Togawa, Naoyuki

Patent Trials and Appeals Board

Mar 19, 2020

13984373 - (D) (P.T.A.B. Mar. 19, 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.
13/984,373 08/08/2013 Naoyuki Togawa 417733US99PCT 7507
22850 7590 03/19/2020
OBLON, MCCLELLAND, MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA, VA 22314
EXAMINER
WEILER, KAREN S
ART UNIT PAPER NUMBER
IPLA
NOTIFICATION DATE DELIVERY MODE
03/19/2020 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):
OBLONPAT@OBLON.COM
iahmadi@oblon.com
patentdocket@oblon.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte NAOYUKI TOGAWA
____________

Appeal 2019-004234
Application 13/984,373
Technology Center IP00
____________

Before ERIC B. GRIMES, DEBORAH KATZ, and
ULRIKE W. JENKS, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 1, 3–6 and 9–18. We have jurisdiction under
35 U.S.C. § 6(b). We AFFIRM.
STATEMENT OF THE CASE
The Specification describes an “on-chip PCR reaction utilizing a gel-
held type DNA microarray utilizing the molecular sieving effect of the spot
gel.” Spec. ¶ 1. High hybridization efficiency is achieved when using porous
gels as opposed to already-known gel DNA microarrays. Id. ¶ 9. By

1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R.
§ 1.42(a). Appellant identifies the real party in interest as Mitsubishi
Chemical Corporation. Appeal Br. 2.
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adjusting “the gel concentration (the porous structure of the gel) according to
the size (base length) of a nucleic acid to be amplified (nucleic acid as a
detection target), the molecular sieving effect of the gel can be improved and
the detection method having a higher specificity can be provided.” Id. ¶ 18.
The Specification describes that a “‘reaction on a microarray’ means a
‘reaction in the entire reaction system including a microarray and a reaction
solution’, and does not particularly mean a reaction only on the surface of
and in the inside of a gel in an array utilizing the gel.” Id. ¶ 22.
Claims 1, 3–6 and 9–18 are on appeal, and can be found in the Claims
Appendix of the Appeal Brief. Claim 1, reproduced below, is illustrative of
the claimed subject matter:
Claim 1: A method for detecting a nucleic acid, the method
comprising:
contacting a plurality of gels, in which a probe is immobilized,
with a reaction solution comprising a nucleic acid that serves as a
template for nucleic acid amplification, a primer set for nucleic acid
amplification, a nucleotide unit and a DNA extension enzyme;
subjecting the gels and the reaction solution to a heat cycle for
performing a nucleic acid amplification reaction;
selecting nucleic acid fragments having a specific base length
from among the amplified nucleic acid fragments; and
detecting the selected nucleic acid fragments,
wherein:
the selecting of the nucleic acid fragments having the specific
base length occurs by utilizing a molecular sieving effect of the gels;
the specific base length of the selected nucleic acid fragments
ranges from 50 bases to 3000 bases;
the plurality of gels are contained on a common substrate;
each gel of the plurality of gels is held in a well or through-hole
of the common substrate;
a gel concentration of the gels in which the probe is
immobilized is 2.5 to 5% by mass;
a ratio (V/S) of a volume of each gel of the plurality of gels (V
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(μm3)) to the surface
area of the gel in which the probe is immobilized that is in
contact with the reaction solution (S (μm2)) is 50 or more; and
the common substrate comprises:
(i) hollow fiber containing carbon black; and
(ii) a resin material containing carbon black.
Appeal Br. 18 (Claims Appendix)
REFERENCE(S)
The prior art relied upon by Examiner is:
Name Reference Date
Nagahama et al.
(“Nagahama”)
US 2006/0084060 Al Apr. 20, 2006
Takahashi et al.
(“Takahashi”)
JP 2005249702 A Sept. 15, 2005
Grunenwald, Optimization of Polymerase Chain Reactions, Methods in
Molecular Biology Vol. 226: PCR Protocols, edt. J. M. S. Barilell and D.
Stirling
Strizhkov et al., PCR Amplification on a Microarray of Gel Immobilized
Oligonucleotides: Detection of Bacterial Toxin- and Drug-Resistant
Genes and Their Mutations, 29 Bio Techniques 844–57 (2000)
(“Strizhkov”)
Yershov et al., DNA analysis and diagnostics on oligonucleotide
microchips, 93 Proc. Natl. Acad. Sci. USA, 4913–18 (1996) (“Yershov”)
REJECTION(S)
Appellant requests review of the following grounds of rejection made
by Examiner:
I. Claims 1, 3–6, 9, 10 and 15–18 under 35 U.S.C. § 103(a) as
unpatentable over Strizhkov, as evidenced by Yershov, in view of
Nagahama, and further in view of Takahashi.
II. Claims 1, 3–6 and 9–18 under 35 U.S.C. § 103(a) as unpatentable
over Strizhkov, as evidenced by Yershov, in view of Nagahama and
Takahashi, and further in view of Grunenwald.
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Obviousness over Strizhkov, Yershov, Nagahama, and Takahashi
Because both of the rejections turn on the same issues, we will
consider the rejections together. The issue with respect to these rejections is
whether the preponderance of evidence of record supports Examiner’s
conclusion that the method of detecting nucleic acids held in a gel substrate
that is formed as a well or through hole is obvious?
Findings of Fact
FF1. Strizhkov teaches “PCR amplification on a microarray of gel-
immobilized compounds on a chip (MAGIChip™).” Strizhkov 844.
“A microchip for PCR amplification contained about 1 pmol
oligonucleotide primers immobilized through their 5' terminal amino
groups inside 100 x 100 x 20-μm polyacrylamide gel pads or 100 x
100 x 40-μm porous mixed polyacrylamide gel pads spaced by a 200-
μm hydrophobic glass surface.” Id. at 845.
FF2. Strizhkov teaches using standard acrylamide gels (citing Yershov) or
porous gels containing 1.5% acrylamide. Id. at 845. “Porous gels are
more advantageous, providing the faster diffusion rate of large
molecules and the higher level of amplification than the standard
ones, but they are less stable.” Id. at 850.
FF3. Yershov, cited by Strizhkov, teaches “[a] matrix of glass-immobilized
gel elements was prepared as described [] by polymerization of 20-μm
thin polyacrylamide (8% acrylamide/0.28% bisacrylamide) gel on a
glass surface treated by Bind-Silane (LKB).” Yershov 4914.
FF4. Strizhkov teaches that “[s]tandard and porous [] gels have been used
for PCR amplification and are accessible to globular proteins of about
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100 kDa in size and to DNA of 100-150 bp and about 400 bp,
respectively.” Strizhkov 850.
FF5. Strizhkov teaches amplifying B. anthracis PCR products, specifically,
“[t]he 103-bp lef fragment” and “the 248-bp pag4 fragment.” Id. at
845.
Amplification of the anthrax toxin gene fragments.
Microchip gel pads contained the immobilized forward
lef-F [] or pag4-F primers. The PCR amplification
solution contained the unbound forward lef-F and pag4-F
primers, fluorescently labeled reverse lef-R and pag4-R
primers and either lef or pag4 products. The kinetics of
amplification was monitored in real time as the
accumulation of fluorescently labeled duplexes formed
by the extended immobilized lef-F primer (curve 1) or
pag4-F primer (curve 2) and the complementary DNA
strands of either lef (A) or pag4 (B) products.
Id. at 850 (legend Figure 2).
The PCR buffer contained 2.5 mM MgC12, 10 mM KCl,
10 mM Tris-HCl, pH 8.3, 0.1 % bovine serum albumin
(BSA) (Sigma), 200 μM each dNTP (Sigma), 5 U
AmpliTaq® DNA polymerase, Stoffel Fragment of Taq
DNA polymerase (Applied Biosystems, Foster City, CA,
USA), 1-10 pmol each of the forward unlabeled and
reverse labeled primers and 104 copies of bacterial
genomic or product DNA.
Id. at 845.
FF6. Nagahama teaches “a gel containing 2%-7% by mass of N,N-
dimethylacrylamide and a biological substance immobilized on and/or
in the gel.” Nagahama, Abstract, see ¶ 28 (more preferably a gel made
up of “N,N-dimethylacrylamide is 2.5% to 5.0% by mass”).
“Biological substances immobilized on and/or in the gel in the
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microarray serve as capture probes for nucleic acids or proteins which
hybridize or bind to the biological substances.” Id. ¶ 52.
FF7. Nagahama teaches a biological substance-immobilized gel
microarray, made of gel-filled hollow tubes. Id. ¶¶ 12–17. The
“microarray which is obtained by allowing a plurality of the above
gel-filled hollow tubes (e.g., hollow fibers) to be tied in a bundle and
cutting the tube bundle in a direction intersecting with the longitudinal
direction of the tubes.” Id. ¶ 19.
FF8. Nagahama teaches that “[t]he hollow tubes . . . may each be used as a
base unit for supporting the biological substance immobilized gel.” Id.
¶ 46. Nagahama teaches that the spaces between the hollow fibers are
filled with resin (id. ¶ 48) and that the resin material is supplemented
with carbon black. Id. ¶ 59.
FF9. Nagahama teaches hollow tubes wherein the “surface area of each
compartment is preferably 10-6 m2 or less.” Id. ¶ 18. “[H]ollow fibers
with an outer diameter of 0.3 mm, an inner diameter of 0.2 mm.” Id.
¶ 57. Additionally, the hollow fibers have a thickness of about 500 μm
(0.5 mm). Id. ¶ 70.
FF10. Takahashi2 teaches a DNA chip made up of hollow tubular bodies.
Takahashi, Abstract. Takashi teaches filling the hollow tubes with the
gel-like substance made of acrylamide containing 2 to 20%
acrylamide monomer by mass. Id. at 11. Takahashi teaches
incorporating materials that can detect biological substances, such as
nucleic acid, into the gel. Id.

2 Takahashi is not paginated, we refer to page numbers of Takahashi as if it
was numbered consecutively beginning with the first page.
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FF11. Takahashi teaches a hollow tubular body having a diameter of 0.32
mm and a thickness of 0.1 mm. Id. at 12.
FF12. Takahashi teaches that in order to reduce noise “the hollow tubular
body containing an appropriate amount of black pigments, such as
carbon black.” Id. at 12. The hollow tubular bodies of Takahashi are
made of polycarbonate and contain 1% carbon black. Id. at 12.
Principle of Law
“If the claim extends to what is obvious, it is invalid under § 103.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007). “The 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 413, 425 (CCPA 1981). “[O]ne cannot show non-obviousness by
attacking references individually where, as here, the rejections are based on
combinations of references.” Id. at 426.
Analysis
Examiner finds that Strizhkov teaches most of the elements recited in
the claims such as immobilizing oligonucleotides in a porous gel, subjecting
the gels to a reaction solution, and applying heat cycles for performing a
nucleic acid amplification reaction. Non-Final Act.3 3; FF1–FF5. Examiner
acknowledges that Strizhkov does not exemplify the recited gel
concentration, or that the gel is held in a well or through hole on a common

3 Non-Final Office Action mailed March 27, 2018 (“Non-Final Act.”).
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substrate containing hollow fibers and resin that include carbon black. Non-
Final Act. 4. Examiner relies on the teachings of Nagahama and of
Takahashi for disclosing these limitations. Non-Final Act. 4; FF6–FF12.
Examiner concludes that
[o]ne [of ordinary skill in the art] would have been motivated to
employ an array of gel-filled hollow fibers instead of gel pads
because this facilitates the mass production of large numbers of
identical microarrays upon bundling of the gel-filled fibers with
an adhesive resin (e.g. [Nagahama] paragraphs [0013]-[0017]
and [0046]-[0051]), which is ideal for performing PCR analysis
on multiple different samples.
Non-Final Act. 5. Examiner concludes that based on the teachings
Nagahama, one would of been motivated to employ gels having an
acrylamide concentration between 2.5 to 5% because “this gel composition
is optimal for obtaining a uniform distribution of fluorescence intensity in
each compartment and higher hybridization efficiency (e.g. [Nagahama]
paragraphs [0007]-[0008], [0028], Working Example 1 and Figure 1, and
Working Example 2 and Figure 2).” Non-Final Act. 5. Furthermore,
Examiner concludes that based on the teachings of Takahashi “[o]ne [of
ordinary skill in the art] would have been motivated to include carbon black
in the hollow fibers and resin because so doing reduces background signal
(or noise) during fluorescence measurement of nucleic acid signal.” Id. at 6.
Appellant contends that there is no motivation to replace the gel pad
of Strizhkov with cylindrical wells or through-holes because this would limit
the diffusion of the DNA fragments into the gel, and thereby defeat a central
objective of Strizhkov’s process. See Appeal Br. 9, 14, 16; Reply Br. 3.
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Claim 1
We have reviewed Appellant’s contentions in light of the art cited by
Examiner and find that Examiner has the better position. Examiner identifies
the suitability for “mass production of large numbers of identical
microarrays upon bundling of the gel-filled fibers with an adhesive resin” as
taught by Nagahama as motivation to change Strizhkov’s gel format. Ans. 4
(citing Nagahama ¶¶ 13–17, 46–51). Examiner identifies that Strizhkov
already recognizes that their porous gel format is not ideal because the gel is
prone to tearing. Id. at 5 (citing Strizhkov 850). Examiner finds that “the
hollow tubes or fibers disclosed by Nagahama et al. serve as a base unit for
supporting the advantageous gels of porous polyacrylamide.” Id. at 5 (citing
Nagahama ¶ 46 (“The hollow tubes . . . may each be used as a base unit for
supporting the biological substance immobilized gel”). Examiner finds that
Nagahama et al. explicitly recognize that there is a need in the
field of capture oligonucleotide-immobilized gel microarrays
for an improvement in the technology that addresses the issue
faced by Strizhkov et al.: “there has been a problem that when
the microarrays after hybridization are measured for
fluorescence intensity in each of their compartments where
capture probes are immobilized, the fluorescence intensity is
higher in the outer regions of the compartments, but lower in
the center regions of the compartments” (e.g. paragraph
[0006]). Nagahama et al. describe their invention as meeting
this need by providing a uniform distribution of fluorescence
intensity in each compartment and a higher value for total
fluorescence intensity summed over the entire area of each
compartment (e.g. paragraph [0007]).
Id. at 5. Takahashi suggests adding carbon black to the hollow fiber tubes as
another way to reduce noise from the gel imbedded hollow tubular bodies.
FF12. Here, Examiner identifies mass-production of the microarray,
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stabilizing the gel, in conjunction with improved fluorescent detection as
motivation to modify Strizhkov’s gel pads into gel filled hollow fiber tubes.
We find no error with Examiner’s identified motivation as a reasonable basis
for concluding the claims are rendered obvious based on the combination of
Strizhkov, Yershov, Nagahama, and Takahashi.
In support of their “no motivation” argument, Appellant contends that
Examiner’s proposed modification of Strizhkov would change its principle
of operation and would render Strizhkov unsatisfactory for its intended
purpose. Appeal Br. 9. Appellant relies on In re Gordon, 733 F.2d 900 (Fed.
Cir. 1984) as legal authority for this contention. Id. While the proposed
modification would result in a device with reduced surface area available for
diffusion of substances into the gel matrix, the modified device still would
operate according to the same principles as the unmodified device. Namely
the imbedded oligonucleotide linked to the gel matrix would still capture
complementary nucleic acid, therefore, the operation (i.e. function) of the
bound oligonucleotide is still the same as in Strizhkov. Appellant’s
arguments with respect to the exposed surface area available for diffusing
substances in and out of the gel matrix of the hollow tube is directed to the
efficiency of the material flowing in and out of the gel, and is not directed to
the change in function of the substances attached to the gel. Here, the
combination as suggested by Examiner may result in decreased diffusion of
materials in and out of the gel matrix but comes with the improved benefit of
ease of production of the microarray as well as improved detection as taught
in Nagahama, and Takahashi. See FF6–FF12; In re Urbanski, 809 F.3d
1237, 1243 (Fed. Cir. 2016) (holding that a combination of references may
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be obvious even if the combination is at the expense of a benefit of one of
the references).
We conclude, considering the totality of the cited evidence and
arguments, that the preponderance of the evidence supports Examiner’s
conclusion of obviousness with respect to claim 1. Appellant has not
provided sufficient rebuttal evidence or evidence of secondary
considerations that outweighs the evidence supporting Examiner’s
conclusion. As Appellant does not argue the claims separately, claims 5, 6,
10, 9–14, 16–18 fall with claim 1. 37 C.F.R. § 41.37 (c)(1)(iv).

Claims 3 and 15
With respect to the rejections of claims 3 and 15, Appellant relies on
the same arguments relied upon with respect to claim 1, discussed above.
See Appeal Br. 13–16. Thus, for the reasons discussed above, we find that
Examiner has established a prima facie showing of obviousness with respect
to claims 3 and 15, which Appellant has failed to rebut. Accordingly, we
affirm the rejection of these claims as well.

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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 3–6, 9,
10, 15–18
103 Strizhkov,
Yershov,
Nagahama,
Takahashi
1, 3–6, 9,
10, 15–18

1, 3–6, 9–
18
103 Strizhkov,
Yershov,
Nagahama,
Takahashi
1, 3–6,
9−18

Overall
Outcome
1, 3−6,
9−18

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). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED