Ex Parte 7670832 et al

Patent Trial and Appeal Board

Jun 22, 2015

90012369 (P.T.A.B. Jun. 22, 2015)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
90/012,369 06/21/2012 7670832 43387-225389 4718
67292 7590 06/29/2015
BARNES & THORNBURG LLP (Biofire)
11 SOUTH MERIDIAN STREET
INDIANAPOLIS, IN 46204
EXAMINER
TURNER, SHARON L
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
06/29/2015 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex Parte UNIVERSITY OF UTAH RESEARCH FOUNDATION
Patent Owner and Appellant
____________

Appeal 2015-000154
Reexamination Control 90/012,369
Patent U.S. 7,670,832 B2
Technology Center 3900
____________

Before ROMULO H. DELMENDO, RICHARD M. LEBOVITZ, and
JEFFREY B. ROBERTSON, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by Patent Owner from the Patent
Examiner’s final rejections of claims 1, 2, 4, 7–11, and 14–17 of US
7,670,832 B2 in this ex parte reexamination proceeding. The Board’s
jurisdiction for this appeal is under 35 U.S.C. §§ 6(b), 134(b), and 306. We
reverse.
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

2
I. STATEMENT OF CASE
This appeal involves US 7,670,832 B2 (“the ’832 patent”) which
issued March 2, 2010. The inventors are listed as Carl T. Wittwer and Kirk
M. Ririe. The real party in interest and patent assignee in this ex parte
reexamination proceeding is University of Utah Research Fundation (“Patent
Owner”). Appeal Br. 2.
A Request for Ex Parte Reexamination of the ‘832 patent was filed by
a Third Party Requester on June 21, 2012 in which reexamination of claims
1, 2, 4, 7–11, and 14 was requested. Claims 15–17 were added by
amendment. Reexamination of the ’832 patent culminated in a Final Office
Action rejecting claims 1, 2, 4, 7–11, and 14–17. Patent Owner appeals
from this determination.
An oral hearing was held May 27, 2015. A transcript of the hearing
will be entered into the record in due course.
Patent Owner informs us that the appeal (Appeal No. 2012-008405) in
Application 11/926,775, which is a divisional application of the ’832 Patent,
is a related appeal. Appeal Br. 3. In that appeal, this Board affirmed
rejections of different system claims based on different prior art evidence
relative to the current appeal. Ex parte Wittwer, http://e-
foia.uspto.gov/Foia/RetrievePdf?system=BPAI&flNm=fd2012008405-01-
26-2015-1.

Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

3
II. CLAIMS
Claims 1 and 11 are representative and read as follows (underlining
and brackets are relative to the original claims) (bold added to emphasize
disputed claim limitations)
Claim 1: A device for performing PCR and monitoring the
reaction of a sample comprising a nucleic acid and a
fluorescent dye comprising:
a reaction vessel with the sample therein, wherein the
sample further comprises a polymerase and a pair of primers
configured for amplifying a locus of the nucleic acid and
wherein the fluorescent dye in the sample provides a detectable
signal that can be used to generate a melting curve,
a heat exchange component for heating and cooling the
sample,
a control device programmed for repeatedly operating the
heat exchange component to subject the sample to thermal
cycling to generate an amplification product,
an excitation source for optically exciting the sample to
cause the sample to fluoresce, a photo detector for detecting
temperature-dependent fluorescence levels from the sample,
and
a processor programmed to generate [a] the melting
curve of the amplification product contained within the same
reaction vessel in which the amplifying takes place, [during or]
subsequent to amplification.

Claim 11: A device for performing PCR and monitoring the
reaction of a sample comprising a nucleic acid and a double-
stranded nucleic acid binding dye, wherein the dye provides a
detectable signal that can be used to generate a melting curve,
comprising:
a heat exchange component for heating and cooling the
sample,
a control device programmed for repeatedly operating the
heat exchange component to subject the sample to thermal
cycling,
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

4
an excitation source for optically exciting the sample to
cause the sample to fluoresce,
a photo detector for detecting temperature-dependent
fluorescence levels from the sample,
a processor programmed to generate the melting
curve during or subsequent to amplification, and
further comprising a reaction vessel with the sample
therein, wherein the sample further comprises a polymerase
and a pair of primers configured for amplifying a locus of the
nucleic acid and wherein the dye is operable to allow the
generating of the melting curve to occur within the reaction
vessel.

Each of the claims requires a processor programmed to generate a
“melting curve” of the nucleic amplification product in the reaction vessel.
A “melting curve” is described in the ’832 patent as follows: “Plotting
fluorescence as a function of temperature as the thermal cycler heats through
the dissociation temperature of the product gives a PCR product melting
curve.” ‘832 patent, col. 5, ll. 2–5. In other words, a melting curve shows
the change in fluorescence of the fluorescent dye as the double-stranded
nucleic acid denatures (“melts”) over a temperature range. The melting
curve can be used to differentiate amplification products since different
products will have different melting temperatures. Id. at col. 5, ll. 5–17.

III. ISSUE
The claimed reaction vessel requires the components for PCR
(polymerase and primers) and the components to generate a melting curve
(processor and fluorescent dye). Thus, to conclude the claimed subject
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

5
matter obvious, there must be a reason to have combined the PCR and
melting curve components in a single reaction vessel.

IV. REJECTIONS
There are two groups of rejections. One group involves Atwood and
the second group involves Bouma, each cited for the same teachings. The
rejections set forth by the Examiner are as follows:

Atwood
1. Claims 1, 2, 4, 7–9, 11, and 14 stand rejected under 35 U.S.C.
§ 103(a) as obvious in view of Atwood
1
and Hosoi.
2

2. Claim 10 stands rejected under 35 U.S.C. § 103(a) as obvious in
view of Atwood, Hosoi, and Johnson.
3

3. Claims 1, 2, 4, 7–9, 11, and 14 stand rejected under 35 U.S.C.
§ 103(a) as obvious in view of Atwood and Morrison.
4

4. Claim 10 stands rejected under 35 U.S.C. § 103(a) as obvious in
view of Atwood, Morrison, and Johnson.

Bouma
5. Claims 1, 2, 4, 7–9, 11, and 14 stand rejected under 35 U.S.C.
§ 103(a) as obvious in view of Bouma
5
and Hosoi.

1
John Atwood, US 5,766,889 (June 16, 1998).
2
Shigeru Hosoi et al., US 5,861,124 (January 19, 1999).
3
Larry Johnson, EP 0 236 069 A2 (Pub. May 2, 1997).
4
Larry E. Morrison et al., “Solution-Phase Detection of Polynucleotides
Using Interaction Fluorescent Labels and Competitive Hybridization” 183
Analytical Biochemestry 231 (1989).
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

6
6. Claim 10 stands rejected under 35 U.S.C. § 103(a) as obvious in
view of Bouma, Hosoi, Johnson.
7. Claims 1, 2, 4, 7–9, 11, and 14 stand rejected under 35 U.S.C.
§ 103(a) as obvious in view of Hosoi, Johnson, Morrison, Bouma, and Haff.
6

V. DISCUSSION
We address all the rejections together since they involve the same
issues and were argued together by Patent Owner. Appeal Br. 16, 26.

Rejection
Each of Atwood and Bouma is cited in the rejections for a teaching of
a device and method for determining the growth in concentration of a target
nucleic acid during PCR. Answer 5. The Examiner found that Atwood and
Bouma describe the claimed reaction vessel with each of its component
parts. Id. at 5–7. The Examiner also found that Atwood and Bouma
describe polymerase, primers, and a fluorescent dye as claimed. Id. The
Examiner acknowledged that neither Atwood nor Bouma describes “a
processor programmed to generate the melting curve of the amplification
product contained within the same reaction vessel in which the amplifying
takes place.” Id. at 7. For this feature, the Examiner cited Hosoi and
Morrison. Id. at 8–13.
The Examiner concluded that it would have been obvious to one of
ordinary skill in the art to “determine the melting (denaturation) temperature

5
Stanleu Bouma et al., US 5,585,242 (December 17, 1996).
6
Lawerence Haff et al., US 5,720,923 (Febuary 24, 1998).
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

7
of the amplified DNA products [of Atwood and Bouma] as taught in Hosoi
and Morrison” for the known advantages of melting curves, such as “for
distinguishing amongst various forms of double stranded DNA.” Id. at 11.
Additional publications were cited in Rejections 2, 4, 6, and 7, but these
were relied upon either for limitations in dependent claims or for
substantially the same teachings as in Atwood, Bouma, Hosoi, and
Morrison.
Claim 11
Claim 11 is directed to a device “for performing PCR and monitoring
the reaction of a sample comprising a nucleic acid and a double-stranded
nucleic acid binding dye, wherein the dye provides a detectable signal that
can be used to generate a melting curve.” Patent Owner contends that the
Examiner erred in her analysis because while some teachings existed in the
art that double-stranded (“ds”) nucleic acid binding dyes could be used to
generate melting curves, “the conditions believed to be necessary to generate
such melting curves are incompatible with PCR.” Appeal Br. 22.
To support this position, Patent Owner provided a declaration by a co-
inventor of the ’832 patent, Carl T. Wittwer, Ph.D. (“Wittwer Decl.”). Dr.
Wittwer testified that while the Henco patent
7
teaches that a dsDNA binding
dyes could produce a melting curve, the dsDNA binding dye would inhibit
PCR at the saturation amounts of the dye taught by Henco as necessary to
obtain a melting curve. Wittwer Decl. ¶¶ 8–10.
The Examiner responded:

7
Karsten Henco et al., US 5,871,908 (February 16, 1999).
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

8
while [Henco] does teach a simplified embodiment with the use
of such dyes under saturating conditions (which Wittwer
disparages), this single embodiment does not disparage the
alternate use of such dyes at low concentrations, including for
generating both growth and melting curves, see for example
Henco Fig. 10, 12:30-33, Higuchi 1992 and 1993. Notably,
Henco Figure 10 is a combination graph which shows both
growth curves (1–5) as well as melting curve analysis (6)
Answer 26.
The description of Figure 10 in Henco is as follows:
FIGS. 10a and 10b describe the schematic course of
temperature and the related single steps in the process
according to the invention. In FIG. 10a, the course of analysis
using the PCR technique is illustrated, in FIG. 10b, the course
of an amplification at homogenous Temperature (37° C), e.g.,
in the 3SR technique (see below), is given.
Henco, col. 10, ll. 25–31.
Both Figures 10a and 10b have a temperature gradient labeled “6” at
the end of the PCR reaction. Id. at col. 10, ll. 40–41.
Patent Owner argued that Henco teaches that the EtBr is placed “in a
separate compartment, to be added to the reaction mixture only after PCR
was complete. See, e.g., Henco, FIG. 1; col. 7, ll. 25–51.” Appeal Br. 23.
To decide whether a device would have been obvious in light of the
prior art, it must be determined whether, at the time of invention, “a person
of ordinary skill in the art would have had reason to attempt to make the . . .
device, . . . and would have had a reasonable expectation of success in doing
so.” PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360
(Fed. Cir. 2007). A preponderance of the evidence supports Patent Owner’s
position regarding the unpredictability and lack of an expectation of success
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

9
of using a dsDNA binding dye to produce a melting curve in a reaction
vessel in which PCR is accomplished.
The Examiner acknowledged that Henco describes saturating amounts
of a fluorescent dye when performing a temperature gradient analysis.
Answer 26; Henco, col. 12, ll. 45–53. The Examiner did not provide
evidence to dispute Mr. Wittwer’s testimony that saturating amounts of
EtBr, a double-stranded DNA fluorescent dye, inhibits PCR. However, the
Examiner points to Figure 10 and column 12, lines 30–33, of Henco to
support the contention that lower concentrations of EtBr can be used. This
evidence is not persuasive. Figures 10a and 10b do not reveal the amounts
of labeled probe utilized during the temperature gradient phase. Moreover,
as indicated in the passage quoted above, Henco refers to “labeled probe,”
which is not necessarily a dsDNA dye. Column 12, lines 30–33, of Henco
refers to low concentrations of a dye being used in its disclosed process, but
such disclosure does not explicitly state that the process includes melting
curve analysis. Moreover, such disclosure conflicts with Henco’s own
disclosure about the need for saturating amounts of dye when obtaining a
melting (denaturation) curve (col. 11, 45–59). Consequently, we do not
find that the evidence supports the Examiner’s conclusion that low amounts
of dsDNA dye, compatible with PCR, could be used in a reaction vessel with
polymerase, a pair of primers, where the dsDNA binding dye “provides a
detectable signal that can be used to generate a melting curve” as recited in
claim 11.
Accordingly, the rejections of claim 11, and claim 16 which depends
from it, are reversed.
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

10

Claim 14
Claim 14 is directed to a device for performing PCR and monitoring
the reaction of a sample comprising a nucleic acid and a fluorescent dye.
The claim requires a reaction vessel comprising primers, polymerase, and a
“nucleic acid probe labeled with the fluorescent dye to provide a detectable
signal that can be used to generate the melting curve.” The rejection is the
same as for claim 11. However, Hosoi and Morrison are cited for their
teaching of labeled probes to perform melting curve analysis. Answer 14,
32.
Patent Owner argued “the common belief in the art was that a
hybridizing labeled oligonucleotide could not be present during PCR and
subsequently be used to generate a signal for generating a melting curve.”
Appeal Br. 29. As evidence of this, Patent Owner identified four
publications which were said to teach that oligonucleotides, when included
with primers for PCR, would be degraded when PCR was carried out. Id. at
29–31. Based on these publications, Patent Owner stated these publications
“evidence the commonly-held belief (at the time of the present invention)
that such a system could not be used to generate a melting curve, since any
hybridizing probe is destroyed and, thus, would not be present for the
duration of the temperature transition required to establish a melting curve.”
Id. at 31.
The Examiner responded:
Appellant objects to this response arguing that the probe
is subsequently degraded. This is however of no matter to the
claims or for detection. All that is required is that the dye or
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

11
label be present during amplification. As pointed out, it may be
the distinction between degraded and un-degraded probe
fragments that is measured and detected, and thus such
hydrolyzed reagents are equally useful as would be recognized
in the art.
Answer 33.
The Examiner’s response is not supported by the weight of the
evidence. There must be a reason to have combined, in a reaction vessel,
polymerase, primers, and labeled nucleic acid probes for determining a
melting curve. Patent Owner cast doubt on the Examiner’s reasoning by
providing substantial evidence that the probes would be degraded and
therefore not useful for carrying out melting curve analysis. Appeal Br. 29–
31. The Examiner’s statement that only dye need be present in the reaction
vessel and that such degraded (hydrolyzed) reagents are useful ignores the
reason to put the probes into the reaction vessel: to produce a melting curve.
The Examiner did not explain how the probes, when degraded, would enable
melting curve analysis and why one of ordinary skill in the art would have
had reason to put such probes in the PCR mixture when their degradation
would have been expected. The Examiner did not otherwise undermine
Patent Owner’s evidentiary supported arguments.
Accodingly, the rejections of claim 14 are reversed.

Claims 1 and 17
Claims 1 and 17 are to the same device as in claims 11 and 14. The
reaction vessel with the primer and polymerase comprises fluorescent dye
that can be used to generate a melting curve, but the dye is not limited to a
Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

12
dsDNA nucleic acid binding dye as for claim 11 or a probe labeled with a
dye as for claim 14.
The Examiner maintains that the devices described in Hosoi and
Morrison would be capable of performing amplification and melting in the
same vessel as required by the claims. Answer 28–29. The Examiner makes
similar assertions for Atwood and Bouma. Id. However, the reaction
vessels must each contain the primer, polymerase, and fluorescent dye.
Thus, even if the device structures were known, the question is whether the
skilled worker would have added a fluorescent dye to determine a melting
curve to a vessel with PCR components. As discussed above, Patent Owner
provided evidence that skilled worker would not have added the fluorescent
dyes described in Hosoi, Morrison, and Henco to perform melting analysis
in a sample comprising polymerase and primers for PCR because it would
be unpredictable whether PCR would work under melting analysis
conditions or that fluorescently labeled primers used in melting analysis
would be compatible with PCR.
For the foregoing reason, the rejections of claims 1 and 17, and
dependent claims 2, 4, 7–10, and 15, are reversed.

VI. SUBSTANTIAL NEW QUESTION OF PATENTABILITY
Patent Owner contends that the cited publications do not present
substantial new questions of patentbility. Appeal Br. 11. Because we have
reversed all the rejections of all the appealed claims on the merits, it is
unnecessary for us to reach this issue.

Appeal 2015-000154
Reexamination Control 90/012,369
Patent 7,670,832

13
REVERSED

PATENT OWNER:

BARNES & THORNBURG LLP (BIOFIRE)
11 SOUTH MERIDIAN STREET
INDIANAPOLIS, IN 46204

THIRD PARTY REQUESTER:

2ND REEXAM GROUP - NOVAK DRUCE + QUIGG LLP
1000 LOUSIANA STREET
FIFTY-THIRD FLOOR
HOUSTON, TX 77002