Ex Parte Kincaid

Board of Patent Appeals and Interferences

Jun 15, 2010

10422163 (B.P.A.I. Jun. 15, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ROBERT H. KINCAID
__________

Appeal 2009-013965
Application 10/422,163
Technology Center 1600
__________

Decided: June 15, 2010
__________

Before DONALD E. ADAMS, MELANIE L. McCOLLUM, and
STEPHEN WALSH, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to
microarray feature location and quality control evaluation methods. The
Examiner has rejected the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b). We affirm-in-part.
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STATEMENT OF THE CASE
Claims 61, 66-68, 72-75, and 85-96 are pending and on appeal (App.
Br. 3). We will focus on claims 95, 61, 68, 73, 74, and 85, which read as
follows:
95. A method of locating features on a microarray, the method
comprising:
contacting a microarray with a labeled control target and a labeled test
target under hybridization conditions, wherein the microarray comprises an
array of features on a substrate, each feature comprising an oligomer test
probe and an oligomer control probe, wherein said oligomer control probes
hybridize to the labeled control target and an oligomer test probe hybridizes
to the labeled test target;
locating each of said features by detecting a control target signal
emitted by the labeled control target hybridized to the control probe at each
feature, wherein said locating comprises interrogating the microarray with a
microarray scanner, and further wherein said locating is not dependent upon
placement quality of the oligomer test probe at each feature.
61. The method of Claim [95, wherein the method further comprises
separately detecting a test signal emitted by the hybridized labeled test
target; and correlating the detected test signal and the detected control target
signal],
wherein the control probe is directly labeled with a control probe label
that emits a control probe signal when excited by light, the control probe
signal being different from the control target signal.
68. A method of locating features on a microarray with a microarray
scanner, the microarray comprising a substrate having a surface, the method
comprising:
providing an array pattern of features on the surface of the substrate,
wherein each feature of said array pattern of features comprises
(i) a control probe, the control probe being directly associated
with a control probe label that emits a control probe signal when
exposed to a light; and
(ii) an oligomer test probe, the oligomer test probe being
directly associated with a test probe label that emits a test probe signal
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when exposed to the light, the test probe signal being different from
the control probe signal;
locating each feature by detecting the control probe signal from each
feature, wherein said locating comprises interrogating the microarray with
the microarray scanner, such that the microarray scanner detects the control
probe signal from each feature in a control detection channel of the scanner,
the microarray scanner detecting the test probe signals in a separate test
detection channel of the scanner, wherein said locating is not dependent
upon placement quality of the oligomer test probe at each feature; and
evaluating data collected on the detected control probe signals and the
detected test probe signals.
73. The method of Claim 68, further comprising:
depositing a hybridization solution on the microarray based on the
collected data, the hybridization solution comprising a test target that
comprises a test target label, the test target label emitting a test target signal
when excited by light, the test target signal being different from each of the
control probe signal and the test probe signal, the test target hybridizing to at
least some of the oligomer test probes, such that the test target label is
indirectly associated with the hybridized oligomer test probes;
interrogating the microarray, such that the microarray scanner further
detects the test target signal on the hybridized oligomer test probes in a
separate test detection channel of the scanner; and
evaluating characteristics of the hybridization between the oligomer
test probe and the test target using data collected from each of the separate
detection channels of the scanner.
74. The method of Claim 73, wherein the hybridization solution
further comprises a control target that is specifically complementary to the
control probe, the control target comprising a control target label, the control
target hybridizing to the control probes on each feature, such that the control
target label is indirectly associated with the control probe at each feature,
and
wherein the control target label emits a control target signal when
excited by light, the control target signal being different from each of the
control probe signal, the test probe signal and the test target signal, and
wherein interrogating the microarray comprises detecting the control
target signal with microarray scanner in a separate control detection channel
of the scanner.
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85. A method of performing a nondestructive quality control
evaluation of a microarray comprising:
providing a labeled control probe to a plurality of feature locations on
the surface of a microarray substrate, the labeled control probe on the
microarray emitting a control probe signal when excited by a light;
locating each feature location of said plurality of feature locations by
detecting the control probe signal at each feature location of said plurality of
feature locations, wherein said locating comprises interrogating the
microarray;
evaluating data acquired from the interrogation, wherein evaluating
comprises using the data acquired for modifying a subsequent deposition;
and
subsequently depositing an oligomer test probe to each of said feature
locations of the microarray based on the acquired data, such that a feature
comprising the labeled control probe and the oligomer test probe is provided
at each feature location.
Claims 95, 96, and 66 stand rejected under 35 U.S.C. § 103(a) as
obvious over Stuelpnagel et al. (US 2002/0051971 A1, May 2, 2002) in
view of Stern (US 5,981,956, Nov. 9, 1999) (Ans. 3).
Claims 61 and 67 stand rejected under 35 U.S.C. § 103(a) as obvious
over Stuelpnagel in view of Stern and Ramberg (US 5,962,225, Oct. 5,
1999) (Ans. 8).
Claims 68 and 72-74 stand rejected under 35 U.S.C. § 103(a) as
obvious over Stuelpnagel in view of Granados et al. (US 5,955,268, Sep. 21,
1999) and Stern (Ans. 10).
Claim 75 stands rejected under 35 U.S.C. § 103(a) as obvious over
Stuelpnagel in view of Granados, Stern, and Lockhart et al. (WO 97/27317
A1, Jul. 31, 1997) (Ans. 22).
Claims 85-87 stand rejected under 35 U.S.C. § 103(a) as obvious over
Besemer et al. (US 5,945,334, Aug. 31, 1999) in view of Noblett
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(US 6,362,004 B1, Mar. 26, 2002) and Troll (US 5,721,435, Feb. 24, 1998)
(Ans. 24).
Claim 88 stands rejected under 35 U.S.C. § 103(a) as obvious over
Besemer in view of Noblett, Troll, and Stern (Ans. 29).
Claims 89 and 90 stand rejected under 35 U.S.C. § 103(a) as obvious
over Besemer in view of Noblett, Troll, Stern, Granados, and Ramberg
(Ans. 31).
Claim 91 stands rejected under 35 U.S.C. § 103(a) as obvious over
Besemer in view of Noblett, Troll, Lockhart, and Ramberg (Ans. 36).
Claim 92 stands rejected under 35 U.S.C. § 103(a) as obvious over
Besemer in view of Noblett, Troll, Lockhart, Ramberg, and Stern (Ans. 39).
Claim 93 stands rejected under 35 U.S.C. § 103(a) as obvious over
Besemer in view of Noblett, Troll, Lockhart, Ramberg, and Granados
(Ans. 40).
Claim 94 stands rejected under 35 U.S.C. § 103(a) as obvious over
Besemer in view of Noblett, Troll, Lockhart, Ramberg, Granados, and Stern
(Ans. 43).
PRINCIPLES OF LAW
“It is axiomatic that, in proceedings before the PTO, claims in an
application are to be given their broadest reasonable interpretation consistent
with the specification and that claim language should be read in light of the
specification as it would be interpreted by one of ordinary skill in the art.”
In re Sneed, 710 F.2d 1544, 1548 (Fed. Cir. 1983) (citation omitted).
Obviousness “analysis need not seek out precise teachings directed to
the specific subject matter of the challenged claim.” KSR Int’l v. Teleflex
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Inc., 550 U.S. 398, 418 (2007). Instead, it proper to “take account of the
inferences and creative steps that a person of ordinary skill in the art would
employ.” Id. “A person of ordinary skill is also a person of ordinary
creativity, not an automaton.” Id. at 421.
I
The Examiner rejects claims 95, 96, and 66 as obvious over
Stuelpnagel in view of Stern (Ans. 3).
The Examiner relies on Stuelpnagel for teaching a method having
many of the limitations of claim 95 (id. at 3-5). In particular, the Examiner
relies on Stuelpnagel for teaching “a microarray in the form of a microarray
of microspheres wherein a plurality of locations each have an individual
microsphere,” each location bearing a microsphere being considered a
“feature” (id. at 3-4). The Examiner finds:
Each microsphere comprises an oligomer test probe in the form
of a capture probe that hybridizes to a test target in the form of
target analyte . . . and an oligomer control probe in the form of
an identifier binding ligand (i.e., IBL . . . ), which hybridizes to
a[n] oligomer control target in the form of a decoder binding
ligand (i.e., DBL . . . ).
(Id. at 4.) The Examiner also finds that the “test target (i.e., target sequence)
is labeled . . . and the DBL (i.e., control target) is also labeled” (id.). In
addition, the Examiner finds that Stuelpnagel teaches “locating each of the
features by detecting a control target signal emitted by the labeled control
target hybridized to the control probe at each feature” (id.)
The Examiner relies on Stern for teaching “using a microarray scanner
to detect signals emitted by nucleic acids” (id. at 5). The Examiner
concludes that it would have been obvious to modify Steulpnagel’s method
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“so that the signal emitted by [the] control target label i[s] detected in a
channel of the microarray scanner as taught by Stern” (id. at 6).
Appellant argues that “the proposed combination of Stuelpnagel and
Stern fails to teach or suggest . . . ‘locating each of said features by detecting
a control target signal emitted by the labeled control target hybridized to the
control probe at each feature’ (emphasis added)” (App. Br. 9).
Issue
Does the evidence support the Examiner’s conclusion that Stuelpnagel
teaches or suggests locating each feature of a microarray by detecting a
control target signal emitted by the labeled control target hybridized to the
control probe at each feature?
Findings of Fact
1. Stuelpnagel discloses “microfluidic devices for the detection of
a target analyte in a sample” (Stuelpnagel, ¶ [0007]).
2. In particular, Stuelpnagel discloses microfluidic devices
including a detection module, the detection module comprising “an array
substrate with a surface comprising discrete sites and a population of array
microspheres (sometimes referred to herein as beads) distributed on the
array surface,” each microsphere comprising a bioactive agent (id. at
¶¶ [0172]-[0173] & [0193]).
3. In order to use its device, Stuelpnagel discloses:
The sample is introduced to the array in the detection module,
and then immobilized or attached to the beads. In one
embodiment, this is done by forming an attachment complex
(frequently referred to herein as a hybridization complex when
nucleic acid components are used) between a capture probe and
a portion of the target analyte.
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(Id. at ¶ [0284].)
4. Stuelpnagel also discloses that “the microspheres may
additionally comprise identifier binding ligands for use in certain decoding
systems” (id. at ¶ [0211]).
5. In particular, Stuelpnagel states:
The detection module of the microfluidic devices described
herein are based on previous work comprising a bead-based
analytic chemistry system in which beads, also termed
microspheres, carrying different chemical functionalities are
distributed on an array substrate comprising a patterned surface
of discrete sites that can bind the individual microspheres. The
beads are generally put onto the substrate randomly, and thus
several different methodologies can be used to “decode” the
arrays.
(Id. at ¶ [0173].)
6. Stuelpnagel also discloses that coding/decoding “may be done
in a variety of ways,” including “the use a decoding binding ligand (DBL),
generally directly labeled, that binds to either the bioactive agent or to
identifier binding ligands (IBLs) attached to the beads” (id. at ¶ [0174]).
7. In addition, Stuelpnagel discloses:
“[D]ecoding” can use optical signatures, decoding binding
ligands that are added during a decoding step, or a combination
of these methods. The decoding binding ligands will bind
either to a distinct identifier binding ligand partner that is
placed on the beads, or to the bioactive agent itself, for example
when the beads comprise single-stranded nucleic acids as the
bioactive agents. The decoding binding ligands are either
directly or indirectly labeled, and thus decoding occurs by
detecting the presence of the label.
(Id. at ¶ [0175].)
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8. Stuelpnagel also discloses:
Once the identity (i.e. the actual agent) and location of each
microsphere in the array has been fixed, the detection array is
exposed to samples containing the target analytes, although . . .
this can be done prior to or during the analysis as well. . . . The
target analytes will bind to the bioactive agents . . . and results
in a change in the optical signal of a particular bead, resulting in
detection.
(Id. at ¶ [0176] (emphasis added).)
9. In addition, Stuelpnagel discloses that, “after the array is made,
it is ‘decoded’ in order to identify the location of one or more of the
bioactive agents, i.e. each subpopulation of beads, on the substrate surface”
(id. at ¶ [0230] (emphasis added)).
10. Stuelpnagel also discloses determining “the location of every
bioactive agent . . . using decoder binding ligands (DBLs)” (id. at ¶ [0236]
(emphasis added)).
Analysis
Stuelpnagel discloses a microfluidic device “for the detection of a
target analyte in a sample,” the device including a detection module
comprising “an array substrate with a surface comprising discrete sites and a
population of array microspheres (sometimes referred to herein as beads)
distributed on the array surface” (Findings of Fact (FF) 1-2). To decode the
array, Stuelpnagel discloses allowing decoding binding ligands (DBLs),
which have been labeled, to bind to identifier binding ligands (IBLs) placed
on the beads and detecting the presence of the labels (FF 4-7). Stuelpnagel
discloses fixing “the identity . . . and location of each microsphere in the
array” (FF 8); that the array “is ‘decoded’ in order to identify the location of
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one or more of the bioactive agents” (FF 9); and determining “the location
of every bioactive agent . . . using decoder binding ligands (DBLs)” (FF 10).
Thus, we cannot agree with Appellant that Stuelpnagel does not disclose
“locating” each feature of the microarray.
Conclusion
The evidence supports the Examiner’s conclusion that Stuelpnagel
teaches or suggests locating each feature of a microarray by detecting a
control target signal emitted by the labeled control target hybridized to the
control probe at each feature. We therefore affirm the obviousness rejection
of claim 95. Claims 96 and 66 have not been argued separately and
therefore fall with claim 95. 37 C.F.R. § 41.37(c)(1)(vii).
II
The Examiner rejects claims 61 and 67 as obvious over Stuelpnagel in
view of Stern and Ramberg (Ans. 8).
In rejecting these claims, the Examiner relies on Stuelpnagel and
Stern as discussed above (id.). The Examiner additionally finds that
Stuelpnagel teaches that “the control probe is directly labeled with a control
probe label that emits a control probe signal when excited by light; namely,
the IBL is a fluorescent molecule” (id.). In addition, the Examiner finds that
Stuelpnagel teaches that “detection uses labels having different optical
signatures . . . , and that the detected optical signals result from different
ratios of mixtures of fluorochromes” (id.). However, the Examiner
acknowledges that “neither Stuelpnagel et al nor Stern explicitly teaches the
control probe signal is different from the control target signal; i.e., that each
type of nucleic acid is differentially labeled” (id.).
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The Examiner relies on Ramberg for teaching a method
wherein a plurality of different nucleic acids, in the form of
labeled probes, wherein each different type of nucleic acid (i.e.,
capture probe and reporter probe) has a different type of label
. . . , which has the added advantage of allowing minimization
of the number of false signals . . . because the detection of one
label is independent of the detection of the other.
(Id. at 8-9.) The Examiner concludes that it would have been obvious “to
have modified the labeled control target nucleic acids and labeled control
probe nucleic acids in the method of Stuelpnagel et al in view of Stern so
that each of the different types of nucleic acids is labeled with a different
label as taught by Ramberg” because such a “modification would have
resulted in a method having the added advantage of allowing independent
detection of each of the labels . . . allowing minimization of the number of
false signals as taught by Ramberg” (id. at 9).
Appellant argues that “the proposed combination of Stuelpnagel-
Stern-Ramberg fails to teach or suggest that ‘the control probe is directly
labeled with a control probe label that emits a control probe signal when
excited by light, the control probe signal being different from the control
target signal,’ as required by claims 61 and 67” (App. Br. 11 (emphasis
omitted)).
Issue
Does the evidence support the Examiner’s conclusion that
Stuelpnagel, Stern, and Ramberg teach or suggest a control probe directly
labeled with a control probe label that emits a control probe signal when
excited by light, the control probe signal being different from the control
target signal?
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Findings of Fact
11. Stuelpnagel discloses that complementary nucleic acids are
suitable IBL-DBL binding pairs (Stuelpnagel, ¶ [0212]).
12. Stuelpnagel also discloses that “the IBL is a molecule whose
color or luminescence properties change in the presence of a selectively-
binding DBL” or “in the presence of various solvents” (id. at ¶¶ [0213]-
[0214]).
13. In addition, Stuelpnagel discloses that “the DBL may be
attached to a bead, i.e., a ‘decoder bead’, that may carry a label such as a
fluorophore” (id. at ¶ [0215]).
14. Stuelpnagel also discloses:
[E]ach subpopulation of microspheres may comprise a unique
optical signature or optical tag that is used to identify the
unique bioactive agent of that subpopulation of microspheres;
that is, decoding utilizes optical properties of the beads such
that a bead comprising the unique optical signature may be
distinguished from beads at other locations with different
optical signatures. This assigns each bioactive agent a unique
optical signature such that any microspheres comprising that
bioactive agent are identifiable on the basis of the signature.
These optical signatures comprised dyes, usually chromophores
or fluorophores, that were entrapped or attached to the beads
themselves. Diversity of optical signatures utilized different
fluorochromes, different ratios of mixtures of fluorochromes,
and different concentrations (intensities) of fluorochromes.
(Id. at [0218].)
15. In addition, Stuelpnagel discloses:
In a preferred embodiment, the arrays do rely solely on the use
of optical properties to decode the arrays. However, . . . it is
possible in some embodiments to utilize optical signatures as an
additional coding method, in conjunction with the other
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methods outlined below. . . . [T]he use of two populations of
beads, one with an optical signature and one without, allows the
effective doubling of the array size. The use of multiple optical
signatures similarly increases the possible size of the array.
(Id. at ¶ [0219].)
16. Ramberg discloses methods “for the detection of nucleic acid
sequences” that “may include one, two, or three levels of specificity to
minimize false positive signals” (id. at col. 4, ll. 2-10).
17. Ramberg discloses that the “initial level of specificity utilizes
protection molecules . . . to bind to specific target sequences of interest . . . ,
form[ing] the protected nucleic acid sequence (PNAS)” (id. at col. 4, ll. 23-
30).
18. Ramberg also discloses that a second level of specificity
involves the use of a capture probe and that a “third level of specific
detection involves the addition of a labeled reporter probe,” both the capture
and reporter probes being “capable of associating with the PNAS” (id. at
col. 4, ll. 46-59, & col. 5, ll. 9-13).
19. In addition, Ramberg discloses that the “reporter probe may be
labelled with any labels known in the art such as . . . with a fluorescent
reporter molecule” (id. at col. 5, ll. 16-21).
20. Ramberg also discloses that the “capture probe or protection
molecule could be labeled so that the captured PNAS could be detected” (id.
at col. 15, ll. 8-10).
21. In addition, Ramberg discloses:
[The capture and labeling steps] could also be combined into a
single hybridization/capture step with no purification in
between. Since each probe is unique to its own target sequence,
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there should be no danger of cross hybridization to produce
false signals. This possibility is further reduced by the fact that
each probe carries a different label (i.e. capture with Dig vs.
reporter with FITC).
(Id. at col. 19, ll. 14-21, & col. 8, ll. 2-7.)
Analysis
Stuelpnagel discloses that complementary nucleic acids are suitable
IBL-DBL binding pairs (FF 11). The Examiner has not pointed to a clear
teaching in Stuelpnagel that both nucleic acids of the IBL-DBL binding pair
are labeled. However, Stuelpnagel clearly discloses that the DBL is labeled
such as with a fluorophore (FF 6, 7, & 13). In addition, Stuelpnagel
discloses that “the IBL is a molecule whose color or luminescence properties
change” (FF 12). Thus, we conclude that it would have been obvious to
label the IBL nucleic acid, as well as the DBL nucleic acid, with a label that
emits a signal when excited by light.
Stuelpnagel also discloses the use of diverse optical signals (FF 14-
15). In addition, Ramberg discloses different probes having different labels
(FF 21). In view of these disclosures, we agree with the Examiner that it
would have been obvious for the IBL and DBL labels to emit different
signals “allowing independent detection of each of the labels” (Ans. 9).
We recognize that Ramberg discloses different labels on two probes
that hybridize to a common target rather than two nucleic acids that
hybridize to each other (FF 18). However, the Examiner is not relying on
Ramberg to show that it would have been obvious to include labels on both
the IBL and the DBL (Ans. 49). Instead, the Examiner is merely relying on
Ramberg to show that it was known in the art to include different labels on
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different nucleic acids (Ans. 8-9). We agree with the Examiner that a person
of ordinary skill in the art would have applied Ramberg’s teachings, yielding
the method with labeled probes that Appellant now claims. We also do not
agree with Appellant that Ramberg generally fails to overcome the
deficiencies of Stuelpnagel and Stern, because we concluded that
Stuelpnagel and Stern were not generally deficient.
Conclusion
The evidence supports the Examiner’s conclusion that Stuelpnagel,
Stern, and Ramberg teach or suggest a control probe directly labeled with a
control probe label that emits a control probe signal when excited by light,
the control probe signal being different from the control target signal. We
therefore affirm the obviousness rejection of claim 61. Claim 67 has not
been argued separately and therefore falls with claim 61. 37 C.F.R.
§ 41.37(c)(1)(vii).
III
The Examiner rejects claims 68 and 72-74 as obvious over
Stuelpnagel in view of Granados and Stern (Ans. 10). The Examiner also
rejects claim 75 as obvious over Stuelpnagel in view of Granados, Stern, and
Lockhart (id. at 22).
The Examiner relies on Stuelpnagel for teaching a method having
many of the limitations of these claims (id. at 10-20). However, the
Examiner acknowledges that Stuelpnagel does “not explicitly teach the
oligomer test (i.e., capture) probe is labeled” or “that each of the labels are
detected with a microarray scanner in a separate channel” (id. at 12 & 13).
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The Examiner relies on Granados for teaching “labeling the oligomer
test (i.e., capture) probe” (id. at 12). The Examiner concludes that it would
have been obvious to modify Stuelpnagel’s method “so that the oligomer test
(i.e., capture) probe is also fluorescently labeled as taught by Granados”
(id.).
The Examiner relies on Stern for teaching “using a microarray scanner
to detect signals emitted by different labels on the nucleic acids” (id. at 14).
The Examiner concludes that it would have been obvious to modify the
method of Stuelpnagel and Granados “so that the different control probe
signal and test probe signal are each detected in the different channels of the
microarray scanner as taught by Stern” (id.).
Appellant argues that “the proposed combination of Stuelpnagel-
Stern-Granados fails to teach or suggest . . . ‘locating each feature by
detecting the control probe signal from each feature’” (App. Br. 15
(emphasis omitted)).
With regard to claim 73, Appellant argues that “the proposed
combination of references fails to teach or suggest ‘depositing a
hybridization solution on the microarray based on the collected data’” (id. at
16 (emphasis omitted)).
With regard to claim 74, Appellant argues that “the proposed
combination of references fails to teach or suggest ‘the control target signal
being different from each of the control probe signal, the test probe signal
and the test target signal’” (id. at 18 (emphasis omitted)).
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With regard to claim 75, which depends from claim 74, Appellant
argues that “Lockhart fails to cure the deficiencies discussed above in the
context of claims 68, 73 and 74” (id. at 19).
Issues
Does the evidence support the Examiner’s conclusion that
Stuelpnagel, Granados, and Stern teach or suggest locating each feature by
detecting the control probe signal from each feature?
With regard to claim 73, does the evidence support the Examiner’s
conclusion that Stuelpnagel, Granados, and Stern teach or suggest depositing
a hybridization solution on the microarray based on the collected data?
With regard to claim 74, does the evidence support the Examiner’s
conclusion that Stuelpnagel, Granados, and Stern teach or suggest the
control target signal being different from each of the control probe signal,
the test probe signal, and the test target signal?
Findings of Fact
22. Stuelpnagel discloses:
[T]he methods of the invention are useful in array quality
control. Prior to this invention, no methods have been
described that provide a positive test of the performance of
every probe on every array. Decoding of the array not only
provides this test, it also does so by making use of the data
generated during the decoding process itself.
(Stuelpnagel, ¶ [0277].)
23. Granados discloses:
The capture probes are labeled with a “signal generating
system” which, as used herein, means a label or labels that
generate differential signals in the presence and absence of
target. Thus, a signal is generated in a “target dependent
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manner” which means that in the absence of target sequence, a
given signal is emitted which undergoes a detectable change
upon hybridization between a capture probe and its target
sequence.
(Granados, col. 4, ll. 17-25.)
24. For example, Granados discloses that, “in the case where a
capture probe is labeled with an intercalation dye, the fluorescent signal
emitted from the dye increases in intensity upon hybridization between the
capture probe and its complementary target sequence” (id. at col. 5, ll. 37-
40).
25. In addition, Granados discloses that, “in the event a capture
probe is labeled with a PORSCHA dye, a complementary target sequence
labeled with another PORSCHA dye will change the spectral properties of
the PORSCHA dye on the capture probe upon hybridization” (id. at col. 5,
ll. 47-51).
Analysis
Stuelpnagel discloses that the IBL, which the Examiner considers the
control probe (Ans. 11), “is a molecule whose color or luminescence
properties change in the presence of a selectively-binding DBL” (FF 12). As
discussed above, Stuelpnagel discloses fixing “the identity . . . and location
of each microsphere in the array” (FF 8); that the array “is ‘decoded’ in
order to identify the location of one or more of the bioactive agents” (FF 9);
and determining “the location of every bioactive agent . . . using decoder
binding ligands (DBLs)” (FF 10). Thus, we cannot agree with Appellant
that Stuelpnagel does not disclose or suggest “locating” each feature by
detecting its control probe signal.
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With regard to claim 73, the Examiner finds that it would have been
obvious “to have based the deposition of the hybridization solution in the
microarray on the collected data because a person of ordinary skill in the art
. . . would only use the array if the collected quality control data indicated
that the array was of sufficient quality for use” (Ans. 54). We agree.
Stuelpnagel discloses depositing a hybridization solution on the
microarray after the decoding step (FF 8). In addition, Stuelpnagel discloses
using the decoding step to test the quality of the array (FF 22). When the
user of Stuelpnagel’s method decides to continue after the quality testing,
i.e., go on to deposit the hybridization solution because the quality test data
shows the microarray is adequate for use, the hybridization solution is being
deposited “based on the collected data.” Appellant has not adequately
explained why we should disregard the meaning of Stuelpnagel’s decoding
step, which collects data for the purpose of making a decision to continue
using the microarray.
With regard to data collected on the detected test probe signals, we
note that the Examiner relies on Granados to disclose labeling the test probes
(Ans. 12). Granados discloses that the “capture probes are labeled with a
‘signal generating system’ which . . . means a label or labels that generate
differential signals in the presence and absence of target” (FF 23). Thus,
when Stuelpnagel and Granados are considered together, we agree with the
Examiner that it would have been obvious to consider the data collected on
the detected test probe signals (i.e., signals from the capture probe), as well
as the data collected on the detected control probe signals (i.e., signals from
the IBL), in conducting Stuelpnagel’s quality testing.
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With regard to claim 74, Stuelpnagel discloses that complementary
nucleic acids are suitable IBL-DBL binding pairs (FF 11). Stuelpnagel also
discloses that the DBL is labeled such as with a fluorophore (FF 6, 7, & 13).
In addition, Stuelpnagel discloses that “the IBL is a molecule whose color or
luminescence properties change” (FF 12). Stuelpnagel also discloses the use
of diverse optical signals (FF 14-15). In view of these disclosures, as well as
the disclosures in Granados of different labels (FF 23-25), we agree with the
Examiner that it would have been obvious for the DBL label to emit a signal
that is different from the IBL signal, as well as from the signals emitted by
the capture probe and the target.
Conclusion
The evidence supports the Examiner’s conclusion that Stuelpnagel,
Granados, and Stern teach or suggest locating each feature by detecting the
control probe signal from each feature. We therefore affirm the obviousness
rejection of claim 68. Claim 72 has not been argued separately and therefore
falls with claim 68. 37 C.F.R. § 41.37(c)(1)(vii).
The evidence also supports the Examiner’s conclusion that
Stuelpnagel, Granados, and Stern teach or suggest depositing a hybridization
solution on the microarray based on the collected data. We therefore affirm
the obviousness rejection of claim 73.
In addition, the evidence supports the Examiner’s conclusion that
Stuelpnagel, Granados, and Stern teach or suggest the control target signal
being different from each of the control probe signal, the test probe signal,
and the test target signal. We therefore affirm the obviousness rejections of
claims 74 and 75.
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IV
The Examiner rejects claims 85-87 as obvious over Besemer in view
of Noblett and Troll; claim 88 as obvious over Besemer in view of Noblett,
Troll, and Stern; claims 89 and 90 as obvious over Besemer in view of
Noblett, Troll, Stern, Granados, and Ramberg; claim 91 as obvious over
Besemer in view of Noblett, Troll, Lockhart, and Ramberg; claim 92 as
obvious over Besemer in view of Noblett, Troll, Lockhart, Ramberg, and
Stern; claim 93 as obvious over Besemer in view of Noblett, Troll, Lockhart,
Ramberg, and Granados; and claim 94 as obvious over Besemer in view of
Noblett, Troll, Lockhart, Ramberg, Granados, and Stern (Ans. 24-45).
The Examiner relies on Besemer for teaching a method having many
of the limitations of claim 85 (id. at 24-25). In particular, the Examiner
finds that “each array of Besemer et al (including the identifying mark) is
interpreted as a feature location in accordance with the instant specification”
(id. at 58-59). However, the Examiner acknowledges that Besemer does
“not teach the reference mark (i.e., control) is a probe; i.e., a nucleic acid”
(id. at 25).
The Examiner relies on Noblett for teaching “a reference mark in the
form of a nucleic acid control probe” (id. at 26). The Examiner concludes
that it would have been obvious to modify Besemer’s method “so that the
reference mark is a nucleic acid, and thus a control probe, as taught by
Noblett” (id.).
The Examiner relies on Troll for teaching “fluorescent reference
marks” (id. at 27). The Examiner concludes that it would have been obvious
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to modify the method of Besemer in view of Noblett “so that the reference
fiducial control probe is fluorescent[, as] taught by Troll” (id.).
The Examiner relies on Stern, Granados, Ramberg, and Lockhart for
disclosing features of claims that depend from claim 85 (id. at 29-45).
Appellant argues:
the proposed combination of references fails to teach or suggest
“depositing an oligomer test probe to each of said feature
locations of the microarray based on the acquired data, such
that a feature comprising the labeled control probe and the
oligomer test probe is provided at each feature location”
(emphasis added).
(App. Br. 20).
Issue
Does the evidence support the Examiner’s conclusion that Besemer,
Noblett, and Troll teach or suggest that a feature comprising the labeled
control probe and the oligomer test probe is provided at each feature
location?
Findings of Fact
26. The Specification states that “[m]icroarrays typically comprise
a plurality of polymers, e.g., oligomers, . . . on a substrate in an array
pattern” (Spec. 1).
27. The Specification discloses: “The plurality of probes and/or
targets in each location in the array is known in the art as a ‘nucleic acid
feature’ or ‘feature’. A feature is defined as a locus onto which a large
number of probes and/or targets all having the same nucleotide sequence are
immobilized.” (Id. at 1-2.)
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28. However, the Specification states the “the term ‘feature’ for the
purposes of the invention is defined as a locus comprising both a control
probe and an oligomer test probe immobilized thereon” (id. at 6).
29. Besemer discloses “a method for making [a] chip package . . .
compris[ing] the steps of first forming a plurality of probe arrays on a
substrate and separating the substrate into a plurality of chips” (Besemer,
col. 2, ll. 15-20).
30. Besemer Figure 1a is reproduced below:

Besemer “FIG. 1a illustrates a wafer 100 on which numerous probe
arrays 110 are fabricated” (id. at col. 4, ll. 45-46).
31. Besemer discloses: “Wafer 100 includes a plurality of
marks 145 that are located in streets 150 (area adjacent to the probe arrays).
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Such marks may be used for aligning the masks during the probe fabrication
process. In effect, the marks identify the location at which each array 110 is
to be fabricated.” (Id. at col. 5, ll. 7-12.)
32. Noblett discloses a microarray scanning system “having a least
one fiducial mark on [a] planar substrate as a means for positioning and
aligning the substrate for subsequent spot placement, analysis, or
comparison procedures” (Noblett, Abstract).
33. Noblett discloses that its invention “will have the effect of
automatically registering features such as microarray spots that have been
accurately placed relative to the fiducial mark locations” (id. at col. 3, ll. 32-
35).
34. Noblett Figure 2 is reproduced below:

Noblett “FIG. 2 is a diagrammatical view of the sample surface of [a]
microarray sample . . . including an array of target spots” (id. at col. 3, ll. 43-
45).
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35. Noblett discloses:
The microarray sample 100 includes at least one
microarray 121 deposited on the sample surface 103. The
microarray 121 comprises a plurality of target spots 123,
usually arrayed in rows and columns. . . . [A] first fiducial
mark 125 and a[n] optional second fiducial mark 127 are
disposed on the test surface 103 proximate the microarray 121.
The first fiducial mark 125 is a spot of approximately the same
size as the size of the target spot 123, and may include the same
target material forming the target spots 123.
(Id. at col. 5, ll. 32-41.)
Analysis
The Specification discloses: “The plurality of probes and/or targets in
each location in the array is known in the art as a ‘nucleic acid feature’ or
‘feature’. A feature is defined as a locus onto which a large number of
probes and/or targets all having the same nucleotide sequence are
immobilized.” (FF 27.) However, the Specification states the “the term
‘feature’ for the purposes of the invention is defined as a locus comprising
both a control probe and an oligomer test probe immobilized thereon”
(FF 28). Thus, in the context of claim 85, we interpret the term “feature” to
mean a location in the microarray onto which both a control probe and an
oligomer test probe are immobilized.
In rejecting claim 85, the Examiner considers “each array of Besemer
et al (including the identifying mark) . . . as a feature location” (Ans. 58-59).
However, the evidence of record does not support the Examiner’s conclusion
that one of ordinary skill in the art would consider one of Besemer’s
arrays 110, together with at least a portion of the street 150 between two
arrays that includes at least one mark 145, to be a feature location. On the
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contrary, Besemer describes each of elements 110 as a separate array and
refers to street 150, on which is located mark 145, as an “area adjacent to the
probe arrays” (FF 30-31). Similarly, Noblett refers to element 121 as a
microarray, refers to the first fiducial mark 125 as being “disposed on the
test surface 103 proximate the microarray 121,” and identifies a microarray
spot 123 as a “feature” (FF 33-35). Thus, we do not agree that the Examiner
has set forth a prima facie case that Besemer, Noblett, and Troll, as
combined, disclose or suggest that a feature comprising the labeled control
probe and the oligomer test probe is provided at each feature location.
Conclusion
The evidence does not support the Examiner’s conclusion that
Besemer, Noblett, and Troll teach or suggest that a feature comprising the
labeled control probe and the oligomer test probe is provided at each feature
location. We therefore reverse the obviousness rejections of claim 85 and of
claims 86-94, which depend from claim 85.
SUMMARY
We affirm the obviousness rejections of claims 61, 66-68, 72-75, 95,
and 96. However, we reverse the obviousness rejections of claims 85-94.
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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-IN-PART

alw

AGILENT TECHNOLOGIES, INC.
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