Ex Parte Klunder et al

Patent Trial and Appeal Board

Jan 3, 2017

12999641 (P.T.A.B. Jan. 3, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/999,641 12/17/2010 Derk Jan Wilfred Klunder 2008P00726WOUS 7190
24737 7590 01/05/2017
PTTTT TPS TNTFT T FfTTTAT PROPFRTY fr STANDARDS
EXAMINER
465 Columbus Avenue HORLICK, KENNETH R
Suite 340
Valhalla, NY 10595 ART UNIT PAPER NUMBER
1637
NOTIFICATION DATE DELIVERY MODE
01/05/2017 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):
marianne. fox @ philips, com
debbie.henn @philips .com
patti. demichele @ Philips, com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DERK JAN WILFRED KLUNDER, ANKE PIERIK,
ALEKSEY KOLESNYCHENKO, MARIUS IOSIF BOAMFA,
and RICHARD JOSEPH MARINUS SCHROEDERS
Appeal 2016-000301
Application 12/999,641
Technology Center 1600
Before JEFFREY N. FREDMAN, ERICA A. FRANKLIN, and
ELIZABETH A. LaVIER, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving a method and
device for amplification and detection of target nucleic acid sequences. The
Examiner rejected the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
The thermal requirements of the PCR process and of the
surface hybridization process are very different. The PCR
amplification process requires (fast) temperature cycling
1 Appellants identify the Real Party in Interest as KONINKLIJKE PHILIPS
N. V. (see App. Br. 3).
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Application 12/999,641
wherein part of the cycle the sample is above the dsDNA
melting temperature. On the other hand the surface
hybridization needs to take place at a temperature below the
nucleic acid melting point....
The present multiple-zone concept allows decoupled
optimization of these two processes, i.e. the amplification and
the surface hybridization.
(Spec. 2:1-8).
The Claims
Claims 1—26 are on appeal. Claim 1 is representative and reads as
follows:
1. Method for amplification and detection of target nucleic
acid sequences in an amplification solution in a reaction
container, comprising the steps of
providing a reaction container comprising at least one
surface hybridization zone in which capture probes are
immobilized on a surface of a flow channel, wherein said
capture probes are substantially complementary to regions on
said target nucleic acid sequences;
adding the amplification solution to said reaction
container;
generating a temperature zone profile in the reaction
container with at least two kinds of thermally decoupled zones,
wherein one kind of zone is identical or at least overlapping
to/with the surface hybridization zones, wherein the surface
hybridization zones have a generated temperature allowing for
hybridization of the capture probes to the target nucleic acid
sequences;
performing an amplification of target nucleic acid
sequences in the reaction container; and
detecting amplified nucleic acid sequences in periodic or
defined intervals during and/or after amplification, wherein
amplified nucleic acid sequences are detected by hybridization
of capture probes to said amplified nucleic acid sequences in
said surface hybridization zone.
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Application 12/999,641
The Issue
The Examiner rejected claims 1—26 under 35 U.S.C. § 103(a) as
obvious over Zhang,2 Hashimoto,3 and Enzelberger4 (Ans. 2—3).
The Examiner finds Zhang and Hashimoto teach “continuous-flow
devices in which nucleic acid amplification and detection take place in
thermally-decoupled zones” (Ans. 3). The Examiner acknowledges that
Zhang and Hashimoto do not “disclose that capture probes in the surface
hybridization zone are immobilized within a flow channel” (id.).
The Examiner finds Enzelberger teaches “that within devices
comprising a plurality of temperature zones, for amplifying and detecting
nucleic acids, capture probes are immobilized within a flow channel” (id.).
The Examiner finds it obvious “to immobilize capture probes within a flow
channel in a hybridization temperature zone in the method/device of either
of Zhang et al. or Hashimoto et al. because this was taught by Enzelberger”
(id.).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that Zhang, Hashimoto, and
Enzelberger render the claims obvious?
2 Zhang et al., Miniaturized PCR chips for nucleic acid amplification and
analysis: latest advances and future trends, 35 Nucleic Acids Res. 4223—
4237 (2007) (“Zhang”).
3 Hashimoto et al., Polymerase chain reaction/ligase detection
reaction/hybridization assays using flow-through microfluidic devices for
the detection of low-abundant DNA point mutations, 24 Biosensors
Bioelectronics 1915—1923 (2006) (“Hashimoto”).
4 Enzelberger et al., US 6,960,437 B2, issued Nov. 1, 2005 (“Enzelberger”).
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Application 12/999,641
Findings of Fact
1. The Specification teaches that a “thermally decoupled zone in
the context of the present invention relates to a zone or a compartment of a
reaction container in which the temperature can be controlled, adjusted and
maintained essentially independently from other zones or compartments or
other kinds of zones or compartments of the reaction container” (Spec.
29:14—18).
2. The Specification teaches “zones of the same kind of zone may
be thermally coupled or alternatively in other embodiments be thermally
decoupled from each other, i.e. the temperature of zones of the same kind
may be controlled, adjusted and maintained conceitedly or independent from
each other” (Spec. 29:19-22).
3. The Specification teaches the “shape of the flow channel itself
is not relevant for the operation except that it determines the times that the
fluid experiences the temperature steps” (Spec. 24:26—28).
4. The Specification teaches “[i]t is not necessary to have
hybridization zones for each cycle” (Spec. 24:28—29).
5. Hashimoto teaches “development of a polymer flowthrough
biochip system. The PCR and LDR were operated in a continuous-flow
format, which allowed for microarray readout for the detection of low-
abundant mutations directly from an input of a small amount of genomic
DNA into the biochip” (Hashimoto 1917, col. 1).
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Application 12/999,641
6. Figure 2 of Hashimoto is reproduced below:
Zip code array
PCH mixture
(30 cycles) {13 cycles’
Armsaiing/extension
or
Annealing,6igat?on
{60 -'C!
Denaturing
(94 ;'C)
Art n eaitng/exte ns i on
, or
r Annealtnfl/ltoation
(60 Ai
PCR prcduct
. y-shsps nfesr ...
Fig. 2. Schematic representation of the CFPCR/CFLDR and zip
code array biochips. The total length of the thermal cycling
channel was 2.28m and consisted of a 30-cycle PCR (~ 1.57m
long) and a 13-cycle LDR (~0.71m long). The top inset
represents the PMMA zip code array microfluidic chip. The
bottom inset is an enlarged schematic of the Y-shaped passive
micromixer for mixing the PCR product with the LDR cocktail.
Three different Kapton film heaters were attached to the
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Application 12/999,641
appropriate positions on the CFPCR/CFLDR chip for providing
the required isothermal zones. Thermocouples were inserted
between the microchip cover plate and the film heaters for
monitoring the set temperatures.
(Hashimoto 1918).
7. Hashimoto teaches “[fjluid access channels (DNA sample and
wash buffers) were 100 pm in width and 50 pm in depth. Both channels
merged into one common channel and emptied into the hybridization
chamber, which measured 500 pm in width, 50 pm in depth, and 6.7mm in
length” (Hashimoto 1917, col. 2).
8. Hashimoto teaches
A syringe pump . . . was used to drive the PCR and the LDR
mixture at the same volumetric flow rate through the flow­
through biochip via capillary tubes. The resultant CFPCR
product was sequentially mixed with the LDR cocktail via a Y-
shaped passive micromixer depicted in the bottom inset of Fig.
2. . . . The arrangement of temperature zones on the
microchannel (95 °C for denaturing and 60 °C for
annealing/extension (PCR) and annealing/ligation (LDR)) is
depicted in Fig. 2. The resultant LDR products were directly
pumped into the hybridization chamber and subjected to
hybridization to the surface-tethered zip code probes at 55 °C.
The hybridization chamber was flushed with a wash buffer (2x
SSPE-0.1% SDS) following introduction of the LDR cocktail
and then, imaged with the near-IR laser-induced fluorescence
scanner.
(Hashimoto 1919, col. 2).
9. Enzelberger teaches
detection is facilitated by immobilizing one or more nucleic
acids to a region of a flow channel or reaction chamber. Such
nucleic acids can serve as probes to bind selected amplification
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Application 12/999,641
products, for example. By spatially depositing the nucleic acids
in known locations, the presence or absence of particular target
nucleic acids can be ascertained according to the location at
which a target nucleic acid binds to the array of nucleic acids.
(Enzelberger 5:46—54).
10. Enzelberger teaches “[i]f a very high degree of temperature
control is required (e.g., for studies conducted to optimize reaction
conditions), the devices can be manufactured such that the temperature at
each junction can be separately regulated” (Enzelberger 19:51—54).
11. Enzelberger teaches
nucleic acids are deposited within a flow channel or array
junction to function as probes that hybridize to complementary
target nucleic acids that are present within the flow channel or
junctions (e.g., nucleic acid extension or amplification products
that are formed). Binding between a probe and target nucleic
acid can be detected by a variety of methods known in the art.
In some instances, the nucleic acid probes are deposited to form
a type of nucleic acid microarray within a flow channel or
junction. By depositing the nucleic acid probes in certain
patterns, detection of the absence or presence of a particular
target nucleic acid can be readily ascertained spatially, i.e,
according to the location on the microarray at which a signal is
generated.
(Enzelberger 37:1—14).
12. Zhang teaches “[wjith the advent of microfabrication
techniques, the miniaturization of the DNA probe detection has proven to be
feasible, and both DNA hybridization and PCR amplification can be
incorporated on a single chip to directly detect the PCR products” (Zhang
4232, col. 2).
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13. Zhang teaches the “coupling of functional biochip and
informational biochip not only allows functional operations such as sample
preparation and PCR amplification by controlling the biological microfluids,
but also provides information on the amount, sequence and even DNA/RNA
target source through DNA hybridization microarrays” (Zhang 4233, col. 1).
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Analysis
We begin with claim interpretation because before a claim is properly
interpreted, its scope cannot be compared to the prior art. Claim 1 recites
“generating a temperature zone profile in the reaction container with at least
two kinds of thermally decoupled zones.” The Specification explains that
“thermally decoupled” “relates to a zone ... in which the temperature can
be controlled . . . independently from other zones” (FF 1). Thus, this
limitation of claim 1 simply requires at least two different temperature
regions in a reaction device.
Claim 1 further requires “wherein one kind of zone is identical or at
least overlapping to/with the surface hybridization zones.” The
Specification teaches “the temperature of zones of the same kind may be
controlled . . . conceitedly or independent from each other” (FF 2). Thus,
we interpret this limitation as requiring that one of the amplification zones
share some aspect with the hybridization zone such as similar temperature.
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Hashimoto teaches a method of polymerase chain reaction
amplification (FF 5) comprising: (a) providing a surface hybridization zone
with immobilized capture probes complementary to target nucleic acid
sequences, here represented by the PMMA zip code array microfluidic chip
(FF 6); (b) adding amplification solution to a reaction container, here
represented by the pump that “was used to drive the PCR and the LDR
mixture at the same volumetric flow rate through the flow-through biochip”
(FF 8); (c) generating a temperature profile with two kinds of thermally
decoupled zones, wherein one kind is identical or overlapping with the
surface hybridization zones, here represented by figure 2 of Hashimoto
teaching two annealing zones at 60 °C, a denaturing zone at 94 °C, and
teaching that the zip code array zone was similar in temperature to the
annealing zone with a temperature of 55 °C (FF 6, 8); (d) performing an
amplification of target nucleic acids (FF 6); and e) detecting amplified
nucleic acid sequences after amplification by hybridization of capture probes
to said amplified nucleic acid sequences, here performed on the zip code
array chip (FF 6, 8).
As the Examiner notes, and Appellants contend “Hashimoto fails to
disclose a method wherein a reaction container in which an amplification of
a target nucleic acid is performed includes ‘capture probes immobilized on a
surface of a flow channel’ wherein the capture probes are ‘substantially
complementary to regions on the target nucleic acid sequences’” (App. Br.
12; cf. Ans. 3).
We do not find this argument persuasive because the Examiner does
not rely upon Hashimoto alone but rather relies upon Enzelberger’s teaching
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that “nucleic acids can also be immobilized within the flow channels of the
devices. Usually the nucleic acids are immobilized with a temperature zone
or region at which reaction occurs” (FF 10). Thus, Enzelberger evidences
that the ordinary artisan would have found it obvious to modify Hashimoto’s
device by placing capture probes within the flow channels of the device.
In particular, Enzelberger teaches placing capture probes such as those
of Hashimoto into flow channels, teaching “nucleic acid probes are
deposited to form a type of nucleic acid microarray within a flow channel or
junction. By depositing the nucleic acid probes in certain patterns, detection
of the absence or presence of a particular target nucleic acid can be readily
ascertained spatially” (FF 11).
Appellants contend “the hybridization in Hashimoto is not performed
in the same reaction container as the amplification of the target nucleic acid
sequences” (App. Br. 12). Appellants also contend “[tjhere is no disclosure
in Hashimoto that the microchip where the PCR and LDL reactions are
performed contains a thermally decoupled surface hybridization zone which
allows for hybridization of the capture probes to the target nucleic acid
sequences” (App. Br. 12—13).
We do not find this argument persuasive because Hashimoto teaches
multiple thermally decoupled zones on the PCR/LDR chip as shown in
figure 2 (FF 6) and Hashimoto further teaches that the temperature of the
PMMA zip code hybridization chip is similar to the annealing temperature
on the amplification chip (FF 8). While we agree that Hashimoto does not
teach placement of the amplification and hybridization on a single chip,
Enzelberger teaches hybridization detection in flow channels (FF 11) and
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Zhang teaches “both DNA hybridization and PCR amplification can be
incorporated on a single chip to directly detect the PCR products” (FF 12).
Zhang provides reasons for the combination of amplification and
hybridization onto a single chip, teaching “coupling of functional biochip
and informational biochip not only allows functional operations such as
sample preparation and PCR amplification by controlling the biological
microfluids, but also provides information on the amount, sequence and
even DNA/RNA target source through DNA hybridization microarrays” (FF
13). Thus, the ordinary artisan would have had reason to form a single chip
with multiple temperature zones as taught by Hashimoto with hybridization
detection in the flow channels as taught by Enzelberger for the reasons given
by Zhang.
We recognize, but find unpersuasive, Appellants’ contention that the
“probes on the zip code array in the Hashimoto method do not have
substantially complementary regions to the target nucleic acid sequences”
(App. Br. 13). Enzelberger evidences that the use of probes complementary
to target nucleic acids was well known prior to Appellants’ invention (FF
11) and that the ordinary artisan would have recognized that selection of zip
code probes or specific target complementary probes represents a selection
between two well-known alternative methods of detecting amplified nucleic
acids.
Appellants also separately address the teachings of Zhang and
Enzelberger (App. Br. 13—14). However, “[n]on-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references.” In re Merck & Co., 800
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F.2d 1091, 1097 (Fed. Cir. 1986). A reference “must be read, not in
isolation, but for what it fairly teaches in combination with the prior art as a
whole.” Id. Hashimoto, Zhang, and Enzelberger, together, render obvious
the method and device of claims 1 and 13 for the reasons already given.
Appellants specifically contend that “Enzelberger fails to teach or
suggest the generation of a surface hybridization zone having a temperature
that allows for hybridization of the capture probes to the target nucleic acid
sequences within the reaction container whatsoever” (App. Br. 15).
We find this argument unpersuasive both on the facts in Enzelberger
itself and in relation to the combination with Hashimoto and Zhang.
Enzelberger teaches “nucleic acids are deposited within a flow channel or
array junction to function as probes that hybridize to complementary target
nucleic acids” (FF 11). This teaching specifically suggests hybridization
within the flow channel which is itself part of the reaction container.
Moreover, combination of these elements onto a single chip, as suggested by
Zhang (FF 12—13), reasonably renders this element obvious.
Appellants contend that the “provision of a reaction container having
at least one surface hybridization zone having a temperature allowing for
hybridization of the capture probes to the target nucleic acid sequence is not
a routine optimization or obvious improvement over the cited references”
(App. Br. 16).
We find this argument unpersuasive because Hashimoto already
teaches a reaction container that allows different temperatures for different
zones as shown in figure 2 (FF 6). The ordinary artisan, in forming a single
chip as suggested by Zhang (FF 12—13), would have reasonably recognized
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that the hybridization zone in the flow channels taught by Enzelberger could
be optimized because Enzelberger teaches “[i]f a very high degree of
temperature control is required (e.g., for studies conducted to optimize
reaction conditions), the devices can be manufactured such that the
temperature at each junction can be separately regulated” (FF 10). Thus,
temperature is recognized as a variable that would be optimized to obtain the
best possible reaction conditions.
We recognize, but find unpersuasive, Appellants’ contention that
“these features provides significant advantages over the prior art, including
allowing conditions for hybridization and detection to be adjusted
independently from the amplification process, increased flexibility of the
method and increased accuracy in the detection step” (App. Br. 17).
Appellants do not identify any comparative data showing an unexpected
benefit or otherwise supporting a secondary consideration that rebuts the
Examiner’s obviousness analysis. See In re Geisler, 116 F.3d 1465, 1470
(Fed. Cir. 1997) (“[Ajttomey argument [is] not the kind of factual evidence
that is required to rebut a prima facie case of obviousness”).
Appellants separately list claims 13—21 and claims 22—23, but contend
“reasons stated with respect to the method of independent claim 1, Zhang,
Hashimoto and Enzelberger taken singly or in combination fail to teach or
suggest the device of claim 13 or dependent claims 14—21” (App. Br. 18; cf.
App. Br. 19).
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Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
combination of Zhang, Hashimoto, and Enzelberger renders the claims
obvious.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over Zhang, Hashimoto, and Enzelberger. Claims 2—26
fall with claim 1.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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