Joon Won. Park et al.

Patent Trials and Appeals Board

Oct 25, 2019

12140226 - (D) (P.T.A.B. Oct. 25, 2019)

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.
12/140,226 06/16/2008 Joon Won Park NSB-000400US 3099
68514 7590 10/25/2019
Don D. Cha
12640 W. Cedar Drive
Suite 1
Lakewood, CO 80228
EXAMINER
BERTAGNA, ANGELA MARIE
ART UNIT PAPER NUMBER
1637
NOTIFICATION DATE DELIVERY MODE
10/25/2019 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):
DCHA@HDCIPLAW.COM
kmcinnish@hdciplaw.com
matthew.hdc@gmail.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
________________

Ex parte JOON WON PARK, BONG JIN HONG,
and SUNG HONG KWON1
________________

Appeal 2019-000526
Application 12/140,226
Technology Center 1600
________________

Before JEFFREY N. FREDMAN, JOHN G. NEW, and
JAMIE T. WISZ, Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the word “Appellant” to refer to the “applicant” as defined in
37 C.F.R. § 1.142. Appellant identifies Postech Academy-Industry
Foundation and Posco as the real parties-in-interest. App. Br. 2.
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SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 23–34 and 42. Specifically, claims
23–26, 29, 31–33, and 42 stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Henderson et al. (US
5,763,768, June 9, 1998) (“Henderson”), Ashby et al. (U.S. 2003/0033863
A1, February 20, 2003) (“Ashby”), B. J. Hong et al., Nanoscale-Controlled
Spacing Provides DNA Microarrays with the SNP Discrimination Efficiency
in Solution Phase, 21 LANGMUIR 4257–261 (2005) (“Hong”), and T. Leskela
et al., Sensitive Genus-Specific Detection of Legionella by a 16S rRNA
Based Sandwich Hybridization Assay, 62 J. MICROBIOL. METHODS, 167–79
(2005) (“Leskela”).
Claims 23–25, 27–33, and 42 stand rejected as unpatentable under
35 U.S.C. § 103(a) as being obvious over the combination of Henderson,
Ashby, Hong, and Dellinger et al. (US 6,103,474, August 15, 2000)
(“Dellinger”).
Claim 34 stands rejected as unpatentable under 35 U.S.C. § 103(a) as
being obvious over the combination of Henderson, Ashby, Hong, Leskela,
and Cai et al. (US 2004/0213910 A1, October 28, 2004) (“Cai”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellant’s claimed invention is directed to a method for detecting a
presence of target ligand in a fluid medium. Abstr.
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REPRESENTATIVE CLAIM
Claim 23 is representative of the claims on appeal and recites:
23. A method for determining the identity of a target
oligonucleotide in a fluid medium comprising:

(i) contacting the fluid medium with a solid substrate
comprising a plurality of different first probe
oligonucleotides to form a first probe oligonucleotide-
target oligonucleotide complex when the target
oligonucleotide is present in the fluid medium,
wherein each of the different first probe
oligonucleotides is located at a predefined region of
the solid substrate, and wherein the nucleotide length
of said first probe oligonucleotides is shorter than the
length of said target oligonucleotide such that at least
a portion of said target oligonucleotide remains
uncomplexed in said first probe oligonucleotide-target
oligonucleotide complex, and wherein the solid
substrate further comprises:

a plurality of dendrons on its surface, wherein each
of the dendrons comprises:

a central atom, and

a base portion attached to the central atom and
having a plurality of termini that are attached to the
surface of the solid substrate, and wherein each of
the plurality of different first probe oligonucleotides
is attached to the central atom optionally through a
linker;

(ii) measuring the binding force between a second probe
oligonucleotide that is present on the tip of an atomic
force microscope (AFM) and said uncomplexed
portion of said target oligonucleotide in said first
probe oligonucleotide-target oligonucleotide
complex; and
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(iii) identifying the target oligonucleotide by analyzing
the location of increased binding force within the
solid substrate.

App. Br. 12.

ISSUES AND ANALYSES
We agree with, and adopt, the Examiner’s findings, reasoning, and
conclusion that the claims on appeal are obvious over the combined cited
prior art. We address the arguments raised by Appellant below.

Issue
Appellant argues that the Examiner erred in finding that a person of
ordinary skill in the art would have used the combined teachings of the
references cited by the Examiner to arrive at the claimed invention. App.
Br. 10.

Analysis
The Examiner finds that Henderson teaches methods comprising the
use of atomic force microscope (“AFM”) to detect target ligands present in a
solution. Final Act. 6 (citing Henderson Abstr., col. 3, ll. 25–45, Figs. 2,
13). The Examiner finds that Henderson teaches: (1) contacting a fluid
medium with a solid substrate upon which a probe that binds to the target
ligand is immobilized, and (2) determining the presence of a probe-target
ligand complex by measuring the binding force between any target ligand
bound to the substrate-immobilized probe and a detection molecule that is
immobilized upon an AFM cantilever tip and also binds to the target ligand,
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by which an increase in force between the probe-target ligand complex and
the detection molecule indicates the presence of the target ligand in the fluid
medium. Id. (citing Henderson col. 9, ll. 1–23, col. 11, ll. 1–30, cols. 12–13
ll. 45–8, Figs. 2, 10, 13).
The Examiner finds that Henderson further teaches that its methods
may be used to detect a target nucleic acid via its hybridization to its
complement, but also finds that Henderson does not expressly teach that the
nucleic acid detection embodiments are conducted in a “sandwich assay”
using substrate-immobilized and AFM tip-immobilized oligonucleotides.
Final Act. 6–7. The Examiner also finds that Henderson does not teach that
the solid substrate upon which the probe is immobilized is coated with an
array of dendrons on its surface or immobilizing a plurality of different
probes at predetermined locations on the substrate. Id. at 7. Furthermore,
the Examiner finds, Henderson does not teach an oligonucleotide sandwich
assay configuration. Id.
The Examiner finds that Ashby teaches a high-throughput AFM
method for simultaneously detecting interactions between a plurality of
different pairs of biological molecules. Final Act. 7 (citing Ashby ¶ 14).
The Examiner finds that the method taught by Ashby comprises contacting a
fluid medium with a solid substrate having a plurality of different probes
(i.e., test molecules) immobilized upon it at predetermined locations and
measuring the binding force between a detection molecule immobilized on
an AFM tip and a test molecule. Id. (citing Ashby ¶¶ 14, 37–39, 41–48).
The Examiner finds that Ashby also teaches that a plurality of different
AFM tips, each having a different detection molecule immobilized upon it,
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may be used to measure simultaneously interactions between a plurality of
different test molecule detection molecule pairs. Id. at 7–8.
The Examiner finds that Ashby does not teach using dendrons to
attach the probes to the solid substrate, but finds that Hong teaches methods
for conducting nucleic acid hybridization reactions on an array comprising a
dendron coating. Final Act. 8 (citing Hong Abstr.). Specifically, the
Examiner finds that Hong teaches a planar, nonporous solid support coated
with an array of cone-shaped dendrons, each of which has a central atom to
which an oligonucleotide probe is attached. Id. (citing Hong schemes 1–2,
4257–258). The Examiner finds that Hong teaches that the central atom is
also attached to a base portion having a plurality of termini that are attached
to the solid support. Id.
Finally, the Examiner finds that Leskela teaches solid-phase sandwich
hybridization assays for detecting a target nucleic acid in a fluid sample.
Final Act. 9 (citing Leskela Abstr., 168, 170–71). The Examiner finds that
Leskela also teaches that this method is highly sensitive and can provide
attomolar sensitivity. Id. (citing Leskela Abstract, 173, Table 2).
The Examiner concludes that it would have been prima facie obvious
to a person of ordinary skill in the art to immobilize a plurality of different
probes at predetermined locations on a solid substrate, as taught by
Henderson. App. Br. 9. The Examiner finds that a skilled artisan would
have been motivated to do so with a reasonable expectation of success in
view of the teachings of Ashby, which indicate that this would afford the
ability to detect and identify a plurality of different target ligands in the fluid
medium in a high-throughput format. Id. Furthermore, the Examiner finds,
a person of ordinary skill would have understood from the teachings of
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Hong that dendron-coated arrays offer an “ideal” array surface with
precisely controlled spacing between immobilized molecules, which serves
to eliminate non-specific binding to the array surface and also to maximize
hybridization efficiency by mimicking solution hybridization conditions. Id.
The Examiner further concludes that it would also have been obvious
to a skilled artisan to employ the methods suggested by the teachings of
Henderson, Ashby, and Hong in a sandwich assay format. Final Act. 9. The
Examiner points out that Henderson expressly teaches that its method can be
used to detect a target nucleic acid; furthermore, the Examiner finds such an
artisan would also have recognized from the above teachings of Leskela that
nucleic acid detection using a sandwich assay format would provide a much
more sensitive and specific means of detecting nucleic acids than the
conventional hybridization methods suggested by Henderson and Hong. Id.
at 9–10.
Appellant argues that the method taught by Henderson requires: (1) a
functionalized particle that is attached to the AFM; and (2) use of two
antibodies to detect an antigen. App. Br. 9. Appellant contends that, in
contrast to the method recited in Appellant’s claims, the method taught by
Henderson is similar to an ELISA2 assay, except that an AFM is used. Id.

2 The sandwich ELISA (enzyme-linked immunosorbent assay) assay
involves attachment of a capture antibody to a microplate. Then, samples
containing unknown amount of the target protein or analyte of interest are
added and bind to the capture antibody. After washing steps to rid the
microplate of unbound substances, an HRP [horseradish peroxidase]
conjugate is added for detection. See GENERAL SANDWICH ELISA
PROTOCOL, available at: https://www.thermofisher.com/us/en/home/
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Appellant argues that, unlike hybridization of oligonucleotides where
the strength of detection depends on the number of hydrogen bonds between
the probe and the target oligonucleotide, binding of an antigen to an
antibody generally forms a much stronger bond, and the antibody and
antigen are specific to one another. App. Br. 9. Appellant asserts that it is
well known to one skilled in the art that binding of an antigen to an antibody
is more like a “lock-and-key” interaction in which the antigen is thought to
be “inserted” into a pocket of the antibody to provide a strong interaction.
Appellant disputes the Examiner’s finding that Henderson teaches
detection of a target nucleic acid. App. Br. 9. Appellant asserts, rather, that
a close reading of Henderson shows it teaches away from Appellant’s
claimed method. Id. Specifically, Appellant points to columns 3–4, lines
49–8 of Henderson, which teaches that:
A variety of molecular pairs can be used in the molecular
detection system described herein. Some representative
examples are listed in Table 1. Some of the molecular pairs listed
in Table 1 have been tested by other groups but have not been
evaluated using the modified scanning probes and methods
described here. They will be useful in comparing reproducibility
and reliability of the different systems. Other molecular pairs
have not been tested but are important for diagnostic
applications. As representative examples of test cases we present
data describing molecular force detection using an antibody-
antigen system, and supportive data using a protein-DNA
system. The antibody system is a “sandwich” type assay in which
the antigen is trapped between two antibodies. In our
implementation, one antibody is immobilized on a solid surface,

references/ protocols/cell-and-tissue-analysis/elisa-protocol/general-elisa-
protocol.html (last visited October 16, 2019).

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and the second is attached to the probe. When the antigen is
introduced, it is trapped between the two antibodies, forming a
trimolecular complex. The force necessary to rupture this
complex provides the macroscopic signal, in the form of a direct
force measurement or, more pertinent to this application, in the
form of a change in a resonance property of the probe. The
protein DNA system includes a recombinant yeast transcription
factor, Gal 4, and its target DNA duplex sequence[.] In this
assay, the Gal 4 protein is attached to the probe, and the DNA
target is attached to a solid surface. The interaction between the
protein and the DNA is detected and measured as described
above for the antibody-antigen interaction.

Appellant argues that Henderson does not, therefore, teach detecting
oligonucleotide via hybridization. App. Br. 10. At most, contends
Appellant, Henderson contemplates attaching the DNA target to the solid
surface and using the probe that is attached to the cantilever to detect the
DNA target. Id. Therefore, Appellant asserts, the detection of a DNA target
contemplated in Henderson does not involve a sandwich-type assay and,
more importantly, the detection of the DNA target taught by Henderson does
not involve a three-complex system but a one-to-one hybridization (i.e., two-
part) assay. Id.
Appellant argues further that Henderson teaches that a detection
method using an AFM is sensitive enough to detect interaction between
single molecules. App. Br. 10 (citing, e.g., Henderson col. 1, ll. 53–55).
According to Appellant, if the AFM method is this sensitive, there would
have been no motivation for one skilled in the art to use the sandwich-type
three-part assay recited in the claims, because it is more cumbersome and
requires more time and cost than a simple two-part assay. Id. at 11.
Furthermore, Appellant asserts, if a skilled artisan would have been
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motivated to obtain a greater sensitivity, such a person would have been
motivated to use a higher amount of nucleotide hybridization between the
target oligonucleotide and the probe oligonucleotide. Id.
Specifically, Appellant argues, in order to achieve a greater
sensitivity, one skilled in the art would immobilize the target nucleotide on a
solid substrate directly without using a “first probe nucleotide.” In this
manner, a longer length probe nucleotide on the AFM tip could be used to
provide a stronger binding force measurement, and hence a greater
sensitivity and selectivity. App. Br. 10. Consequently, Appellant argues, a
person of ordinary skill in the art would not have been motivated to use a
three-part assay for detecting oligonucleotides.
We are not persuaded by Appellant’s argument. Contrary to
Appellant’s argument, Table 1 of Henderson expressly teaches, in addition
to the protein/DNA interaction described by Appellant, DNA/DNA
interactions. Table 1 of Henderson is reproduced below:

Table 1 lists representative examples of molecular pairs that can
be used in the detection system of Henderson

Furthermore, Henderson teaches that: “The AFM is extraordinarily
sensitive, being capable of detecting force interactions between individual
molecules, chemical groups and even single quantized hydrogen bonds.
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Specific examples include: avidin/biotin interactions, DNA-DNA
interactions, antibody-antigen interactions, chemical group interactions, and
individual hydrogen bonds.” Henderson col. 1, ll. 53–59 (emphasis added,
internal references omitted). Therefore, and contrary to Appellant’s
argument, Henderson teaches that its sandwich assay methods can be used to
measure DNA-DNA interactions. Moreover, Henderson suggests an assay
in which a test DNA sequence can be bound between first and second DNA
hybridizing probes, in a manner similar to the antibody-antigen-antibody
assay taught in the quoted passage supra.
In short, Henderson expressly teaches a sandwich-type assay, and also
teaches that its methods can be used to measure DNA/DNA interactions.
Furthermore, we do not find Appellant’s argument with respect to the
alleged lack of motivation by a skilled artisan to use the technique taught by
Henderson. Appellant argues that:
[O]ne skilled in the art would immobilize the target nucleotide
on a solid substrate directly without using a “first probe
nucleotide.” In this manner, a longer length probe nucleotide on
the AFM tip could be used to provide a stronger binding force
measurement, and hence a greater sensitivity and selectivity.

App. Br. 11. Appellant’s argument seems to misapprehend the point of
Henderson (and of Appellant’s claims) which is to detect the presence of an
analyte in a solution by first binding it to a probe bound to the substrate.
Appellant provides no suggestion as to how the target molecule would be
“immobilize[d] on a solid substrate directly,” however, such immobilization
is directly suggested by both Henderson and Appellant’s claims as being
performed by a sandwich assay, i.e., binding/hybridizing the test substance
to a probe anchored to the substrate. Henderson teaches that the AFM
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technique is suitably sensitive for measuring DNA interactions, such that the
strength of the hydrogen bond interactions, as Appellant notes, would reflect
the amount of hybridization. See Henderson col. 1, ll. 53–59; App. Br. 7–8.
Indeed, the enhanced sensitivity of the AFM technique permits accurate
measurement of DNA/DNA interactions based upon less, not more,
hybridization between the second probe and the test sequence.
Finally, Appellant argues that Henderson teaches away from
Appellant’s claimed invention. We disagree. A reference may be said to
“teach away” when “a person of ordinary skill, upon reading the reference,
would be discouraged from following the path set out in the reference, or
would be led in a direction divergent from the path that was taken by the
applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). Appellant
points to no teaching or suggestion of Henderson that would discourage or
divert a skilled artisan from arriving at Appellant’s claimed invention. To
the contrary, and as we have explained, Henderson directly suggests that its
method is of sufficient sensitivity such that it can be used to measure DNA-
DNA interactions.
Consequently, we affirm the Examiner’s rejection of the claims.

CONCLUSION
The Examiner’s rejection of claims 23–34 and 42 under 35 U.S.C.
§ 103(a) is affirmed.
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
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Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
23–26, 29, 31–
33, 42
103(a) Henderson,
Ashby, Hong,
Leskela
23–26, 29,
31–33, 42

23–25, 27–33,
42
103(a) Henderson,
Ashby, Hong,
Dellinger
23–25, 27–
33, 42

34 103(a) Henderson,
Ashby, Hong,
Leskela, Cai
34
Overall
Outcome
23–34, 42