LIAO, Yong

Patent Trials and Appeals Board

Jan 2, 2020

15559054 - (D) (P.T.A.B. Jan. 2, 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.
15/559,054 09/17/2017 Yong LIAO 10023.0002 9055
136922 7590 01/02/2020
SZDC Law P.C.
1629 K Street N.W.
Suite 300
Washington, DC 20006
EXAMINER
OYEYEMI, OLAYINKA A
ART UNIT PAPER NUMBER
1637
NOTIFICATION DATE DELIVERY MODE
01/02/2020 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):
USPTO@dockettrak.com
info@szdclaw.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte YONG LIAO
____________

Appeal 2019-004961
Application 15/559,054
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.

KATZ, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 seeks our review, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 1–3 (Appeal Brief filed November 30,
2018 (“Br.”) 5.)
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. Appellant identifies the Real Party in Interest as the
inventor, Dr. Yong Liao. (See Br. 3.)
Appeal 2019-004961
Application 15/559,054

2
INTRODUCTION
Appellant’s Specification provides a kit for quantitatively detecting
hepatitis B virus covalently closed circular DNA (“cccDNA”).
(Specification filed September 17, 2017 (“Spec.”) ¶ 1.) The Specification
discloses that cccDNA plays an important role in the replication of hepatitis
B virus and the establishment of infection status. (Id. ¶ 4.) Hepatitis
cccDNA is formed from incomplete closure Ring DNA (“rcDNA”). (Id.
¶ 3.) Hepatitis B virus rcDNA is characterized by a DNA fissure or gap
region between two ends of the rcDNA. (Id.) The DNA fissure region is
extended and repaired in the infected cell nucleus, thereby forming complete
double-stranded cccDNA. (Id.) Methods for quantitative detection of
cccDNA distinguish between cccDNA and rcDNA by identifying the
presence or absence of a complete ring. (Id. ¶ 5.)
The Specification describes a prior art process for real-time
quantitative PCR detection of cccDNA. (Id. ¶ 15.) The process uses a
TaqMan probe with a light-emitting group and a quenching group. (Id.) If
the negative strand is complete (cccDNA), a primer guides the Taq enzyme,
which reaches and cleaves the bound TaqMan probe. (Id.) The light-
emitting group is then released from the quenching group and produces a
fluorescent signal. (Id.) However, if the negative chain is not complete
(rcDNA), the upstream primer cannot pass through the chain gap, and the
probe is not activated. (Id.) The Specification argues “this method is a gold
standard for cccDNA quantification in clinical liver puncture specimens, but
the specificity of this method is particularly low.” (Id.) In contrast, the
Specification asserts the invention is an improvement over the prior art by
Appeal 2019-004961
Application 15/559,054

3
using DNase that is safe for closed loop DNA to remove non-cccDNA;
using a rapid, simple and inexpensive PCR to qualitatively detect cccDNA;
and using a probe method and EvaGreen fluorescent dye method to conduct
a digital PCR for absolute quantitative detection of cccDNA. (Id. ¶ 17.)
Appellant’s claim 1 recites:
A composition for detecting hepatitis B virus cccDNA,
comprising

an upstream primer consisting of the DNA sequence set
forth in SEQ ID NO. 1,

a downstream primer consisting of the DNA sequence set
forth in SEQ ID NO. 2, and

a probe consisting of the DNA sequence set forth in SEQ
ID NO. 3 and a light-emitting group and a quenching group.

(Br. 12.) Independent claim 2 recites a kit including the primers and probe
of claim 1, an extraction agent, ATP-Dependent DNase, a fluorescent dye, a
first PCR DNA polymerase, and a second digital PCR DNA polymerase.
(Id.)
The Examiner rejected the claims as follows:
Appeal 2019-004961
Application 15/559,054

4
Claims
Rejected 35 U.S.C. § Reference(s)/Basis Final Act.
1 103 Zhong,2 GenBank,3 An,4 SantaLucia5 8–11
2, 3 103 Zhong, GenBank, An, SantaLucia, Xu6 11–13

ANALYSIS
The Examiner finds Zhong teaches a composition for detecting
hepatitis B virus cccDNA using real-time PCR. (Final Office Action mailed
June 29, 2018 (“Final Act. 9”), citing Zhong 1906.) The composition
includes an upstream primer, a downstream primer, and a TaqMan probe
including a light-emitting group, e.g., 6-carboxyfluorescein (“FAM”), and a
fluorescent quencher, e.g., carboxytetramethylrhodamine (“TAMRA”). (Id.)
The Examiner finds Zhong teaches that the cccDNA-selective primers and
probe target the gap region between the viral genome’s direct repeat regions,
DR1 and DR2. (Id.) Specifically, the Examiner finds the primers consist of
sequences disclosed by GenBank Accession No. KJ843187 as follows: the

2 Zhong et al., Quantitation of HBV covalently dosed circular DNA in micro
formalin fixed paraffin-embedded liver tissue using rolling circle
amplification in combination with real-time PCR, 412 Clinica Chimica Acta
1905–1911 (2011).
3 M. M. Gonzalez Lopez Ledesma et al., Hepatitis B virus isolate Ag26,
complete genome, GenBank Accession No. KJ843187.1 (2014).
4 An et al., US 2003/0050470 A1, published March 13, 2003.
5 John SantaLucia, Jr., Physical Principles and Visual-OMP Software for
Optimal PCR Design, in Methods in Molecular Biology 3–33 (Anton
Yuryev ed. 2007).
6 Xu et al., CN 101397592 A, published April 1, 2009. Machine translation
made of record.
Appeal 2019-004961
Application 15/559,054

5
upstream cccDNA primer consists of nucleotides 1521–1538; the
downstream cccDNA primer consists of nucleotides 1884–1868; and the
cccDNA probe consists of nucleotides 1825–1845. (Id.)
The Examiner acknowledges that Zhong does not teach primers and a
probe with the claimed sequences. (Id.) However, the Examiner finds that
the claimed sequences were known in the prior art. (Id.) Particularly,
GenBank Accession No. KJ8437187 teaches the complete genome of
hepatitis B virus isolate Ag26, including sequences 100% identical to: SEQ
ID NO.1 at nucleotides 1559–1576, SEQ ID NO.2 at nucleotides 1881–
1864, and SEQ ID NO. 3 at nucleotides 1778–1800. (Id., citing GenBank.)
The Examiner finds that An teaches an algorithm for designing
various probes and primers based on disclosed nucleotides sequences. (Id. at
10, citing An ¶¶ 65–67.) The Examiner finds that “one of ordinary skill in
the art would have recognized that the principles of designing primers and
probes based on a disclosed nucleotide sequence would have applied to any
nucleotide sequence under study.” (Id.) The Examiner further finds that
SantaLucia teaches that an experienced molecular biologist would have a
reasonable expectation of success in “casually” designing primers and
probes for a PCR reaction. (Id. at 10–11, citing SantaLucia 14.) The
Examiner concludes it would have been obvious to a person of ordinary skill
in the art to use alternatives known sequences in Zhong’s detection
composition for cccDNA, as it was matter of routine practice to select
primer and probe sequences from known template sequences for amplifying
and detecting HBV cccDNA. (Id.)
Appeal 2019-004961
Application 15/559,054

6
Appellant contends that GenBank does not teach or suggest any
partial sequence that can be used as a primer or probe. (Br. 6.) Appellant
argues that the skilled artisan would “need to conduct undue experiments to
find suitable primers and probes” for detecting hepatitis B virus cccDNA.
(Id. at 6–7.) Appellant argues that An and SantaLucia do not provide any
guidance on the design of primers and probes for detecting hepatitis B virus.
(Id. at 7.) Appellant argues therefore, that the combined prior art does not
teach or suggest all of the elements of independent claims 1 and 2. (Id.)
We are not persuaded by Appellant’s argument with respect to the
scope of the prior art and the reasonable expectation of success. The
Examiner cites Zhong for teaching that hepatitis B virus cccDNA primers
and probes are designed by targeting the gap region between the two direct
repeat regions (DR1 and DR2) of the viral genome. (Zhong 1906.) Zhong
further teaches that the specificity and sensitivity of PCR quantitative
detection methods depend on “preferential amplification of cccDNA by
selective primers [] located on both sides of the gap of HBV relaxed circular
DNA (rcDNA).” (Id. at 1905.) Contrary to Appellant’s argument, the prior
art provides specific guidance on designing primers and probes for detecting
hepatitis B virus cccDNA. Following Zhong’s teachings, it would have been
obvious for a person skilled in the art to identify primers and probes in the
region of base pairs 1500–1870 as overlapping the gap and direct repeat
regions. “Obviousness does not require absolute predictability of success. . .
. [A]ll that is required is a reasonable expectation of success.” Medichem,
S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006). Because the
Appeal 2019-004961
Application 15/559,054

7
prior art establishes a reasonable expectation of success, we are not
persuaded that the Examiner erred.
Appellant also argues that “the claimed invention achieves superior
and unexpected results.” (Br. 8.) Specifically, Appellant asserts that Figure
5 of the Specification shows a detection level of 100 copies/μl and that “the
lower limit of detection of cccDNA could reach a single copy.” (Id.)
Appellant contends that “the dynamic detection range of cccDNA in Zhong
is 102 copies/ml to 1010 copies/ml.” (Id., citing Zhong 1908.) Appellant
asserts that the “sensitivity of the present invention is 10–100 times better”
than that of the prior art. (Id.)
The Examiner responds that Appellant’s Specification discloses “a
dynamic range of detection of HBV cccDNA at 105 copies/μL to 101
copies/μL using the instant primers and probe.” (Examiner’s Answer mailed
April 2, 2019 (“Ans.”) 12, citing Spec. ¶¶ 35, 90.) The Examiner finds that
this dynamic range, converted to copies/ml overlaps Zhong’s dynamic range.
(Id.) Likewise, the Examiner finds that converting the units of Figure 5 from
copies/μl to copies/ml results in a detection limit of 103 copies/ml, which
falls within Zhong’s dynamic range. (Id. at 13, citing Spec. ¶ 94.) Indeed,
the evidence shows that Zhong teaches a “credible lower limit of the
detection of HBV cccDNA was 0.01 copies/cell” (Zhong 1908).
We agree with the Examiner that Appellant’s evidence is not
probative of nonobviousness. “Unexpected results that are probative of
nonobviousness are those that are different in kind and not merely in degree
from the results of the prior art.” Galderma Labs., L.P. v. Tolmar, Inc., 737
F.3d 731, 739 (Fed. Cir. 2013) (internal citations omitted). “Results which
Appeal 2019-004961
Application 15/559,054

8
differ by percentages are differences in degree rather than kind, where the
modification of the percentage is within the capabilities of one skilled in the
art at the time.” (Id.) Appellant has not established that the allegedly
superior and unexpected results are different in kind. Therefore, we are not
persuaded of Examiner error.
Accordingly, we affirm the Examiner’s rejection of claim 1.
Appellant does not provide separate arguments for the rejection of the
dependent claims. (See Br. 7, 10.) Accordingly, we affirm the Examiner’s
rejection of claims 2 and 3 as being obvious under 35 U.S.C. § 103.

CONCLUSION
Upon consideration of the record and the reasons given, the rejection
of claims 1–3 is sustained.
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
1 103 Zhong, GenBank, An,
SantaLucia
1
2, 3 103 Zhong, GenBank, An,
SantaLucia, Xu
2, 3
Overall
Outcome
1–3

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