Vala Sciences, Inc

Patent Trials and Appeals Board

Jul 14, 2021

2020005380 (P.T.A.B. Jul. 14, 2021)

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.
13/865,121 04/17/2013 Patrick M. McDonough VALSC1500US 1673
38000 7590 07/14/2021
Terrance A. Meador
4422 Del Mar Avenue
San Diego, CA 92107
EXAMINER
DINES, KARLA A
ART UNIT PAPER NUMBER
1639
MAIL DATE DELIVERY MODE
07/14/2021 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte PATRICK M. MCDONOUGH and JEFFREY H. PRICE
____________

Appeal 2020-005380
Application 13/865,121
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
JOHN G. NEW, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims directed to
a method of operating an automated microscopy system for measuring
biomarker labels. The Examiner has rejected the claims as obvious. 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 Vala Sciences as the Real Party in Interest
(Appeal Br. 3).
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STATEMENT OF THE CASE
Background
The increasing incidence of cancer in an aging population and the
growing use of targeted cancer drugs requiring companion diagnostics using
biomarkers are driving the rising need for automated testing and
standardization. (Spec. 4.) Cancer diagnostics are becoming increasingly
complex due to the increasing number of biomarkers upon which therapeutic
decisions are based. (Id.) Classically, the pathologist diagnoses cancer by
viewing tissue sections stained with hematoxylin and eosin (H & E),
Papanicalou (Pap), and/or others, as depicted in Table 1 of Appellant’s
Specification. (Spec. 4, Table 1.) New genes/biomarkers can be measured
via immunohistochemistry (bright field or immunofluorescence labels) for
cellular molecules including proteins, or chromogenic in situ hybridization
(CISH), or fluorescence in situ hybridization (FISH) for nucleic acids (RNA
or DNA). (Spec. 4.) A challenge that arises from the growing number of
diagnostic tests includes the creation of a test that enables both scoring of the
key diagnostic molecules in the tumor or surrounding normal tissue, directly
in the same tissue section used by the clinician to perform the initial classical
diagnosis. (Spec. 5.) The Specification teaches a method that integrates a
pathology diagnostic step with gene/biomarker test(s) to enable the
pathologist to perform both steps side-by-side on the same instrument and
tissue section. (Spec. 7.) This integrative tool makes pertinent information
immediately available to the pathologist or cancer research scientist for rapid
identification of both known and novel biomarker patterns. (Spec. 9.)
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Claims
Claims 1 and 4–15 are on appeal, and can be found in the Claims
Appendix of the Appeal Brief (Appeal Br. 16–18). Claim 1 is representative
of the claims on appeal, and reads as follows:
1. A method of operating an automated microscopy system for
measuring biomarker labels, comprising:
[A] labeling tissue sections with first biomarkers
comprising fluorescent labels for diagnostic molecules
comprising genes, mRNA, and proteins;
[B] an automated microscopy-executed step of acquiring
images of the fluorescently-labeled tissue sections;
[C] labeling the same tissue sections with second
biomarkers comprising classical diagnostic bright field dyes;
[D] an automated microscopy-executed step of scanning
the classically-labeled tissue sections to acquire images of
them;
[E] an automated microscopy-executed step of displaying
the fluorescent images and the bright field images together; and,
[F] an automated microscopy-executed histocytometry
step of generating and displaying measurements of first or
second biomarkers on a cell-by-cell basis comprising image
segmentation and measurement analysis of biomarker quantities
in each cell and each cell compartment.
Appeal Br. 16 (Claims Appendix) (bracketing and lettering added for
reference convenience).
Rejections
A. The Examiner rejected claims 1, 4–9, and 15 under 35 U.S.C.
§ 103(a) as being unpatentable over Cline2 in view of Hunter3
and Ingermanson4 (Final Act. 3–8).

2 Cline et al., US 2008/0032328 A1, published Feb. 7, 2008.
3 Hunter et al., US 2007/0016373 A1, published Jan. 18, 2007.
4 Ingermanson et al., US 2010/0192084 A1, published on July 29, 2010.
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B. The Examiner rejected claims 10–13 under 35 U.S.C. § 103(a)
as being unpatentable over Cline, Hunter, Ingermanson, and in
further view of Key5 (Final Act. 9–11).
C. The Examiner rejected claim 14 under 35 U.S.C. § 103(a) as
being unpatentable over Cline, Hunter, Ingermanson, Key, and
in further view of Tafas6 (Final Act. 11–12).
Principle of Law
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003), and “a reason that would have prompted a person of
ordinary skill in the relevant field to combine the elements in the way the
claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007).
Obviousness over Cline, Hunter, and Ingermanson
The Examiner rejects claims 1, 4–9, and 15 based on the combination
of Cline, Hunter, and Ingermanson, and rejects claims 10–13 by additionally
including Key, and claim 14 by additionally including Tafas. Since all of
these rejections rely upon the underlying teachings of Cline, Hunter, and
Ingermanson regarding “generating and displaying measurements of first or
second biomarkers on a cell-by-cell basis” as recited in claim element 1F,
the same issue is dispositive for all of these rejections, so we will consider
the rejections together.
The Examiner reasons that the combination of Cline, Hunter, and
Ingermanson renders the claimed invention obvious. (Final Act. 6.) The

5 Key, M., WO 2009/085576 A2, published July 9, 2009.
6 Tafas et al., US 2010/0315502 A1, published Dec. 16, 2010.
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Examiner finds that Cline teaches an automated microscopy system for
imaging tissue stained with both molecular markers and morphological
stains and a means for displaying images. (Final Act. 4 (citing Cline ¶ 15).)
The Examiner also finds that Cline teaches overlaying molecular image
information with H&E dye stained images and measuring the color and
intensity of nuclei in the sample thereby constituting the generation and
display of measurements of first or second biomarkers on a cell-by-cell
basis. (Id. (citing Cline ¶¶ 7, 8).) The Examiner finds that Hunter teaches
multicompartment models for cellular translocation events where many
potentially important molecular targets are regulated in their expression
levels and where these targets include the release of specific DNA binding
proteins which regulate gene transcription (i.e., genes and mRNA). (Id.
(citing Hunter ¶ 44).) Further, the Examiner finds that Ingermanson teaches
that cell-by-cell experimental data are easily manipulated by tools accessed
via tools for image analysis and that cell data can be viewed and exported
into common Excel compatible formats. (Id. (citing Ingermanson ¶ 59).)
Does the preponderance of the evidence of record support the
Examiner’s conclusion that the combination of Cline, Hunter, and
Ingermanson renders the method as recited in claim 1 obvious?
Findings of Fact
FF1. Cline teaches an automated microscopy system for imaging
tissue stained with both molecular markers and morphological stains and a
means for displaying images. (See Cline ¶¶ 9, 15; Final Act. 4.)
FF2. Cline teaches providing a tissue on a substrate, applying one or
more molecular probes adapted to provide fluorescent molecular markers,
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and obtaining a first digital image of the tissue section and the fluorescent
molecular markers. (See Cline ¶¶ 9, 30; Final Act. 4.)
FF3. Cline teaches that the tissue section is labeled with a
morphological marker such as a traditional dye, placed at the same location
under the microscope to obtain a bright field image or second digital image
of the tissue section. (See Cline ¶¶ 9, 49; Final Act. 4.)
FF4. Cline teaches displaying both the fluorescent and bright field
images together. (See Cline ¶¶ 9, 58, 59; Final Act. 4.) Cline teaches using
feature points such as center of nuclei and orientation of membrane
structures in order to align the images. (Cline ¶ 9.)
FF5. Cline teaches overlaying image information with H&E dye
stained images and measuring the color and intensity of nuclei in the sample.
(See Cline ¶¶ 7, 8; Final Act. 4.) Cline teaches that the method further
comprises the steps of segmenting at least one of the images into nuclei,
epithelia and stroma, and creating a mask of the stroma. (See Cline ¶ 11.)
FF6. Cline teaches that their imaging methods provide greatly
improved value to quantitative pathology and that image analysis algorithms
can benefit from the added channels to separate tissue compartments. (See
Cline ¶ 72; Final Act. 5.)
FF7. Cline teaches that their imaging methods are not limited to
morphological stains or fluorescent biomarkers or even to pathology, and
thus, encompass any stain that enables some informative aspect or feature of
a biological sample to be visualized so that it can be digitally imaged and
processed would be suitable for these methods, e.g., cytological or
morphological stains, immunological stains such as immunohisto- and
immunocyto-chemistry stains, etc. (See Cline ¶ 79; Final Act. 5.)
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FF8. Cline teaches two or more markers presented digitally on the
same tissue section where these markers, such as fluorescent markers, are
used to identify the expression of proteins and pathways for disease in tissue
by sequential digitizing and processing the images based, in part, on cell
morphology and biological pathways. (See Cline ¶ 6; Final Act. 7.)
FF9. Cline teaches that probes are bound to overexpressed proteins
in diseases such as cancer and the tissue microarray elements are imaged in a
fluorescent microscope. The tissue microarray is then stained to show the
morphology and digitized. (See Cline ¶ 8.)
FF10. Cline teaches that the method may comprise the step of viewing
one or more of the images with a virtual microscope for communication over
a communications network. (See Cline ¶ 13; Final Act. 9.)
FF11. Cline teaches that the means for storing the digital images
stained with molecular markers and morphological stains may be remotely
located from the processors and may be accessed through any suitable
connection device or communications network including the internet. (See
Cline ¶ 74; Final Act. 10.)
FF12. Cline teaches that the automated system for carrying out the
method generally comprises a means for at least temporarily storing the
digital images stained with the molecular markers and the morphological
stains. (See Cline ¶ 15.)
FF13. Hunter teaches the development of multicompartment models
for cellular translocation events where many potentially important molecular
targets are regulated in their expression levels and also by their subcellular
or spatial localization. (See Hunter ¶ 44; Final Act. 4.)
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FF14. Hunter teaches that the cell contains protein complexes that can
be dissociated by proteolysis to release specific DNA binding proteins which
regulate gene transcription and that any of these processes can be targets for
improving clinical efficacy and reducing side-effects. (See Hunter ¶ 44;
Final Act. 4–5.)
FF15. Hunter teaches that the identification of discrete compartments
has been achieved by compartment specific labeling using dyes. (See
Hunter ¶ 45; Final Act. 5.)
FF16. Ingermanson teaches that each unique cell has a set of unique
measurements. (See Ingermanson ¶ 220; Final Act. 5.)
FF17. Ingermanson teaches cell-by-cell experimental data are easily
manipulated by tools accessed via tools for image analysis and that cell data
can be viewed and exported into common Excel compatible formats. (See
Ingermanson ¶ 59; Final Act. 5–6.)
FF18. Key teaches that the test sample can be a biopsy specimen or a
tissue section. (See Key, 16:18–19, 25–26; Final Act. 9.) Key teaches a
calibrator cell pellet for use as a standard for quantifying the intensity of
staining, for example, for normalizing staining as a calibrated standard
thereby allowing more accurate quantitation of staining intensity. (See Key,
19:18–23; Final Act. 9.)
FF19. Key teaches that the calibrator cell pellet is similar to a positive
control in that it contains the molecule of interest; however, the calibrator
cell pellet also has a known amount of the molecule of interest, and thus
using this method provides a quantitative method of determining the
concentration of an unknown molecule. (See Key, 30:9–14, 19–20; Final
Act. 9.)
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FF20. Tafas teaches that it may be advantageous after receiving a
microscopic image to be able to revisit the slide in the future and regulations
may require that a specimen sample on a microscope slide be archived in
order to allow post-diagnostic review of a diagnostic decision. (See Tafas
¶ 13; Final Act. 11.)
Analysis
Claim 1
The Examiner concludes that the combination of references teaches
and/or suggests every claim limitation as recited in claim 1. (Ans. 14–19.)
In particular, the Examiner finds that Cline teaches (1) an automated
microscopy system in which a tissue section with two biomarkers is stained,
one fluorescently labeled and another stained with classical diagnostic bright
field dyes, in a method in which the digital images of the biomarkers are
displayed together under a microscope, (2) the method further comprises
segmenting at least one of the images into nuclei, epithelia, and/or stroma
such that the color and intensity of these labeled segments is measured and
identifying one or more molecular pathways based on the biomarkers such
that the identified molecular pathways is quantified as a function of one or
more segmented morphological structures; and (3) these measurements of
the biomarker(s) labeled constitute a measurement analysis of biomarker
quantities in each cell and in each cell compartment. (Ans. 14–17; FF1–FF5
and FF8.) The Examiner further reasons that an ordinary skilled artisan
would have understood cellular compartments to mean any closed structure
within the cytosol such as a nucleus, mitochondria, and microtubules. (Ans.
16.) Moreover, the Examiner reasons that by overlaying molecular image
information of H&E dye stained images and fluorescent stained images, and
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measuring the color and intensity of nuclei, for example, in the tissue
sample, constitutes the generation and display of the first or second
biomarker measurements on a cell-by-cell basis. (Ans. 16–17.)
The Examiner further concludes that an ordinary skilled artisan would
have been motivated to fluorescently label mRNA along with genes and
proteins with diagnostic molecules in light of the teachings of Hunter.
Specifically, Hunter teaches that the cell involves protein complexes that can
be dissociated to release specific DNA binding proteins, which regulate gene
transcription (i.e., genes and mRNA) and that any of these processes can be
targets for improving clinical efficacy. (Final Act. 6; FF14.)
In addition, the Examiner reasons that an ordinary skilled artisan
would have been motivated to generate and display measurements of first or
second biomarkers on a cell-by-cell basis comprising image segmentation
and measurement analysis of biomarker quantities in each cell and each cell
compartment in light of the teachings of Ingermanson because Ingermanson
teaches that each cell has an unique set of measurements and because
cell-to-cell differences are important in cellular analysis. (Final Act. 6;
FF13–FF14.) Therefore, the Examiner concludes the cited references teach
all the limitations of claim 1.
Appellant contends that the combined references fail to teach and/or
suggest every claim limitation, in particular, the claim limitation of an
automated microscopy-executed histocytometry step of generating and
displaying measurements of first or second biomarkers on a cell-by-cell
basis comprising image segmentation and measurement analysis of
biomarker quantities in each cell and each cell compartment. (Appeal Br. 5.)
Appellant asserts that Cline does not teach single cell cytometry for
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quantification of biomarkers or measuring the color and intensity of any
cellular component in the sample in order to generate cell-by-cell
measurements. (Appeal Br. 6.) Rather, Appellant asserts that Cline refers to
regions such as glands where a measurement based on color is derived
largely from a union of identically colored cellular components in that
region. (Id.) These are “cluster centers,” which are used for image
alignment. (Id. (citing Cline ¶ 9).) Appellant further argues that Cline
teaches segmenting a nuclear subregion of a glandular region, but not
specific individual nuclei in the subregion. (Id.) Appellant contends that
Figures 2A and 2B of Cline fail to demonstrate image segmentation and
displays no “measurements of the first or second biomarkers on a
cell-by-cell basis.” (Id. at 7.) Rather, Figure 2A shows an embodiment of
an H&E image and Figure 2B shows the segmentation of the H&E image of
Figure 2A where the segmentation is into two compartments; namely,
clumps of cells (i.e., compartments containing multiple cells), and rarely,
single cells. (Id. at 7–8.) Thus, Appellant contends that Cline only teaches
using enough image measurement information to enable an algorithm to
accurately register two sequential images of the same tissue section so that a
single image showing multiple colors can be displayed. (Id. at 8–9.)
Appellant contends that an ordinary skilled artisan would not turn to
Hunter or Ingermanson to suggest generating and displaying cell-by-cell
measurements of biomarkers in the setting of a pathology laboratory. (Id. at
10 and 12.) Appellant asserts that Hunter relates to drug discovery screening
where cell measurements are used in a high throughput screening of lead
compounds. (Id. at 10.) In order for drug discovery screening to work,
Appellant asserts that the cells must be alive in culture in order for the cells
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to react with the test compounds. (Id.) In contrast, Appellant contends that
pathology comprises the analysis of dead cells in tissue sections. (Id.)
Therefore, Appellant argues that the field of endeavor of Cline and Hunter
are quite different where Cline is directed to the field of automated
pathology and Hunter is directed to the field of high throughput drug
discovery. (Id. at 10–11.)
Similarly, Appellant contends that Ingermanson is directed to a
different field of endeavor compared to Cline where Ingermanson does not
teach or suggest measuring first or second biomarkers on a cell-by-cell basis.
(Id. at 12.) Appellant asserts that Ingermanson is mainly concerned with
management and control of an image processing pipeline by way of a
graphical user interface (GUI). (Id.) Ingermanson performs quantitative
measurements associated with a morphological characteristic such as a cell
nucleus, a cell border, a cell body, etc. (Id.) As such, Appellant contends
that Ingermanson also is directed to high throughput inspection of living
cells contained in wells of a plate as opposed to a histocytometry step. (Id.
at 14.) Thus, Appellant argues that an ordinary skilled artisan would not be
motivated to consider “generating and displaying measurements of first or
second biomarkers on a cell-by-cell basis comprising image segmentation
and measurement analysis of biomarker quantities in each cell and each cell
compartment” as recited in claim 1. (Id. at 13.)
We are not persuaded. We agree with the Examiner’s factual findings
and conclusion, as set out in the Final Action and Answer which we adopt
and incorporate herein by reference. Regarding Appellant’s argument that
the combination of references fails to teach and/or suggest each claim
limitation as recited in claim 1, one cannot show nonobviousness by
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attacking references individually where the rejections are based on
combinations of references. See In re Keller, 642 F.2d 413 (CCPA 1981); In
re Merck & Co., 800 F.2d 1091 (Fed. Cir. 1986). Furthermore,
[t]he test for obviousness is not whether the features of a
secondary reference may be bodily incorporated into the
structure of the primary reference; nor is it that the claimed
invention must be expressly suggested in any one or all of the
references. Rather, the test is what the combined teachings of
the references would have suggested to those of ordinary skill in
the art.

In re Keller, 642 F.2d at 425.
Appellant limits its argument to whether the combined cited
references teach and/or suggest the automated microscopy-executed
histocytometry step recited in claim 1. As such, our discussion will
similarly be limited to discussion of the last claimed step in claim 1 (i.e.,
step [F] supra). It is acknowledged that Cline teaches that the image pixel is
segmented into compartments based on clustering and detection algorithms.
(See Cline ¶ 8; FF5, FF7.) However, Cline also teaches, in one embodiment,
that these segmented compartments of the H&E stained color images can be
measured where the color and intensity of specific cell components such as
glands, epithelia, stroma and/or nuclei is determined. (FF5.) Cline teaches
that the image can then be further segmented such that the color and
intensity of the second biomarker (i.e., H&E dye stained morphological
marker such as hematoxylin for DNA) is measured for a specific cell
component such as a nuclei. (FF1–FF5; see also Cline Figs. 2A and 2B.)
The nucleus of any cell that is labeled in the cell cluster will be illuminated
and an ordinary skilled artisan can quantify the number cells and cell
compartments (e.g., nuclei) that are illuminated, which then allows for the
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identification of molecular pathways as a function of one or more
morphological components. (See Ans. 14–15; FF1–FF6.) Therefore, the
pathologist is examining the image on a cell-by-cell basis because the
individual nuclei are illuminated based on which nuclei are labeled within a
cell cluster. Furthermore, Cline teaches that molecular biomarkers, e.g.,
fluorescently labeled markers such as Her2/neu, etc., advantageously
provide functional and compartmental information that is not visible using
H&E stains alone. (Cline ¶¶ 30–32.) Cline then teaches that identification
of one or more molecular pathways based on the molecular marker where
the molecular pathway is indicative of a disease. (Cline ¶ 11.) Thus,
contrary to Appellant’s argument, the teachings of Cline teach and/or
suggest an automated microscopy-executed histocytometry step of
generating and displaying measurements of first or second biomarkers on a
cell-by-cell basis comprising image segmentation and measurement analysis
of biomarker quantities in each cell and each cell compartment.
Notwithstanding the teachings of Cline, the Examiner further relies on
Ingermanson to support that an ordinary skilled artisan would be motivated
with a reasonable expectation of success to measure the generated and
displayed first or second biomarkers taught in Cline on a cell-by-cell basis.
(Ans. 15.) Ingermanson teaches that each unique cell has a set of unique
measurements. (Id.; FF16.) Ingermanson also teaches that cell-by-cell
experimental data is easily manipulated by tools accessed via tools for image
analysis and that cell data can be viewed and exported into common Excel
compatible formats. (Id.; FF17.) Therefore, we agree with the Examiner’s
conclusion that an ordinary skilled artisan would be motivated with a
reasonable expectation of success to generate and display measurements of
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first or second biomarkers taught in Cline on a cell-by-cell basis because
cell-by-cell experimental data is easily manipulated by tools accessed via
tools for image analysis.
We are not persuaded by Appellant’s argument that an ordinary
skilled artisan would not turn to Hunter or Ingermanson to suggest
generating and displaying cell-by-cell measurements of biomarkers in the
setting of a pathology laboratory because Hunter and Ingermanson are
directed to a different field of endeavor. (Appeal Br. 10 and 12.) To
determine what is “analogous prior art” for the purpose of analyzing the
obviousness of the subject matter at issue two criteria have evolved:
(1) whether the art is from the same field of endeavor, regardless
of the problem addressed, or (2) if the reference is not within the
field of the inventor’s endeavor, whether the reference still is
reasonably pertinent to the particular problem with which the
inventor is involved.

In re Clay, 966 F.2d 656, 658–59 (Fed. Cir. 1992).7 See also In re Klein,
647 F.3d 1343, 1348 (Fed. Cir. 2011) (a reference is reasonably pertinent
and thus analogous if it “would have commended itself to an inventor’s
attention in considering his problem”).8 In KSR, the Court instructed that
“[w]hen a work is available in one field of endeavor, design incentives and

7 See also In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004).
8 See also In re ICON Health and Fitness, Inc., 496 F.3d 1374, 1380 (Fed.
Cir. 2007) (citing In re Paulsen, 30 F.3d 1475, 1481 (Fed. Cir. 1994)
(finding that an inventor considering a hinge and latch mechanism for
portable computers would naturally look to references employing other
“housings, hinges, latches, springs, etc.,” which in that case came from areas
such as “a desktop telephone directory, a piano lid, a kitchen cabinet, a
washing machine cabinet, a wooden furniture cabinet, or a two-part housing
for storing audio cassettes”)).
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other market forces can prompt variations of it, either in the same field or a
different one.” KSR, 550 U.S. at 417.
Cline is generally related to tissue micro array (TMA) processing and
imaging. (See Cline ¶ 1; FF1–FF12.) Cline teaches that TMAs are used for
many analytic and diagnostic purposes includes the diagnosis of diseased
tissue at the molecular level. (Cline ¶ 2.) Hunter is generally related to an
assay of biological material by means of high, speed, high throughput
cytometry using fractionalized intensities of subcellular components in
magnified images. (See Hunter ¶ 2; FF13–FF15.) Ingermanson is generally
related to the technical field of image processing. (See Ingermanson ¶ 9;
FF16–FF17.) More particularly, Ingermanson is related to automated
analysis of magnified images and the instrumentation system used to in the
analysis of the magnified images. (See Ingermanson ¶ 9; FF17.)
Ingermanson teaches magnified images of biological material are obtained
for purposes of study, diagnosis, or determination of experimental results.
(See Ingermanson ¶ 10.) Appellant’s narrow interpretation of the field of
endeavor, i.e., pathology laboratory for Cline, drug discovery screening
where cell measurements are used in a high throughput screening of lead
compounds for Hunter, and management and control of an image processing
pipeline by way of a graphical user interface (GUI) for Ingermanson, is
unpersuasive. (See Appeal Br. 10 and 12.) Appellant offers no legal basis
for such a narrow interpretation. We, therefore, find that each cited
reference is within the same field of endeavor; namely, the field of analytical
and diagnostic processing and imaging of a biological material.
Nonetheless, assuming arguendo, that the cited references encompass
different fields of endeavor, the cited references are reasonably pertinent to
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the particular problem with which the inventor is involved. The problem
identified in the Specification includes creating a test that enables both
scoring of the key diagnostic molecules in a tumor or surrounding normal
tissue, directly in the same tissue section as the clinician uses to perform the
classical initial diagnosis. (See Spec. ¶¶ 5, 6.) The Specification further
teaches that the claimed invention solves this problem by integrating a
pathology diagnostic step with a gene/biomarker test(s) to enable the
pathologist to perform both steps side-by-side on the same instrument. (Id.
¶ 7.) This integrative tool makes pertinent information immediately
available to the pathologist or cancer research scientist for rapid
identification of both known and novel biomarker patterns and enables rapid
integration of sets of cancer biomarker pattern analyses into the tissue and
cellular microscope-image viewpoint of the pathologist to create a
multiplexed high throughput cancer biomarker histocytometry toolset. (Id.
¶ 9.) We find that each cited reference would enable an ordinary skilled
artisan to solve this problem of integrating a diagnostic and identification
step as the cited references are each directly related to improving analytical
and diagnostic processing and imaging of biological materials. (FF1–FF17.)
Thus, even if the cited references encompass different fields of endeavor,
each is reasonably pertinent to the particular problem with which the
inventor is involved.
For the reasons discussed above, we agree with the Examiner’s
conclusion. Appellant has not persuasively shown that the cited
combination of references fails to teach and/or suggest each claim limitation
as recited in claim 1. Thus, we conclude that the preponderance of the
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evidence does support the Examiner’s position and therefore affirm the
rejection of claims 1, and 5–9 and 15 on appeal.
Claim 4
The Examiner finds that Cline suggests that tissues having a
biomarker(s) overexpressed in cancer would be present only in areas of
tissue overexpressing the biomarker(s) and tissues not expressing
biomarkers would not have a detectable biomarker associated with that
tissue, and therefore, necessarily constitutes a gradient between tumor
(biomarker labels detected) and non-tumor (no biomarker labels detected)
areas of the tissue section (Final Act. 7–8; FF4–FF9).
Appellant contends that the combination of references fails to teach
and/or suggest the claim limitation as recited in claim 4. (Appeal Br. 14.)
Appellant asserts that the Office’s interpretation of Cline is misplaced
because there is no basis for the Office to reasonably interpret Cline as
necessarily teaching or inferring that there would be a decrease in
biomarkers displayed in areas outside of cancerous cells which do not
overexpress the biomarker thereby constituting a gradient between tumor
and non-tumor areas of the tissue section. (Id.) Rather, Appellant argues
that Cline teaches sequential imaging and registration methods that enable
“for the first time” two or more markers to be presented on the same tissue
section without any discussion of generating a gradient from the distances
for detecting the presence of tumor outside the tissue section. (Id.)
Appellant argues that such a conclusion is only possible by engaging in
retrospective reasoning, which is unpermitted. (Id.)
We are not persuaded by Appellant’s argument that Cline cannot be
reasonably interpreted as teaching an inference that there would be a
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decrease in biomarkers displayed in areas outside of cancerous cells which
do no overexpress the biomarker thereby constituting a gradient between
tumor and non-tumor areas of the tissue section without utilizing hindsight
reasoning.
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of
ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant’s
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). Appellant does not
direct us to evidence in the record to persuade us that the Examiner
improperly relied upon knowledge that was derived solely from Appellant’s
Specification and not from either the teachings and suggestions of the prior
art or the knowledge of a skilled artisan. As discussed supra, Cline shows
images of cell clusters where one or more individual cell components such
as the nuclei can be measured and quantified based on the cell component
labeled. (See Cline Figs. 2A and 2B; FF4–FF7.) Moreover, the plain and
ordinary meaning of a “concentration gradient” is the difference in the
concentration of a substance between two areas.9 Given that the image will
illuminate which cell components are labeled and which are not, we agree
with the Examiner that an ordinary skilled artisan can determine the gradient
between cell components labeled and those not labeled thereby indicative of
cells labeled and those not labeled, e.g., tumor versus non-tumor cells.
(Final Act. 7.) We are consequently not persuaded by Appellant’s argument.

9 “Transport across membranes,” BBC, available online at
https://www.bbc.co.uk/bitesize/guides/zqdhjty/revision/2, 4 pages at page 2
(2021).
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For the reasons discussed above, we agree with the Examiner’s
conclusion. Appellant has not persuasively shown that the cited
combination of references fails to teach and/or suggest each claim limitation
as recited in claim 4. Thus, we conclude that the preponderance of the
evidence does support the Examiner’s position and therefore affirm the
rejection of claim 4 on appeal.
Claims 10–13
Appellant contends that the cited combination of references fails to
teach and/or suggest the claim limitations as recited in claims 10–13. (Id. at
14–15.) Appellant asserts that Key teaches a calibrator cell pellet standard
that displays a color that is proportional to the amount of a molecule of
interest, which “provides an objective and quantitative method of
determining the concentration of an ‘unknown molecule.’” (Id. at 15.) Such
a teaching, Appellant argues, fails to teach or suggest “displaying images
and measures from an on-slide standard for normalizing the measures of the
biomarkers of other tissues.” (Id.) Appellant argues that to infer any further
functionality, without reference to an explicit passage in Key describing
displaying images and measures from an on-slide standard, is to engage in
retrospective reasoning, which is unpermitted.
We are not persuaded. Appellant does not direct us to sufficient
evidence in the record to persuade us that the Examiner improperly relied
upon knowledge that was derived solely from Appellant’s Specification and
not from either the teachings and suggestions of the prior art or the
knowledge of a skilled artisan. See In re McLaughlin, 443 F.2d at 1395.
Key expressly teaches a calibration method for normalizing staining thereby
allowing more accurate quantitation of staining intensity. (FF18–FF19.)
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Therefore, we find that the Office did not utilize improper hindsight. We are
consequently not persuaded by Appellant’s argument.
For the reasons discussed above, we agree with the Examiner’s
conclusion. Appellant has not persuasively shown that the cited
combination of references fails to teach and/or suggest each claim limitation
as recited in claims 10–13. Thus, we conclude that the preponderance of the
evidence does support the Examiner’s position and therefore affirm the
rejection of claims 10–13 on appeal.
Claim 14
Appellant contends that the cited combination of references fails to
teach and/or suggest the claim limitations as recited in claim 14. (Appeal
Br. 15.) Appellant asserts that Tafas teaches the possibility of future
regulations requiring storage of microscope slides for archival purposes in
order to allow post-diagnosis review of a diagnostic decision. (Id.)
Appellant further asserts that Tafas teaches that the possibility of storing
specimen image data with the slide in order to determine the degree of
degradation of the specimen over time. (Id.) Such teachings, Appellant
argues, fails to reference biomarkers or on-slide standards. (Id.) Appellant
argues that to infer any further characteristics of Tafas’s archive of
microscope slides, without reference to an explicit passage in Tafas
describing displaying images and measures from an on-slide standard, is to
engage in retrospective reasoning, which is unpermitted. (Id.)
We are not persuaded. Appellant does not direct us to sufficient
evidence in the record to persuade us that the Examiner improperly relied
upon knowledge that was derived solely from Appellant’s Specification and
not from either the teachings and suggestions of the prior art or the
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knowledge of a skilled artisan. See In re McLaughlin, 443 F.2d at 1395.
Tafas expressly suggests that it is advantageous to store microscopic images
to be able to revisit the slide in the future and regulations may require that a
specimen sample on a microscope slide be archived in order to allow post-
diagnostic review of a diagnostic decision (FF20). Therefore, we find that
the Office did not utilize improper hindsight. We are consequently not
persuaded by Appellant’s argument.
For the reasons discussed above, we agree with the Examiner’s
conclusion. Appellant has not persuasively shown that the cited
combination of references fails to teach and/or suggest each claim limitation
as recited in claim 14. Thus, we conclude that the preponderance of the
evidence does support the Examiner’s position and therefore affirm the
rejection of claim 14 on appeal.

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SUMMARY
We affirm the rejection of claims 1, 4–9, and 15 under 35 U.S.C.
§ 103(a) over Cline, Hunter, and Ingermanson.
We affirm the rejection of claims 10–13 under 35 U.S.C. § 103(a)
over Cline, Hunter, Ingermanson, and Key.
We affirm the rejection of claim 14 under 35 U.S.C. § 103(a) over
Cline, Hunter, Ingermanson, Key, and Tafas.

Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 4–9, 15 103(a) Cline, Hunter,
Ingermanson
1, 4–9, 15
10–13 103(a) Cline, Hunter,
Ingermanson, Key
10–13
14 103(a) Cline, Hunter,
Ingermanson, Key,
Tafas
14
Overall
Outcome
1, 4–15

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