Agilent Technologies, Inc.

Patent Trials and Appeals Board

Dec 31, 2020

2020003544 (P.T.A.B. Dec. 31, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/987,256 01/04/2016 Brian Phillip Smart 20140314-02/6363.130023 3754
22878 7590 12/31/2020
Agilent Technologies, Inc.
Global IP Operations
5301 Stevens Creek Blvd
Santa Clara, CA 95051
EXAMINER
DAVIS, RUTH A
ART UNIT PAPER NUMBER
1699
NOTIFICATION DATE DELIVERY MODE
12/31/2020 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):
Agilentdocketing@cpaglobal.com
ipopsadmin@agilent.foundationip.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte BRIAN PHILLIP SMART and
KRISTIN BRIANA BERNICK
____________

Appeal 2020-003544
Application 14/987,256
Technology Center 1600
____________

Before ULRIKE W. JENKS, CYNTHIA M. HARDMAN, and
MICHAEL A. VALEK, Administrative Patent Judges.

VALEK, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving
claims to methods for multiplex analysis of a tissue section and a kit related
to such methods. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42(a). Appellant identifies Agilent Technologies, Inc., as the
real party in interest. Appeal Br. 5. Herein, we refer to the Final Action
mailed May 30, 2019 (“Final Act.”); Appellant’s Appeal Brief filed October
28, 2019 (“Appeal Br.”); and Examiner’s Answer mailed January 10, 2020
(“Ans.”).
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STATEMENT OF THE CASE
The Specification states that
[t]he use of chromogens as substrates to detect specific cellular
targets (e.g., antigens) is currently used by pathologists to
diagnose biopsied tissue samples. The ability to detect multiple
targets in the same tissue section, also called “multiplexing”,
has the advantage of providing more validating data regarding
the disease status of the patient.
Spec. ¶ 2. According to the Specification, the methods described therein
“allow multiplexing . . . using a combination of ‘visible’ labels (labels that
can be detected by the human eye using a bright-field microscope) and
‘invisible’ labels (labels that are not visible to the human eye but that can be
detected by a digital scanning microscope).” Id. ¶ 4. The Specification
describes a “near infra-red absorbing (NIR) organic material” as a non-
visible stain that may be used in the disclosed methods. Id. ¶ 54.
Claims 1, 3–18, and 21 are on appeal and can be found in the Claims
Appendix of the Appeal Brief. Claim 1 is illustrative and reads as follows:
1. A method for multiplex analysis of a tissue section,
comprising:
staining a tissue section for a first target and a second
target, wherein the first target is stained with a detectable label
in the visible spectrum and the second target is stained with a
detectable label in the non-visible spectrum;
after the staining for the first target and the staining for
the second target are completed, detecting in a first detection
step the first stain on the tissue section under bright field
microscopy and determining a pattern of the first target on the
tissue section; and
if the pattern for the first target detected in the first
detection step is determined to be pathologically abnormal,
detecting the second stain on the tissue section in the second
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detection step, wherein the step of detecting the second stain
excludes detection by fluorescence microscopy.
Appeal Br., Claims App. A-1.
Appellant seeks review of the following rejections:2
I. Claims 1, 3–6, and 8–17 under 35 U.S.C. § 102 as anticipated by
Wachman;3
II. Claims 1 and 3–17 under 35 U.S.C. § 103 as obvious over Wachman
and Morrison;4
III. Claims 1, 3–6, and 8–18 under 35 U.S.C. § 103 as obvious over
Wachman and Hammer;5 and
IV. Claims 1, 3–6, 8–17, and 21 under 35 U.S.C. § 103 as obvious over
Wachman and Solbakken.6
Appeal Br. 9–10.
Findings of Fact
FF1. Wachman discloses a “screening method for detecting abnormalities
in a sample” that
includes steps of staining a sample with a histologic or
cytologic stain for transmission light microscopy to provide a
stained sample; exposing the stained sample to a plurality of
differentially-labeled biomarkers, wherein each of the
biomarkers is labeled with a distinct transmission stain or
fluorescence probe; [and] at a first location, generating at least
one multi-spectral image of the stained sample using signals

2 Examiner’s rejections under 35 U.S.C. § 112 were withdrawn in the
Answer. Ans. 16.
3 US 2012/0264110 A1, published October 18, 2012 (“Wachman”).
4 US 2014/0267672 A1, published September 18, 2014 (“Morrison”).
5 US 2005/0019265 A1, published January 27, 2005 (“Hammer”).
6 US 2012/0244074 A1, published September 27, 2012 (“Solbakken”).
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obtained from the plurality of differentially-labeled biomarkers
and the histologic or cytologic stain.
Wachman, Abstr.
FF2. Wachman teaches that “[e]mbodiments of the present invention
describe automatic PAP [papanicolaou] screening methods for detecting
abnormalities in cervical cells.” Wachman ¶ 10. In these embodiments, the
cervical cell sample is “stained with PAP stain to help visualize the cell
morphology” and “[a] plurality of biomarkers in the PAP-stained cells are
then labeled using distinct fluorescence probes or transmission stains.” Id.
FF3. After staining, Wachman discloses that “[m]ulti-spectral images of the
cell samples are generated using signals obtained from the plurality of
labeled biomarkers and from the Pap stain” and “can include images from
both visible and near infrared wavelengths, determined by the specific choice
of labels used.” Wachman ¶¶ 10, 19; see also id. ¶ 29 (“The sample may be
illuminated with UV, visible, and/or infrared light.”), claim 2 (reciting that
the “multi-spectral image includes wavelengths in both the visible range and
near-IR range”). Wachman teaches that “[t]he specific choice of biomarker
labels is governed by the need to be able to distinguish them from the
underlying PAP stain being used.” Id. ¶ 19.
FF4. Wachman teaches that a variety of stains and specific labels may be
used in the methods it describes. Wachman ¶ 26. The specific label may be
“an antibody or nucleotide probe . . . coupled to a marker such as a
fluorescent dye, or an enzyme or other means for generating a dye” including
“organic dyes such as . . . Cyanine dyes” and various transmission stains. Id.
FF5. Wachman teaches the
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sample may be scanned manually or in an automated
manner, stopping . . . at locations that are determined by
the presence of one or more indicators, such as the
detection of the presence of a cell, which in turn may be
indicated the detection of a general stain or a specific
label.
Wachman ¶ 28.
FF6. Hammer describes “polymersomes” incorporating “visible or near
infrared emissive agents” and “optionally a targeting moiety associated with
the surface of the polymersome” for use in imaging methods. Hammer,
Abstr. Hammer teaches that the emissive agent “preferably emits light in the
700-11.00 nm spectral regime” and may be “a near infrared (NIR) emissive
species such as di- and tricarbocyanine dyes [and] croconium dyes.” Id. ¶¶ 8,
11. According to Hammer, polymersomes comprising such agents “can be
used in vitro and in vivo to probe sample materials from cells, biological
fluids, and tumor specimens.” Id. ¶ 52.
FF7. Solbakken describes “in vivo imaging agents.” Solbakken, Abstr.
Solbakken teaches that particularly preferred imaging moieties for use in
such agents are those “which have absorption maxima in the visible or near
infrared (NIR) region . . . between 600 and 1300 nm” and include cyanines,
croconium dyes, and dithiolene metal complexes. Id. ¶ 46.
Analysis
I. 102 Rejection: Wachman
Appellant does not argue any claim separately from independent
claim 1 for this rejection. See Appeal Br. 17–18. Accordingly, we select
claim 1 as representative for our analysis and the other rejected claims stand
or fall with that claim. See 37 C.F.R. § 41.37(c)(iv). The issue for this
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rejection is: Does the preponderance of evidence of record support
Examiner’s determination that Wachman anticipates claim 1?
Examiner finds that Wachman discloses a multi-spectral imaging
method in which a “tissue sample is stained with a stain for transmission
light microscopy” and a “plurality of differently labeled biomarkers (targets)
stained with transmission or fluorescent probes (abstract) and stains in the
near infrared wavelength (0010), followed by automated analysis of the
multispectral biomarkers,” i.e., “detection of the stains with and/or without
fluorescence microscopy.” Final Act. 5. Examiner determines that the
“second detection step” recited in claim 1 is “an optional step to occur if a
particular pattern is determined” and “if a pattern of the first target is not
found to be abnormal, then no additional steps are required by the method.”
Id. at 12. Thus, according to Examiner, “the claimed method does not
require a second detection step to be practiced” and Wachman anticipates
even if no such second step is disclosed. Id. at 12–13.
In addition, Examiner finds that Wachman discloses a method
comprising a “second detection step” as recited in claim 1. In particular,
Examiner finds Wachman discloses a method in which the sample is
scanned at “locations determined by the presence of indicators” identified by
“detecting a general stain” and then “further imaged at that location” to
detect the presence of non-visible labels at that position. Id. at 18 (citing
Wachman ¶ 28).
We agree with, and adopt Examiner’s findings and reasoning in
support of the anticipation rejection as set forth in the Final Action and
Answer. See FF1–FF5; Final Act. 5–6, 11–13; Ans. 17–18. We are not
persuaded by Appellant’s arguments to the contrary.
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Appellant argues that Wachman discloses “an automated screening
method” that detects all of the stains “in one step.” Appeal Br. 17–18.
Appellant contends that the method in claim 1 is different because it “recites
a first detection step and a second detection step.” Id. at 18.
As an initial matter, we disagree with the premise of Appellant’s
argument because claim 1 does not require that a second detection step be
performed. Claim 1 recites that the “second detection step” is performed
only “if the pattern for the first target detected in the first detection step is
determined to be pathologically abnormal.” Appeal Br., Claims App. A-1
(emphasis added). Accordingly, given its broadest reasonable interpretation,
claim 1 encompasses an instance where the tissue section is stained as
recited in the first step followed by detection of the first stain and a
determination that the first target is pathologically normal. In that instance,
the recited “second detection step” need not be performed to practice claim
1. Thus, “Examiner did not need to present evidence” that Wachman taught
the recited second detection step to present a prima facie case of
unpatentability. Ex parte Schulhauser, Appeal 2013-007847, 9 (PTAB
2013) (precedential) (“Schulhauser”); see also MPEP 2111.04(II)
(discussing “contingent limitations” that are not required under the “broadest
reasonable interpretation of a method (or process) claim” when the recited
“conditions(s) precedent are not met”).
As Examiner found, Wachman discloses a method in which a plurality
of targets within a tissue sample are stained with both visible (transmission)
and non-visible (fluorescent or near infrared) stains followed by at least one
detection step in which the visible stain is detected, as recited in claim 1.
See FF1–FF5. That disclosure is sufficient to anticipate claim 1 even if
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Wachman did not disclose a “second detection step” as recited in claim 1.
But even if the “second detection step” were not merely a contingent
limitation, we agree with Examiner that Wachman discloses methods
comprising a first and second detection step as recited in claim 1. Wachman
discloses that scanning is performed to produce a multi-spectral image
showing both the visible and non-visible markers. FF1. Moreover,
Wachman discloses both “automated” and “manual” scanning
methodologies. FF5. This includes methods in which additional scanning to
detect the non-visible marker may occur “at locations” indicated by the
detection of the “general stain.” Id. Accordingly, Wachman, in fact,
discloses methods in which a first detection step is performed to detect the
visible stain followed by a second detection step to detect the non-visible
stain using near infrared light. See FF1–FF5.
For these reasons, we determine that the preponderance of the
evidence supports Examiner’s anticipation rejection of representative claim
1. We affirm Examiner’s rejection of claims 3–6, and 8–17 for the same
reasons we affirm the rejection of claim 1.
II. 103 Rejection: Wachman and Morrison
Appellant does not argue any claim separately from independent
claim 1 for this rejection. See Appeal Br. 18–20. We again select claim 1 as
representative for our analysis. The issue for this rejection is: Does the
preponderance of evidence of record support Examiner’s conclusion that
claim 1 is obvious over the cited references?
Examiner’s rejection is premised on findings regarding the methods
taught in Wachman that are similar to those discussed for the anticipation
rejection above. See Final Act. 6–7. Examiner additionally relies on
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Morrison’s teaching regarding “formalin fixed in paraffin wax (FFPE)”
tissue samples, which is relevant to the additional limitations of dependent
claim 7. Id. at 7. Examiner concludes “it would have been obvious . . . to
use a FFPE tissue section in the methods of Wachman as a matter of routine
practice and with a reasonable expectation for successfully imaging a tissue
section.” Id.
We adopt Examiner’s findings and reasoning regarding the scope and
content of the prior art (Final Act. 6–7, 11–12; Ans. 17–19; FF1–FF5) and
agree that claims 1 and 3–17 would have been obvious over Wachman and
Morrison. We address Appellant’s arguments below.
Appellant’s argument that “the combination of Wachman and
Morrison does not disclose or suggest a two-step detection method” (Appeal
Br. 19–20) is not persuasive. As explained above, the “second detection
step” is a contingent limitation and Examiner was not required to show that
step in the prior art in order to establish a prima facie showing for claim 1.
See Schulhauser at 9. Even so, Examiner has shown that Wachman teaches
methods comprising both a first and second detection step as recited in claim
1. See Ans. 17–18. And we agree that Examiner’s findings are supported by
the record. FF1–FF5.
Appellant further argues “[t]he cited references do not disclose or
suggest the [near infrared] agent detection which excludes the fluorescent
detection in the second detection step.” Appeal Br. 20. This argument is
unpersuasive for multiple reasons. First, claim 1 does not require a second
detection step. Second, Wachman specifically teaches the use of NIR agents
as markers and the use of infrared light to detect them. FF3, FF4.
Accordingly, we agree with Examiner that Wachman discloses a method in
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which NIR markers, i.e., non-visible stains, are used to mark a target in a
tissue sample and subsequently detected without the use of fluorescence
microscopy. Ans. 18–19; FF1–FF5.
For these reasons, we determine that the preponderance of the
evidence supports Examiner’s rejection of representative claim 1. We affirm
Examiner’s rejection of claims 3–17 as obvious over Wachman and
Morrison for the same reasons we affirm the rejection of claim 1.
III. 103 Rejection: Wachman and Hammer
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s conclusion that claims 1, 3–6, and 8–18 are
obvious over the cited references?
Examiner’s rejection is premised on findings regarding the methods
taught in Wachman that are similar to those discussed above for the other
rejections. See Final Act. 8–9. Examiner additionally finds that “Hammer
teaches imaging methods (abstract) wherein visible and NIR agents of the
700 - 1100nm spectral range are combined (0008) to image and diagnose
disease in cell samples (0032), wherein the NIR agents may be cyanine or
croconium dyes (0011).” Id. at 9. Examiner concludes it “would have been
obvious to one of ordinary skill in the art to use the instant stains in the
methods of Wachman with a reasonable expectation for successfully
imaging tissue samples.” Id.
We adopt Examiner’s findings and reasoning regarding the scope and
content of the prior art (Final Act. 8–9, 11–13; Ans. 18–19; FF1–FF6) and
agree that claims 1, 3–6, and 8–18 would have been obvious over Wachman
and Hammer. We address Appellant’s arguments below.
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Appellant makes the same arguments concerning Wachman that it
advances for the other rejections. Appeal Br. 21. Those arguments are not
persuasive for the reasons already explained above.
In addition, Appellant points to the statement in Hammer that
“delivery of NIR-emissive probes and delivery of contrast agents of
appropriate sensitivity remains a major technological hurdle.” Appeal Br.
21 (quoting Hammer ¶ 7 (emphasis added)). Based on that statement,
Appellant urges that a skilled artisan “would not expect that an NIR stain
can be used in imaging with a reasonable expectation of success as it
remains a major technological hurdle.” Id.
Appellant’s argument is not persuasive. As Examiner correctly
observes, the statement Appellant quotes from Hammer refers “to delivery
of contrast agents of appropriate sensitivity to [in] vivo deep tissue imaging
[] and not to imaging or detection [of] stains in tissue sections.” Ans. 19.
Indeed, in the same paragraph Hammer states that “significant progress has
been made in constructing target-specific and locally-active NIR-emissive
probes” (Hammer ¶ 7) and goes on to describe emissive agents of the same
composition (e.g., cyanine and croconium dyes) as those recited in
Appellant’s claims. Compare FF6 with Appellant’s claims 11 and 18.
Wachman also teaches the use of NIR markers, including cyanines, and the
use of NIR light to detect them. FF3, FF4. Accordingly, Examiner’s
finding that a skilled artisan would have had a reasonable expectation of
success in using such markers is amply supported by the record.7

7 In contrast, Appellant’s argument that “Wachman is incompatible with
Hammer” because a skilled artisan would understand “polymersomes are
likely to interfere with DNA hybridization” (Appeal Br. 22–23) is
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Finally, “[a]s to claim 18,” Appellant urges that “the combination of
Wachman and Hammer does [not] reveal the non-visible stain as defined in
present claim 18.” Appeal Br. 22–23. Again, we disagree. Claim 18 recites
a “kit for staining a tissue section” comprising “second labeling reagents”
for labeling a target “in the non-visible spectrum” wherein the non-visible
stain “absorbs light in the range of from 700nm to about 1000nm
wavelength” and is “a NIR organic material” comprising groups such as “a
cyanine group” or a “crocanaine group.” Appeal Br., Claims App. A-4.
Both Wachman and Hammer teach the use of such NIR stains for tissue
staining. FF3, FF4, FF6. Moreover, we agree with Examiner’s rationale for
combining the references and reasoning for why it would have been obvious
to provide such reagents in a kit as recited in claim 18. See Final Act. 9.
For these reasons, we determine that the preponderance of the
evidence supports the rejection of claims 1, 3–6, and 8–18 as obvious over
Wachman and Hammer. Thus, we affirm.
IV. 103 Rejection: Wachman and Solbakken
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s conclusion that claims 1, 3–6, 8–17, and 21 are
obvious over the cited references?

unsupported attorney argument that is not persuasive to overcome
Examiner’s evidence-backed findings. See, e.g., In re Geisler, 116 F.3d
1465, 1470 (Fed. Cir. 1997) (“An assertion of what seems to follow from
common experience is just attorney argument and not the kind of factual
evidence that is required to rebut a prima facie case of obviousness.”); In re
De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (explaining that arguments
and conclusions unsupported by factual evidence carry no evidentiary
weight).
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Examiner’s rejection is premised on findings regarding the methods
taught in Wachman that are similar to those discussed above for the other
rejections. See Final Act. 10–11. Examiner additionally finds that
“Solbakken teaches imaging agents suitable for optical imaging include NIR
dyes of the 600 - 1300nm spectral range such as cyanines, phthalocyanines,
naphthalocyanines, croconium dyes, dithiolene complexes (with metal)
wherein the imaging techniques include luminescence imaging,
transmittance imaging, and fluorescence imaging (0046).” Id. at 11.
Examiner concludes it “would have been obvious to one of ordinary skill in
the art to use the instant stains in the methods of Wachman with a reasonable
expectation for successfully imaging tissue samples.” Id.
We adopt Examiner’s findings and reasoning regarding the scope and
content of the prior art (Final Act. 10–13; Ans. 19–20; FF1–FF5, FF7) and
agree that claims 1, 3–6, 8–17, and 21 would have been obvious over
Wachman and Solbakken. We address Appellant’s arguments below.
Appellant makes the same arguments concerning Wachman that it
advances for the other rejections. Appeal Br. 24. Those arguments are not
persuasive for the reasons already explained above.
In addition, Appellant argues that “Solbakken is not directed to
imaging tissue samples at all.” Appeal Br. 25. According to Appellant,
“Solbakken provides in vivo imagining [sic] methods” and “[t]here is no
evidence in Solbakken that the imaging agents disclosed in Solbakken can
be used for staining tissue samples.” Id.
Appellant’s argument is not persuasive. As explained above,
Wachman teaches that NIR stains may be used in its methods. FF3, FF4.
Solbakken teaches that such stains absorb light within the recited spectral
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range and were known to include certain dyes or chemical moieties. FF7.
While it is true that the specific application taught in Solbakken is in vivo
imaging, a skilled artisan would have understood the teachings Examiner
relies on from Solbakken to apply to NIR stains generally. Moreover, a
skilled artisan would have had a reasonable expectation that the dyes taught
in Solbakken could be successfully used in Wachman’s methods because
Wachman teaches both the use of NIR stains generally as well as some of
the same types of NIR stains (e.g., cyanines) as Solbakken.
Finally, as to claim 21, Appellant argues that “neither Watchman
[sic], nor Solbakken discloses immunohistochemistry as a first and a second
detection steps.” Appeal Br. 25–26. We disagree. As Examiner found,
“Wachman teaches that staining may be labeled antibodies (IHC).” Ans. 15;
Wachman ¶ 26 (teaching the specific label may be “an antibody . . . coupled
to a marker such as a fluorescent dye, or enzyme or other means for
generating a dye such as a localized precipitate (e.g. DAB)” and that the
marker may be “directly” or “indirectly” coupled to the label through “a
secondary antibody”). Based on this teaching and Examiner’s related
findings (see Final Act. 15), we agree with Examiner’s conclusion that it
would have been obvious to use immunohistochemistry staining as recited in
claim 21.
For these reasons, we determine that the preponderance of the
evidence supports the rejection of claims 1, 3–6, 8–17, and 21 as obvious
over Wachman and Solbakken. Thus, we affirm.

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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 3–6, 8–17 102 Wachman 1, 3–6, 8–
17

1, 3–17 103 Wachman,
Morrison
1, 3–17
1, 3–6, 8–18 103 Wachman,
Hammer
1, 3–6, 8–
18

1, 3–6, 8–
17, 21
103 Wachman,
Solbakken
1, 3–6, 8–
17, 21

Overall
Outcome
1, 3–18, 21

No time period for taking any subsequent action in connection with this
appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED