Steen H. Matthiesen

Patent Trials and Appeals Board

Feb 27, 2020

13513164 - (D) (P.T.A.B. Feb. 27, 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.
13/513,164 11/02/2012 Steen H. Matthiesen 09138.0123-00000 2515
22878 7590 02/27/2020
Agilent Technologies, Inc.
Global IP Operations
5301 Stevens Creek Blvd
Santa Clara, CA 95051
EXAMINER
CROW, ROBERT THOMAS
ART UNIT PAPER NUMBER
1634
NOTIFICATION DATE DELIVERY MODE
02/27/2020 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 STEEN H. MATTHIESEN
____________

Appeal 2018-006689
Application 13/513,164
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
RYAN H. FLAX, Administrative Patent Judges.

FLAX, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims to a method of hybridizing nucleic acid (or “n.a.”) sequences (or
“n.a.s”). Appellant appeals the Examiner’s rejection of claims 1, 2, 4–29,
35–39, 41–47, 50–58, and 62 under 35 U.S.C. § 103(a) and for obviousness-
type double patenting.1 We have jurisdiction under 35 U.S.C. § 6(b).
We affirm; however, we designate new grounds of rejection under
35 U.S.C. §§ 102(e) and 103(a), and for obviousness-type double patenting,
pursuant to our authority under 37 C.F.R. § 41.50(b).

1 “Appellant” herein refers to the “applicant” as defined by 37 C.F.R. § 1.42.
Appellant identifies “Agilent Technologies, Inc.,” as the real party-in-
interest. Appeal Br. 1.
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STATEMENT OF THE CASE
The application includes two independent claims, 1 and 2.
Independent claim 1, reproduced below, is representative:
1. A method of hybridizing nucleic acid sequences using
a denaturation step performed at or below 82°C or, without a
denaturation step comprising:
providing a first nucleic acid sequence within a cell in a
sample having a preserved cell morphology,
providing a second nucleic acid sequence,
providing a hybridization composition comprising an
effective amount of at least one polar aprotic solvent to enable
hybridization, and
combining the first nucleic acid sequence, the second
nucleic acid sequence, and the hybridization composition for at
least a time period sufficient to hybridize the first and second
nucleic acid sequences within the cell such that the first and
second nucleic acid sequences hybridize within the cell and the
sample morphology is preserved,
wherein the polar aprotic solvent is not dimethyl
sulfoxide;
with the proviso that the hybridization composition does
not contain formamide.
Appeal Br. 24 (Claims Appendix). Independent claim 2 is similar to claim
1, but requires the recited second n.a. sequence to be a part of the
hybridization composition applied to the first n.a. sequence, rather than
merely provided in the method, generally. Id. at 25.
The Specification states that:
The present invention also relates to compositions and methods
for eliminating the denaturation step from hybridization
applications. In one embodiment, the present invention can be
used for the in vivo, in vitro, and in situ molecular examination
of DNA and RNA. In particular, the invention can be used for
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the molecular examination of DNA and RNA in the fields of
cytology, histology, and molecular biology. In other
embodiments, the present invention can be sued [sic] for in situ
hybridization (ISH) applications.
Spec. 1:7–13. The Specification explains that “in situ hybridization (ISH),
includes hybridization to a target in a specimen wherein the specimen may
be in vivo, in situ, or for example, fixed or adhered to a glass slide.” Id. at
1:23–25. The Specification further explains that in such a process,
complementary strands of n.a.s must be separated in a step “termed
‘denaturation,’” which “typically requires aggressive conditions.” Id. at
2:4–5. The Specification states that traditionally in ISH assays, formamide
solutions are used to denature the n.a., but that formamide is a toxic,
hazardous material. Id. at 2:10–28. Denaturation, the Specification
explains, is followed by the “hybridization” step, which includes binding
primers or probes (n.a.s) to the target nucleic acid in the sample. Id. at 2:6–
9.
The Specification states that the invention overcomes, inter alia, the
drawbacks of traditional denaturation steps by reducing denaturation
temperature, eliminating or reducing the use of formamide, or eliminating
the denaturation step entirely. Id. at 3:11–13, 4:27–28. The key to this
objective is explained to be the use of at least one polar aprotic solvent in an
amount effective to denture double-stranded nucleotide sequences and
enable hybridization. Id. at 5:3–8. The Specification identifies as suitable
polar aprotic solvents γ-butyrolactone (GBL), sulfolane (SL), acetonitrile
(AN), glycol sulfite/ethylene sulfite (GS), ethylene carbonate (EC),
propylene carbonate (PC), ethylene thiocarbonate (ETC), ε-caprolactone,
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and N-methyl pyrrolidinone. Id. at 7:10–15, 16:21–17:13; see also id. at 18–
20 (Tables 2 and 3).
The Specification states that the polar aprotic solvent is a part of a
“[h]ybridization composition,” which it defines as “an aqueous solution of
the invention for performing a hybridization procedure, for example, to bind
a probe to a nucleic acid sequence,” and states the composition “may
comprise, e.g., at least one polar aprotic solvent, at least one nucleic acid
sequence, and a hybridization solution.” Id. at 12:18–23. The Specification
states that “‘[h]ybridization solution’ refers to an aqueous solution for use in
a hybridization composition of the invention . . . and may comprise, e.g.,
buffering agents, accelerating agents, chelating agents, salts, detergents, and
blocking agents.” Id. at 12:24–27.
The following rejections by the Examiner are on appeal:
A. Claims 1, 2, 5, 8–13, 15–23, 25–29, 35–38, 42–47, 55–58, and 62
stand rejected under 35 U.S.C. § 103(a) over Kim,2 Bischoff,3 Shimizu,4 and
Matthiesen.5 Answer 3.
B. Claims 4–8, 24, 50, and 51 stand rejected under 35 U.S.C.
§ 103(a) over Kim, Bischoff, and Gray.6 Answer 18.
C. Claim 14 stands rejected under 35 U.S.C. § 103(a) over Kim,
Bischoff, and Kalra.7 Answer 20.

2 US 5,750,340 (issued May 12, 1998) (“Kim”).
3 US 6,656,734 B1 (issued Dec. 2, 2003) (“Bischoff”).
4 US 2007/0166641 A1 (published July 19, 2007) (“Shimizu”).
5 US 2011/0281263 A1 (published Nov. 17, 2011) (“Matthiesen”).
6 US 6,475,720 B1 (issued Nov. 5, 2002) (“Gray”).
7 US 2003/0175852 A1 (published Sept. 18, 2003) (“Kalra”).
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D. Claims 29, 35–39, 41–43, 56–58, and 62 stand rejected under
35 U.S.C. § 103(a) over Kim, Bischoff, Bekki,8 and Matthiesen. Answer 21.
E. Claims 35–38 and 52–54 stand rejected under 35 U.S.C. § 103(a)
over Kim, Bischoff, Bresser,9 and Matthiesen. Answer 23.
F. Claims 29, 37, 38, and 62 stand rejected under 35 U.S.C. § 103(a)
over Kim, Bischoff, and Garcia.10 Answer 26.
G. Claims 52–54 stand rejected under 35 U.S.C. § 103(a) over Kim,
Bischoff, and Amorese.11 Answer 28.
H. Claim 62 stands rejected under 35 U.S.C. § 103(a) over Kim,
Bischoff, and Virtanen.12 Answer 30.
I. Claims 1, 2, 5, 8–13, 15–23, 25–29, 35–38, 42–47, 55–58, and 62
stand rejected on the ground of obviousness-type double patenting over
claims 49–52 of U.S. Patent No. 9,297,035 (“the ’035 patent”) and Bischoff
and Kim. Answer 33.
J. Claims 4–8, 24, 50, and 51 stand rejected on the ground of
obviousness-type double patenting over claims 49–52 of the ’035 patent and
Bischoff, Kim, and Gray. Answer 33.
K. Claim 14 stands rejected on the ground of obviousness-type
double patenting over claims 49–52 of the ’035 patent and Bischoff, Kim,
and Kalra. Answer 35.

8 WO 2007/037341 A1 (published Apr. 5, 2007), and English language
translated U.S. counterpart US 2009/0294305 A1 (published Dec. 3, 2009)
(the latter of which is cited to herein as “Bekki”).
9 US 5,521,061 (issued May 28, 1996) (“Bresser”).
10 US 2006/0030541 A1 (published Feb. 9, 2006) (“Garcia”).
11 US 2004/0241666 A1 (published Dec. 2, 2004) (“Amorese”).
12 US 5,718,915 (issued Feb. 17, 1998) (“Virtanen”).
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L. Claims 29, 35–39, 41–43, 56–58, and 62 stand rejected on the
ground of obviousness-type double patenting over claims 49–52 of the ’035
patent and Bischoff, Kim, Bekki, and Matthiesen. Answer 37.
M. Claims 35–38 and 52–54 stand rejected on the ground of
obviousness-type double patenting over claims 49–52 of the ’035 patent and
Bischoff, Kim, Bresser, and Matthiesen. Answer 38.
N. Claims 29, 37, 38, and 62 stand rejected on the ground of
obviousness-type double patenting over claims 49–52 of the ’035 patent and
Bischoff, Kim, and Garcia. Answer 41.
O. Claims 52–54 stand rejected on the ground of obviousness-type
double patenting over claims 49–52 of the ’035 patent and Bischoff, Kim,
and Amorese. Answer 42.
P. Claim 62 stands rejected on the ground of obviousness-type double
patenting over claims 49–52 of the ’035 patent and Bischoff, Kim, and
Virtanen. Answer 44.
Q. Claims 1, 2, 4–29, 35–39, 41–47, 50–58, and 62 stand rejected on
the ground of obviousness-type double patenting over claims 1–58 of U.S.
Patent No. 9,309,562 (“the ’562 patent”). Answer 45.
FINDINGS OF FACT
We generally agree with the Examiner’s findings of fact and rationale
for obviousness as set forth in the Final Action and Answer, as well as in the
Final Action. See Final Action 2–43; Answer 3–57. However, although the
Examiner cited Matthiesen in the prior art combination in the obviousness
rejection of independent claims 1 and 2 (see Answer 3), the Examiner did
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not discuss the reference substantively.13 Cf. id. at 16. Furthermore,
apparently at least partially for this reason, Appellant presents no substantive
arguments over Matthiesen, arguing only that the Office Action does not
explain how or why Matthiesen’s teachings would be combined with the
other cited prior art. Appeal Br. 18. Upon our review of the record, the
Examiner’s citation to, but failure to discuss Matthiesen in any depth is
puzzling, particularly in view of the complexity of rejections presented in
such absence of analysis. Thus, the following findings of fact (FF) highlight
certain evidence of record:
FF1. Matthiesen was published on November 17, 2011, from an
application filed May 27, 2009. Matthiesen, codes (43), (22).
Therefore, it is prior art to the Appellant’s claims, which have an
earliest possible priority date of December 2, 2009.
FF2. Matthiesen discloses that its
invention provides compositions and methods for the detection
of nucleic acid sequences associated with chromosomal
aberrations. The invention may, for example, eliminate the use
of or reduce the dependence on formamide in hybridization.
Compositions for use in the invention include an aqueous
composition comprising at least one nucleic acid sequence and
at least one polar aprotic solvent in an amount effective to
denature double-stranded nucleotide sequences.
Matthiesen, Abstract.
FF3. Matthiesen discloses its
invention relates generally to compositions and methods for
detecting chromosomal aberrations in vivo, in vitro, and in situ.
The present invention further relates to compositions comprising

13 Each of the Examiner’s § 103 rejections (and several of the obviousness-
type double patenting rejections) rely in some way on Matthiesen, either
directly or indirectly by claim dependency.
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molecular probes [n.a.s] for the detection of particular nucleotide
sequences (including normal sequences and those associated
with chromosomal aberrations and/or infectious disease) and
aqueous compositions comprising at least one polar aprotic
solvent in an amount sufficient to denature double-stranded
nucleotide sequence for use in hybridization, particularly for use
in in situ hybridization (ISH).
Matthiesen ¶ 1.
FF4. Matthiesen discloses its hybridization composition and
procedure is non-toxic. Matthiesen ¶ 15.
FF5. Matthiesen expressly discloses:
In one embodiment, the invention provides a method of
determining whether a chromosomal aberration is present in a
nucleic acid sequence, the method comprising:
providing a molecular probe that detects the chromosomal
aberration,
providing the nucleic acid sequence,
providing an aqueous composition comprising 1% (v/v) to
95% (v/v) of at least one polar aprotic solvent,
combining the molecular probe and the nucleic acid
sequence and the aqueous composition for at least a time period
sufficient to hybridize the molecular probe and the nucleic acid
sequence, and
determining whether the molecular probe has hybridized
to the nucleic acid sequence,
thereby determining whether the chromosomal aberration
is present in the nucleic acid sequence.
Matthiesen ¶¶ 168–174.
FF6. Further to the preceding finding of fact, Matthiesen also
discloses “an aqueous composition of the invention comprising at
least one polar aprotic solvent and a molecular probe that detects the
chromosomal aberration,” which is applied “to said nucleic acid
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sequence for at least a time period sufficient to hybridize the
molecular probe and nucleic acid sequence.” Matthiesen ¶ 182.
FF7. Matthiesen further discloses, “[i]n one embodiment, the
present invention relates to molecular probes for use in, e.g., the fields
of cytology.” Matthiesen ¶ 2. Matthiesen discloses that “[c]ytology
involves the examination of individual cells,” “fixed on [a]
microscope slide,” and “[c]ytological examination of a sample begins
with obtaining a specimen of cells” where a biological sample can be
“cell preparations . . . and isolated or enriched cell component
preparations,” treated “to preserve the tissue for later sample
analysis.” Id. ¶¶ 192–196. Matthiesen teaches that in this process,
nucleic acids of the specimen are denatured at 82°C. Id. ¶ 197.
Matthiesen teaches that hybridization in such a cytological process
occurs in situ, in the sample cells. Id. ¶¶ 201–203.
FF8. Matthiesen discloses “[t]he hybridization compositions and
methods of the invention may, for example, eliminate the use of, or
reduce the dependence on, formamide.” Matthiesen ¶ 43.
FF9. Matthiesen discloses using effective amounts of polar
aprotic solvents at 1% to about 95% in hybridization compositions for
denaturation of n.a.s. Matthiesen ¶¶ 43–45, 145.
FF10. Matthiesen discloses that its polar aprotic solvent can
include γ-butyrolactone (GBL), sulfolane (SL), acetonitrile (AN),
glycol sulfite/ethylene sulfite (GS), ethylene carbonate (EC),
propylene carbonate (PC), ethylene thiocarbonate (ETC),
s-caprolactone, and N-methylpyrrolidone, among many others.
Matthiesen ¶¶ 58, 124–126, Tables 2 and 3; see also id. ¶¶ 48–58, 68,
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114–127 (describing the properties and chemical structures of suitable
polar aprotic solvents).
FF11. Matthiesen teaches the polar aprotic solvent in its
hybridization composition can have a dispersion solubility parameter
between 17.7–22.0 MPa1/2, a polar solubility parameter between 13–
23 MPa1/2, and a hydrogen bonding solubility parameter between 3–13
MPa1/2. Matthiesen ¶¶ 120–122.
FF12. Matthiesen teaches that “[t]he polar aprotic solvents
specified in the present invention speed up this [denaturation and the
reannealing of the probe to target] process considerably and reduce
the harshness and toxicity of the hybridization conditions compared to
formamide.” Matthiesen ¶ 210.
FF13. Matthiesen teaches “the denaturation temperature is from
60 to 70° C., 70 to 80° C., 80 to 90° C. or 90 to 100° C., and . . . [i]n
other embodiments, the compositions of the invention will produce
strong signals when the denaturation temperature is 72, 82, or 92° C,”
and that the invention may allow for hybridization at room
temperature. Matthiesen ¶¶ 43, 213.
FF14. Matthiesen teaches its hybridization process takes less than
8 hours, under 30 minutes, and even under 5 minutes. Matthiesen
¶ 215.
FF15. Matthiesen teaches that its composition can exclude
DMSO. Matthiesen ¶ 127.
FF16. Matthiesen teaches that its composition can include
components such as buffering agents (e.g., 0–1200 mM NaCl and/or
0–200 mM phosphate buffer, 1–50 mM citric acid–pH of 5.0–8.0),
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accelerating agents (e.g., dextran sulfate at 1–80%), chelating agents,
salts, detergents, and blocking agents (e.g., denatured salmon sperm
DNA at 0.05–100 mg/mL). Matthiesen ¶¶ 130, 132, 135, 137, 140,
142.
FF17. Matthiesen teaches that its polar aprotic solvent may cause
the compositions of its invention to exist as one phase, to separate into
multi-phase systems under certain conditions, that some polar aprotic
solvents may exist in two phases at room temperature, and that phases
may be mixed. Matthiesen ¶¶ 150–151, 156.
FF18. Matthiesen is explicit that “[t]he compositions of the
invention can be varied in order to optimize results for a particular
application. For example, the concentration of polar aprotic solvent,
salt, accelerating agent, blocking agent, and hydrogen ions (i.e. pH)
may be varied in order to improve results for a particular application.”
Matthiesen ¶ 158.
FF19. Matthiesen teaches that, after its hybridization process,
sample tissues are intact and maintain good cell morphology.
Matthiesen ¶¶ 248, 260.
FF20. Matthiesen discloses that its sample nucleic acid can be
DNA or RNA, i.e., double or single stranded nucleic acid sequences.
Matthiesen ¶ 67.
FF21. Matthiesen discloses that its probe nucleic acid can be
DNA or RNA, i.e., double or single stranded nucleic acid sequences.
Matthiesen ¶ 81.
FF22. Matthiesen teaches that a heating (energy addition) step in
its hybridization process uses microwaves, hot baths, hot plates, heat
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wire, peltier element, induction heating, or heat lamps. Matthiesen
¶ 483.
FF23. Matthiesen discloses “the step of hybridizing includes the
steps of heating and cooling the hybridization composition, molecular
probe, and nucleic acid sequence.” Matthiesen ¶ 486.
DISCUSSION
I. LEGAL STANDARDS
Arguments made by Appellant in the Appeal Brief and properly
presented in the Reply Brief have been considered; arguments not so-
presented are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2017); see also Ex
parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (“Any
bases for asserting error, whether factual or legal, that are not raised in the
principal brief are waived.”).
“To anticipate a claim, a reference must disclose every element of the
challenged claim and enable one skilled in the art to make the anticipating
subject matter.” PPG Indus., Inc. v. Guardian Indus. Corp., 75 F.3d 1558,
1566 (Fed. Cir. 1996).
“The combination of familiar elements [or steps] according to known
methods is likely to be obvious when it does no more than yield predictable
results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). The test
for obviousness is “whether the teachings of the prior art, taken as a whole,
would have made obvious the claimed invention.” In re Gorman, 933 F.2d
982, 986 (Fed. Cir. 1991). “What matters is the objective reach of the claim.
If the claim extends to what is obvious, it is invalid under § 103.” KSR, 550
U.S. at 419.
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“[T]he law of obviousness-type double patenting looks to the law of
obviousness generally. As . . . explained in Amgen, ‘[t]his part of the
obviousness-type double patenting analysis is analogous to an obviousness
analysis under 35 U.S.C. § 103.’” AbbVie Inc. v. The Mathilda & Terrence
Kennedy Inst. of Rheumatology Trust, 764 F.3d 1366, 1378 (Fed. Cir. 2014)
(second alteration in original) (citing Amgen Inc. v. F. Hoffman-La Roche
Ltd., 580 F.3d 1340, 1661 (Fed. Cir. 2009); see also In re Braithwaite, 379
F.2d 594, 600 n.4 (CCPA 1967) (A nonstatutory double patenting rejection
is “analogous to the non-obviousness requirement of 35 U.S.C. 103,” except
that only the claims of, not the disclosure of, the reference patent underlying
the double patenting rejection is considered prior art.).
With these standards in mind and in view of the Findings of Facts set
forth above, we address the Examiner’s rejections and Appellant’s
arguments there-over.
II. ANTICIPATION AND/OR OBVIOUSNESS OF CLAIMS 1, 2, 4–29, 35–39, 41–
47, 50–58, AND 62 OVER MATTHIESEN
The Examiner developed an unnecessarily complicated series of
obviousness rejections (see supra Statement of the Case) rejecting the claims
primarily over Kim, Bischoff, Shimizu, and Matthiesen, adding Gray for the
certain claims, Kalra for another claim, Bekki for other claims, Bresser for
still other claims, Garcia for others, Amorese for still other claims, and,
finally, adding Virtanen for the final claim, totaling eight separate
obviousness rejections. See generally Answer. Such prior art combinations
may indeed support an obviousness rejection, but make for a prosecution
history that lacks clarity. As noted above, although citing and including it,
generally, in the prior art combinations, the Examiner wholly overlooked the
significance of Matthiesen. In the interest of clarifying the record, we will
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not overlook Matthiesen’s significance in view of the appealed claims. For
this reason, we set forth a new ground of rejection of claims 1, 2, 4–29, 35–
39, 41–47, 50–58, and 62 under (pre-AIA) 35 U.S.C. § 102(e) for
anticipation and/or § 103(a) for obviousness over Matthiesen. See FF1.
Independent claim 1 is set forth above and independent claim 2 is
discussed therewith. Matthiesen anticipates independent claims 1 and 2 in
that it discloses a hybridization method, performed with a denaturation step
at or below 82°C, including providing a first nucleic acid sequence in a cell
sample, the cell morphology being preserved, and hybridizing a second
nucleic acid sequence with the first using a hybridization composition
including an effective amount of a polar aprotic solvent (these components
can both be a part of a hybridization composition) within the cell (in an in
situ cytology process) where, again, cell morphology is preserved; no
DMSO is included in the process and no formamide is used in the process.
FF2–FF10, FF13, FF15, FF19.
Regarding the dependent claims, the subject matter of each is either
expressly disclosed by Matthiesen or would have been obvious in view of
Matthiesen’s express disclosure. These dependent claims are discussed
below.
Claim 4 requires the first nucleic acid sequence to be in a cytology
sample, which is disclosed by Matthiesen. FF7.
Claims 5–8 require various combinations of single and double
stranded n.a. sequences for the claimed first and second n.a. sequences. This
is taught by Matthiesen. FF20, FF21.
Claims 9–14 require providing enough energy, e.g., heating, during
the process to denature and hybridize the claimed nucleic acid sequences, in
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one or more steps, including by using, for example, a microwave. This is
taught by Matthiesen. FF7, FF13, FF22, FF23. The specific temperatures or
temperature ranges recited by claims 15–17 are also taught by Matthiesen.
FF13. Likewise, the claimed heating and cooling of claim 18 is also taught
by Matthiesen. FF23.
Claims 19–23 require certain time periods for the hybridizing to
occur, e.g., as few as 5 minutes. This is disclosed by Matthiesen. FF14.
Claim 24 requires adding a blocking step to the process of claim 1.
Matthiesen teaches this. FF16.
Claims 25–28 require certain amounts of the polar aprotic solvent in
the hybridization composition, e.g., as much as 95% and as little as 1%.
This is disclosed by Matthiesen. FF9.
Claim 29 requires that the polar aprotic solvent be non-toxic.
Matthiesen teaches this. FF4, FF10, FF12.
Claim 35 recites specific solubility and bonding characteristics of the
claimed polar aprotic solvent. These characteristics are disclosed by
Matthiesen. FF11.
Claims 36–39 and 41–43 require specific classes or types of polar
aprotic solvents. These claimed polar aprotic solvents are disclosed by
Matthiesen. FF10.
Claims 44–47 and 50–54 require additional components for the
hybridization composition, for example, buffering agents salts, accelerating
agents, chelating agents, detergents, and blocking agents, as well as specific
types thereof in certain concentrations or amounts. All of this is disclosed,
or at the least taught or suggested by Matthiesen. FF16, FF18 (any specific
amounts not disclosed by Matthiesen are taught thereby to be optimized).
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Claims 55–58 require the hybridization composition to be in single,
two, or mixed phases at room temperature. Matthiesen discloses this. FF17.
Finally, claim 62 mixes several of the limitations/steps discussed
above, for example, combining n.a.s in a cell, preserving cell morphology,
hybridizing (by combining the composition and n.a.s for sufficient time),
and heating and cooling the mixture. As discussed above, this is taught or
suggested by Matthiesen. See, e.g., FF5–FF7, FF13, FF14, FF19, FF23.
As set forth above, Matthiesen discloses within its four corners each
and every limitation and step of each claim on appeal, in the same fashion as
claimed. Thus, Matthiesen anticipates each claim. If, for any reason, it
should be considered that Matthiesen fails to explicitly disclose, or that the
skilled artisan would fail to at once envisage based on Matthiesen’s
disclosure, any limitation or step as set forth in the appealed claims, it is
apparent that such would be a mere obvious modification of Matthiesen’s
teachings, for example, by optimizing any parameters taught by Matthiesen,
which Matthiesen explicitly suggests. Therefore, we set forth a new ground
of rejection of claims 1, 2, 4–29, 35–39, 41–47, 50–58, and 62 under (pre-
AIA) 35 U.S.C. § 102(e) and/or § 103(a) for anticipation and/or obviousness
over Matthiesen.
As for the rejections appealed here, we address Appellant’s
arguments, as they are set forth in Appellant’s briefing, below.
Appellant argues that Kim and Bischoff would not have been
combined because Bischoff is non-analogous art as directed to cell
transfection using a polar aprotic solvent, which is very different from
hybridizing nucleic acids with such a solvent. Appeal Br. 8–11.
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In response, the Examiner argues that the claimed methods hybridize
nucleic acids inside cells (Examiner points to claim 62, however, this also
applies to claims 1 and 2, which recite that the nucleic acids “hybridize
within the cell”) and, therefore, Bischoff’s transfection is reasonably
pertinent to the claims, making the reference analogous to the claimed
invention. Answer 48. Examiner also argues that Bischoff’s transfection
with polar aprotic solvent is useful for allowing nucleic acids into cells,
which is required by Kim, making the two references analogous to one
another. Id. at 46–47.
Appellant’s arguments are not persuasive. Although we agree with
the Examiner’s position, Appellant’s argument is mooted by the new ground
of rejection set forth above.
Appellant also argues that Kim teaches away from the claimed
invention, which requires denaturation at or below 82°C (if it occurs), but
Kim discloses that upon testing the non-formamide solution (glycerol
solution) in denaturation at temperatures ranging from 80°C–115°C, Kim
reported that the range of 95°C–105°C was “most effective” and
temperatures lower than 85°C showed the fluorescence signals to be
“considerably diminished.” Appeal. Br. 12–14 (citing Kim 2:56–63, 9:61–
10:12). Based on this disclosure, Appellant contends:
No person of ordinary skill in the art would read Kim’s study of
denaturation temperature and believe that denaturing at or below
82°C without formamide was achievable. Nor would any person
believe that denaturing with Kim’s solutions could be optimized
by lowering the temperature since Kim established an optimal
temperature of 100°C (at least with respect to Kim’s solutions).
Id. at 14. Appellant further argues that such statements in Kim establish that
the skilled artisan would have no reasonable expectation of success in
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hybridizing n.a. sequences using a denaturation step at or below 82°C. Id. at
15.
In response, the Examiner points to Kim’s Example 2 as teaching a
denaturation step performed at 75°C. Answer 52 (citing Kim 6:10–15
(Example 2)). Appellant counter-argues that even in reading such disclosure
in Kim, the skilled artisan “would not believe that this was true, in light of
Kim’s many other passages stating that a denaturation temperature of
100°C±5°C should be used, and Kim’s experimental data showing that a
denaturation temperature below 85°C was ineffective.” Appeal Br. 15
(citing Kim 7:55–57, 11:31, 16:11–12).
Appellant’s arguments are not persuasive. Although we agree with
the Examiner’s position, Appellant’s argument is mooted by the new ground
of rejection set forth above.
Appellant argues Bekki does not teach using its polar aprotic solvent
in hybridizing n.a. sequences, but as a part of detecting analytes using
photocurrent (photoexciting sensitizing dye) and, further, Bekki’s methods
may result in destruction of cells rather than preserving sample morphology,
as claimed (Appellant states “Bekki is ambivalent” on this). Appeal Br. 17–
18. Appellant argues that this potential cell destroying method would lead a
skilled artisan to not substitute Bekki’s polar solvents in Kim’s hybridization
method and would foreclose a reasonable expectation of success in
preserving sample morphology if Bekki’s solvents were used. Id. at 18.
The Examiner responds that Bekki specifically teaches an n.a.
hybridization solution including cyclic ethylene carbonate and propylene
carbonate. Answer 54 (citing Bekki ¶ 72). Regarding Bekki’s disclosure of
destroying cells (at ¶ 80), the Examiner identifies that this disclosure of the
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reference is not related to hybridization or use of the polar aprotic solvent as
a hybridization solution, but to extracting n.a. from cells to provide an
analyte. Id.
Appellant’s arguments are not persuasive. Although we agree with
the Examiner’s position, Appellant’s argument is mooted by the new ground
of rejection set forth above.
Appellant argues that the claims require a hybridization composition
that does not contain formamide, but Bresser’s hybridization composition
includes 30% formamide. Appeal Br. 19 (citing Bresser 8:65–9:5). Thus,
Appellant argues, the skilled artisan would not arrive at the claimed
composition in view of Bresser’s taught solvents. Id.
In response, the Examiner argues the cited portions of Bresser discuss
using the claimed solvent as a permeation enhancer and as an additive, thus,
it would have been obvious to combine it with the compositions of Kim and
Bischoff for the same purpose. Answer 54–55 (citing Bresser Abstract,
Example 5).
Appellant’s arguments are not persuasive. Although we agree with
the Examiner’s position, Appellant’s argument is mooted by the new ground
of rejection set forth above.
Appellant argues that Garcia does not teach hybridizing an n.a. to
another in a cell, but rather introducing an n.a. into a cell using a synthetic
vector and a polar aprotic compound so that the n.a. is expressed. Appeal
Br. 19–20. Appellant appears to argue that this is, in essence, a teaching
away from the claimed hybridization.
The Examiner responds that Garcia is cited for teaching “the
functionally equivalent solvent or acetonitrile,” which provides the
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advantage of providing a high level of transfection. Answer 55 (citing
Garcia ¶ 93). The Examiner argues that, because of this functional
equivalence, it would be obvious to modify the other prior art to use the
solvent acetonitrile. Id.
Appellant’s arguments are not persuasive. Although we agree with
the Examiner’s position, Appellant’s argument is mooted by the new ground
of rejection set forth above.
Appellant argues Amorese requires the use of formamide, thus, the
skilled artisan would not arrive at the claimed invention using Amorese’s
solvents. Appeal Br. 20.
The Examiner responds that Amorese is cited for teaching alternative
pH and use of phosphate as a buffering agent, but, even were Amorese’s
teachings not relied upon, the claimed pH range would have been obvious
based on its close similarity to that taught by the other cited prior art or upon
routine optimization of the ranges taught by the other cited prior art.
Answer 55–56.
Appellant’s arguments are not persuasive. Although we agree with
the Examiner’s position, Appellant’s argument is mooted by the new ground
of rejection set forth above.
Appellant argues that Kim and Gray teach hybridization compositions
including formamide, while Virtanen teaches polar aprotic solvents, such as
acetonitrile to hybridize n.a.s outside a cell to generate supramolecules.
Appeal Br. 20. Appellant argues that, because Virtanen hybridizes outside a
cell, it would not be relied upon to arrive at the claimed invention or modify
the teachings of Bischoff and Kim. Id. at 20–21.
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The Examiner points out that Gray is not a part of the prior art
combination for the argued rejection (it was in the prior art combination
under Rejection B, discussed above). Answer 56. The Examiner further
responds that Kim has been identified as teaching solvents free of
formamide and Virtanen is relied upon for teaching the functionally
equivalent solvent acetonitrile. Id.
Appellant’s arguments are not persuasive. Although we agree with
the Examiner’s position, Appellant’s argument is mooted by the new ground
of rejection set forth above.
Although we discern no error in the Examiner’s determinations, which
we conclude presented a prima facie case for the claims’ obviousness over
the cited prior art combinations, we nonetheless find the Examiner’s
rejections overly complicated and confusing. However, as discussed above,
we have considered Appellant’s arguments over the rejections in their
entirety, but find them unpersuasive on the record on appeal.
III. OBVIOUSNESS-TYPE DOUBLE PATENTING
Under the doctrine of obviousness-type double patenting, the
Examiner set forth another eight rejections of Appellant’s claims over the
claims of the ’035 patent, in view of the teachings, again, of Kim, Bischoff,
Matthiesen, Gray, Kalra, Bekki, Bresser, Garcia, Amorese, and Virtanen,
and another rejection over claims of the ’562 patent individually.
Appellant does not expressly argue the eight double patenting
rejections over the ’035 patent on their merits, but only refers to the
arguments made over the obviousness rejections regarding the common,
cited prior art, stating that the office action is not specific in identifying
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which limitations are found in the claims of the ’035 patent and which are in
the other cited prior art. Appeal Br. 21.
As discussed above, the subject matter for which the various prior art
was cited can be found in Matthiesen, which, again, the Examiner generally
overlooked in his analysis. Although Matthiesen was cited in the
obviousness-type double patenting rejection as combined with the ’035
patent’s claims, for the same reasons set forth above, we herein substitute
Matthiesen’s teachings for the teachings of each of Kim, Bischoff, Gray,
Kalra, Bekki, Bresser, Garcia, Amorese, and Virtanen, and, therefore,
designate the affirmance of the obviousness rejection over the ’035 patent’s
claims as a new ground.
Similarly, regarding the rejection over the ’562 patent, Appellant
argues the office action is not specific as to how the claim limitations are
found in the ’562 patent’s claims or in the other cited prior art and does not
explain how the ’562 patent’s claims disclose or suggest the pending claims’
elements. Appeal Br. 22.
THE REJECTION OVER THE ’562 PATENT
We begin with a discussion of the rejection over the ’562 patent.
Claim 1 of the ’562 patent is reproduced below:
1. A method of hybridizing nucleic acid sequences
comprising:
providing a first nucleic acid sequence within a sample
having a preserved cell morphology, with a first composition
comprising at least one polar aprotic solvent in an amount
effective to denature a double-stranded nucleotide sequence
while preserving cell morphology, and at least 10% dextran
sulfate,
providing a second nucleic acid composition comprising a
second nucleic acid sequence and a second aqueous composition
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comprising at least one denaturing agent in an amount effective
to denature double-stranded nucleotide sequences, and
combining the first and the second nucleic acid sequence
compositions for at least a time period sufficient to hybridize the
first and second nucleic acid sequences such that the cell
morphology is preserved,
wherein the polar aprotic solvent is not dimethyl sulfoxide
(DMSO).
The ’562 patent 58:48–67. Claim 14 of the ’562 patent indirectly depends
from claim 1 and adds the requirement that the denaturing takes place
between 70–80°C. Id. at 60:5–7. Claim 34 of the ’562 patent also depends
from claim 1 and requires that the claimed composition does not contain
formamide. Id. at 60:57–58.
Based on this subject matter claimed in the ’562 patent as compared to
the steps of Appellant’s claims 1 and 2, we conclude the Examiner
established that the appealed claims would have been obvious over the
claims of the ’562 patent. As noted, the Appellant does not provide any
substantive argument over this rejection; we affirm the rejection.
THE REJECTION OVER THE ’035 PATENT
Turning next to the rejection over the ’035 patent, we find it similarly
cumbersome compared with the Examiner’s obviousness rejections
discussed above because it relies on various combinations of ten different
prior art references with the claims of the ’035 patent when Matthiesen alone
would have sufficed. Rather than simply affirming the Examiner’s eight
rejections over the ’035 patent in view of the various cited prior art
combinations, we set forth a new ground under the doctrine of obviousness-
type double patenting over the claims of the ’035 patent in view of
Matthiesen.
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Independent claim 1 of the ’035 patent is reproduced below:
1. A composition comprising:
(a) a first molecular probe that detects a nucleotide
sequence associated with a chromosomal aberration,
(b) at least one polar aprotic solvent in an amount effective
to denature double-stranded nucleotide sequences within a
sample having a preserved cell morphology, and
(c) a hybridization solution,
wherein the nucleotide sequence is a marker for a
chromosomal aberration,
wherein the polar aprotic solvent has lactone, sulfone,
sulfite, nitrile, and/or carbonate functionality, and
wherein the polar aprotic solvent has a cyclic base
structure.
The ’035 patent, 55:56–56:4. Further, the ’035 patent’s claim 29 requires
that the polar aprotic solvent be non-toxic; claim 30 requires that the
composition not contain formamide; and claim 33 requires the polar aprotic
solvent be selected from a list overlapping the solvents of appealed claims
38 and 43. Id. at 58:24–27, 58:63–59:8. This subject matter would have
rendered obvious the subject matter of appealed independent claims 1 and 2,
particularly in view of Matthiesen, as discussed above. See FF1–FF23.
Furthermore, the subject matter of each appealed dependent claim is taught
or suggested by Matthiesen, as discussed above. Id.; see also supra
Discussion, Section II. For these reasons, the appealed claims would have
been obvious over the claims of the ’035 patent in view of Matthiesen.
We appreciate that Matthiesen is the published version of the
application that issued as the ’035 patent and, therefore, shares the same
specification, and we acknowledge the general rule that an earlier patent’s
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specification is not available as prior art to show obviousness-type double
patenting. See Geneva Pharm., Inc. v. GlaxoSmithKline PLC, 349 F.3d
1373, 1385 (Fed. Cir. 2003). However, here, Matthiesen is also prior art
under 35 U.S.C. § 102(e), therefore, its specification can be consulted like
any other prior art reference in combination with the claims of the ’035
patent. See FF1.
CONCLUSION
In summary:
Claims
Rejected
35
U.S.C. §
Reference(s)
/Basis Affirmed Reversed
New
Ground
1, 2, 5, 8–
13, 15–23,
25–29, 35–
38, 42–47,
55–58, 62
103(a)
Kim,
Bischoff,
Shimizu,
Matthiesen
1, 2, 5, 8–
13, 15–23,
25–29, 35–
38, 42–47,
55–58, 62

4–8, 24,
50, 51 103(a)
Kim,
Bischoff,
Gray
4–8, 24,
50, 51
14 103(a)
Kim,
Bischoff,
Kalra
14
29, 35–39,
41–43, 56–
58, 62
103(a)
Kim,
Bischoff,
Bekki,
Matthiesen
29, 35–39,
41–43, 56–
58, 62

35–38, 52–
54 103(a)
Kim,
Bischoff,
Bresser,
Matthiesen
35–38, 52–
54
29, 37, 38,
62 103(a)
Kim,
Bischoff,
Garcia
29, 37, 38,
62
52–54 103(a)
Kim,
Bischoff,
Amorese
52–54
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Claims
Rejected
35
U.S.C. §
Reference(s)
/Basis Affirmed Reversed
New
Ground
62 103(a)
Kim,
Bischoff,
Virtanen
62
1, 2, 5, 8–
13, 15–23,
25–29, 35–
38, 42–47,
55–58, 62

Nonstatutory
Double
Patenting
1, 2, 5, 8–
13, 15–23,
25–29, 35–
38, 42–47,
55–58, 62

4–8, 24,
50, 51
Nonstatutory
Double
Patenting
4–8, 24,
50, 51
14
Nonstatutory
Double
Patenting
14
29, 35–39,
41–43, 56–
58, 62

Nonstatutory
Double
Patenting
29, 35–39,
41–43, 56–
58, 62

35–38, 52–
54
Nonstatutory
Double
Patenting
35–38, 52–
54
29, 37, 38,
62
Nonstatutory
Double
Patenting
29, 37, 38,
62
52–54
Nonstatutory
Double
Patenting
52–54
62
Nonstatutory
Double
Patenting
62
1, 2, 4–29,
35–39, 41–
47, 50–58,
62

Nonstatutory
Double
Patenting
1, 2, 4–29,
35–39, 41–
47, 50–58,
62

1, 2, 4–29,
35–39, 41–
47, 50–58,
62
102(e) Matthiesen
1, 2, 4–29,
35–39, 41–
47, 50–58,
62
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Claims
Rejected
35
U.S.C. §
Reference(s)
/Basis Affirmed Reversed
New
Ground
1, 2, 4–29,
35–39, 41–
47, 50–58,
62
103(a) Matthiesen
1, 2, 4–29,
35–39, 41–
47, 50–58,
62
1, 2, 4–29,
35–39, 41–
47, 50–58,
62

Nonstatutory
Double
Patenting

1, 2, 4–29,
35–39, 41–
47, 50–58,
62
Overall
Outcome
1, 2, 4–29,
35–39, 41–
47, 50–58,
62

1, 2, 4–29,
35–39, 41–
47, 50–58,
62

TIME PERIOD FOR RESPONSE
This Decision contains new grounds of rejection pursuant to 37 C.F.R.
§ 41.50(b), which provides, “[a] new ground of rejection pursuant to this
paragraph shall not be considered final for judicial review.” 37 C.F.R.
§ 41.50(b) also provides:
When the Board enters such a non-final decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
(1) Reopen prosecution. Submit an appropriate amend-
ment of the claims so rejected or new Evidence relating to the
claims so rejected, or both, and have the matter reconsidered by
the examiner, in which event the prosecution will be remanded
to the examiner. The new ground of rejection is binding upon
the examiner unless an amendment or new Evidence not
previously of Record is made which, in the opinion of the
examiner, overcomes the new ground of rejection designated in
the decision. Should the examiner reject the claims, appellant
may again appeal to the Board pursuant to this subpart.
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(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in MPEP § 1214.01.
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; 37 C.F.R. § 41.50(b)