. 4, 2003

Schena, Mark, Parallell human genome analysis: Microarray-based
expression monitoring of 1000 genes, 93 Proc. Natl. Acad. Sci. USA,
Biochemistry 10614 (1996).

We reverse.

ISSUE
Does the evidence of record support the Examiner’s conclusion that it
would have been obvious to combine Coolidge and Barany to use an
antibody to assay a solid support having immobilized thereon an array of
oligonucleotides for failed oligonucleotides?

FINDINGS OF FACT
FF1 According to the Specification, “there is a need for simple and reliable
techniques for determining the purity and proportion of full length of
oligonucleotide products.” (Spec. 2.)
FF2 The Specification teaches an antibody that binds to a synthetic
oligomer that has an organic protecting group covalently bound thereto, but
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does not bind to the oligomer when the protecting group is not present. (Id.
at 2-3.)
FF3 The Specification teaches that the “invention may be used to test or
screen oligonucleotides that are immobilized on a solid support such as a
microarray for insufficient deprotection or elongation of the oligonucleotides
. . . thereon.” (Id. at 24.)
FF4 The Examiner rejects claims 33-40 and 43 under 35 U.S.C. § 103(a)
as being rendered obvious by the combination of Coolidge and Barany.
(Ans. 4.)
FF5 The Examiner finds that Coolidge teaches “a method of purifying
sequentially synthesized peptides and oligonucleotides.” (Id.)
FF6 The Examiner finds that Coolidge teaches the use of antibodies that
recognize “failed oligonucleotides, e.g. insufficient elongated nucleotides,
for detection purity of oligonucleotides synthesis (Col. 8, line 15-20).” (Id.)
FF7 The Examiner finds that Coolidge teaches that the antibodies “bind to
a synthetic oligonucleotide having organic protecting groups covalently
bound thereto, such as acylating, phosphorylating, carbamylating or 5'-DMT
agent that is reactive toward free 5'-hydroxyl groups of failed
oligonucleotides (Col. 8, line 15-20; Col. 10, line 7-10; Col. 9, line 35-40),”
but do not bind when the protecting group is not present. (Id. at 4-5.)
FF8 The Examiner finds that the Specification at page 13 exemplifies the
use of an antibody to a DMT protecting group, which is one of the same
groups used by Coolidge. (Id. at 9.)
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FF9 Coolidge notes that the oligonucleotide coupling procedure is not
100% effective, which results in oligonucleotides having an incorrect
sequence. (Coolidge, col. 2, ll. 1-4.)
FF10 According to Coolidge, those failed nucleotides “often cause
undesirable reactions if left in mixture with the correct oligonucleotide,” and
thus “their separation and removal are mandated even though tedious
procedures tailored to each specific synthesis are necessitated.” (Id. at col.
2, ll. 4-8.)
FF11 Coolidge teaches that a known mean of addressing the issue is
through the use of capping, in which failed oligonucleotides “are reacted
with a capping agent which prevents the failed . . . oligonucleotide from
participating in subsequent coupling reactions.” (Id. at col. 2, ll. 46-53.)
FF12 Coolidge thus teaches a sequential oligonucleotide synthesis method
that employs 5'-terminus capping agents and affinity agents that are selective
for the capping agent. (Id. at col. 3, ll. 32-36.)
FF13 The affinity agents, which are either free in solution or bound to a
solid support, bind with and remove the capped, failed, oligonucleotides
from the reaction mixture. (Id. at col. 3, ll. 37-44.)
FF14 As to the capping agent used for failed oligonucleotides, Coolidge
teaches that the capping agents has “stability under the conditions for
synthesis of the oligonucleotide and for removal of the protective groups
attached to the oligonucleotide during synthesis.” (Id. at col. 8, ll. 42-57.)
The capped failed sequences are thus not available for further chain
elongation. (See, e.g., id. at col. 23, ll. 34-43.)
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FF15 Coolidge also teaches a separation method in which a capping group
may be used to affinity purify the correctly sequenced oligonucleotide (id. at
col. 3, ll. 46-57), and in those cases the oligonucleotide will be capped with
DMT “or other ether 5'-blocking group” (id. at col. 9, ll. 15-25). In those
cases, the affinity purified oligunucleotide containing the desited sequence
may be eluted from the column by treating with acid to cleave the DMT
from the oligonucleotide. (Id. at col. 23, l. 62-col. 24, l. 7.)
FF16 The Examiner notes that Coolidge does “not teach using DNA array
for mass screening of the insufficient elongation of the failed
oligonucleotides.” (Ans. 5.)
FF17 The Examiner finds that Barany teaches “a microarray identifying a
plurality of oligonucleotide sequences, including single base change,
insertation, deletions, or translation.” (Id.)
FF18 According to the Examiner, Barany teaches the immobilization, as
well as the in situ synthesis of oligonucleotides on the array, wherein the
microarray “comprises a plurality of discrete locations for different
oligonucleotide probes.” (Id.)
FF19 Specifically, Barany notes that “[o]rdered arrays of oligonucleotides
immobilized on a solid support have been proposed for sequencing, sorting,
isolating, and manipulating DNA.” (Barany, col. 3, ll. 50-52.)
FF20 Barany teaches a method of forming an array of oligonucleotides on a
solid support, wherein a solid support has an array of positions suitable for
attachment of an oligonucleotide to a solid support, wherein the array “is
formed by a series of cycles of activating selected array positions for
attachment of multimer nucleotides and attaching multimer nucleotides at
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the activated array positions.” (Id. at col. 6, ll. 15-27.) Barany also notes
that the oligonucleotides may be assembled on the solid support. (Id. at col.
26, ll. 36-41.)
FF21 The Examiner concludes that it would have been obvious at the time
of invention to screen the microarray of Barany for failed oligoncleotides
using the method and antibodies of Coolidge as the “the DNA microarray of
Barany [ ] provides the advantages of mass screening in time-saving and
cost-effective manner, and such technology is common and routine at the
time the invention was made.” (Ans. 5.)
FF22 The Examiner rejects claim 41 under 35 U.S.C. § 103(a) as being
rendered obvious by the combination of Coolidge and Barany as set forth
above, as further combined with Schena. (Id. at 6.)
FF23 The Examiner relies on Schena to reach the limitation of a microarray
having a thousand discrete locations. (Id.)
FF24 The Examiner rejects claim 42 under 35 U.S.C. § 103(a) as being
rendered obvious by the combination of Coolidge and Barany as set forth
above, as further combined with Cattell. (Id.)
FF25 The Examiner relies on Cattell to reach the limitation of using a stored
database on the DNA microarray. (Id.)
FF26 The Examiner rejects claim 44 under 35 U.S.C. § 103(a) as being
rendered obvious by the combination of Coolidge and Barany as set forth
above, as further combined with McClelland. (Id. at 7.)
FF27 The Examiner relies on McClelland to reach the limitation of using “a
web site for indicia of the microarray.” (Id.)

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PRINCIPLES OF LAW
While the analysis under 35 U.S.C. § 103 allows flexibility in
determining whether a claimed invention would have been obvious, KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), it still requires showing
that “there was an apparent reason to combine the known elements in the
fashion claimed by the patent at issue.” Id. “We must still be careful not to
allow hindsight reconstruction of references to reach the claimed invention
without any explanation as to how or why the references would be combined
to produce the claimed invention.” Innogenetics, N.V. v. Abbott Labs., 512
F.3d 1363, 1374 n.3 (Fed. Cir. 2008). Moreover, the Examiner must
consider all of the claim limitations in setting forth a rejection over the prior
art. See, e.g., In re Geerdes, 491 F.2d 1260, 1262-63 (CCPA 1974) (in
considering grounds of rejection, “every limitation in the claim must be
given effect rather than considering one in isolation from the others.”).

ANALYSIS
Appellants argue that Coolidge “fails to disclose reagents or methods
for the detection of . . . 5'-capped oligonucleotides on microarrays
manufactured by either spotting or in-situ synthesis, much less methods for
the detection and measurement of undesired protecting groups on finished
oligonucleotides using microarrays.” (App. Br. 9.) Specifically, Appellants
assert, the antibodies of Coolidge are used to purify select oligonucleotides
out of a mixture of oligonucleotides that have the desired sequence and
failed oligonucleotides, whereas the claims require that the oligonucleotide
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be immobilized on an array, with the antibodies being used to assay for
insufficient deprotection or elongation. (Reply Br. 1-2.)
Appellants assert that Barany does not remedy the deficiencies of
Coolidge as Barany also “provides no disclosure for the detection and/or
measurement of the extent of 5'-capped (failed) oligonucleotides.” (App. Br.
9.)
We agree with Appellants that the combination of Coolidge and
Barany as combined by the Examiner does not teach or suggest the method
of claim 33. Specifically, as noted by Appellants, Coolidge uses the
antibodies to the capping group to separate out from a mixture either the
failed oligonucleotide or the oligonucleotide of the desired sequence.
Coolidge does not teach or suggest using the antibody to assay a solid
support having immobilized thereon an array of oligonucleotides for failed
oligonucleotides. Barany does not remedy that deficiency. Thus, as the
Examiner has not provided any reason as to why the ordinary artisan would
have used the antibody of Coolidge to assay for failed oligonucleotides
immobilized on a microarray, rather than using the antibodies to affinity
purify the desired oligonucleotide from the failed oligonucleotides, we are
compelled to reverse the rejection as to independent claim 33, as well as the
claims dependent thereon.
As to independent claim 40, the Examiner did not address that claim
separately, and did not address the indicia component of the claimed array.
While the Examiner adds McClelland to reject independent claim 44,
McClelland was added to address the limitation of using a web site for
indicia of the microarray, and thus does not remedy the deficiencies of the
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combination of Coolidge and Barany. We are thus also compelled to reverse
the rejection as to independent claims 40 and 44, as well as the claims
dependent thereon.

CONCLUSION(S) OF LAW
We conclude that the evidence of record does not support the
Examiner’s conclusion that it would have been obvious to combine Coolidge
and Barany to use an antibody to assay a solid support having immobilized
thereon an array of oligonucleotides for failed oligonucleotides. We are thus
compelled to reverse all of the rejections on appeal.
Specifically, we reverse the rejection of claims 33-40 and 43 under 35
U.S.C. § 103(a) as being rendered obvious by the combination of Coolidge
and Barany; the rejection of claim 41 under 35 U.S.C. § 103(a) as being
rendered obvious by the combination of Coolidge and Barany, as further
combined with Schena; the rejection of claim 42 under 35 U.S.C. § 103(a) as
being rendered obvious by the combination of Coolidge and Barany, as
further combined with Cattell; and the rejection claim 44 under 35 U.S.C. §
103(a) as being rendered obvious by the combination of Coolidge and
Barany as set forth above, as further combined with McClelland.

Appeal 2009-012113
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REVERSED

alw

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