Ex Parte KRUK

Patent Trial and Appeal Board

Mar 17, 2016

13205095 (P.T.A.B. Mar. 17, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/205,095 08/08/2011
23557 7590 03/21/2016
SALIW ANCHIK, LLOYD & EISENSCHENK
A PROFESSIONAL ASSOCIATION
PO Box 142950
GAINESVILLE, FL 32614
FIRST NAMED INVENTOR
Patricia A. KRUK
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
USF.254XCD1 1261
EXAMINER
YAO, LEI
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
03/21/2016 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):
euspto@slepatents.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PATRICIA A. KRUK1
Appeal2013-007633
Application 13/205,095
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a device
for detecting Bcl-2 in a urine sample, which have been rejected as obvious.
We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
The Specification states that the "invention relates to cancer
screening. Bcl-2 constitutes a biomarker for prognosis, diagnosis, and
monitoring of cancer, such as reproductive cancer." (Spec. 4: 11-13.)
1 Appellant identifies the Real Party in Interest as the University of South
Florida. (Appeal Br. 1.)
Appeal2013-007633
Application 13/205,095
Claims 1, 3-10, and 14 are on appeal. Claim 1 is illustrative and
reads as follows:
1. A device for the rapid detection of Bcl-2 in a sample of urine,
comprising an application zone for receiving a urine sample; a labeling zone
containing a binding agent that binds to Bcl-2 in the sample; and a detection
zone where Bcl-2-bound binding agent is retained to give a signal, wherein
the device is configured such that the signal given for a sample from a
subject with a Bcl-2 level no greater than a threshold concentration is
different from the signal given for a sample from a subject with a Bcl-2 level
greater than a threshold concentration, wherein said threshold concentration
is between 0 ng/ml and 2.0 ng/ml.
The claims stand rejected under 35 U.S.C. § 103(a) as follows:
Claims 1, 3-5, 7-10, and 14 based on Ly,2 Johnson, 3 and either of
Zymed4 or Bender5 (Ans. 3); and
Claims 1, 3-10, and 14 based on any one of de Zoeten,6 Remington,7
or Goodell,8 combined with Johnson and either of Zymed or Bender (Ans.
h.__ '7\
V I}•
2 Ly et al., US 2006/0078986 Al, published Apr. 13, 2006.
3 Johnson et al., Screening plasma and urine from women with ovarian
disease for Bcl-2, survivin and telomerase, 45 PROC. AMER. Assoc. CANCER
RES., abstract #1339 (2004).
4 Zymed Laboratories, Zymed Bcl-2 ELISA Kit (2005).
5 Bender, Product Information and Manual human Bcl-2 ELISA, Bender
MedSystems 1-32 (2005).
6 de Zoeten et al., US 5,611,995, issued Mar. 18, 1997.
7 Remington et al., US 2004/0002168 Al, published Jan. 1, 2004.
8 Goodell et al., US 2002/0098512 Al, published July 25, 2002.
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Application 13/205,095
Issue
I
The Examiner has rejected claims 1, 3-5, 7-10, and 14 as obvious
based on Ly, Johnson, and either of Zymed or Bender. The Examiner finds
that Ly discloses a device for detecting a specific protein, in a sample that
can be urine, which includes the application zone, labeling zone, and
detection zone recited in claim 1. (Ans. 5.) The Examiner finds that
Johnson discloses detecting Bcl-2 in urine samples from patients with
ovarian cancer, Zymed discloses an immunoassay (ELISA) kit for detecting
Bcl-2, and Bender discloses an ELISA that detects Bcl-2 in amounts as low
as 0.5 ng/ml. (Id. at 5-6.)
The Examiner concludes that it would have been obvious to modify
Ly's device to include the anti-Bcl-2 antibodies taught by Zymed or Bender,
motivated by Johnson's teaching of detecting Bcl-2 in urine for non-invasive
detection of ovarian cancer. (Id. at 6.)
Appellant contends that the cited references do not teach and would
not have suggested the threshold concentration recited in claim 1. (Appeal
Br. 2-5.) Appellant also contends that she has presented evidence of
unexpected results. (Id. at 5---6.)
The issues with respect to this rejection are (1) whether a device
meeting the limitations of claim 1 would have been prima facie obvious
based on the cited references, and (2) whether Appellant has provided
evidence of unexpected results that, when weighed with the evidence
favoring obviousness, shows that the claimed device would have been
nonobvious.
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Application 13/205,095
Findings of Fact
1. Ly discloses "analytical devices and methods for performing an
assay to determine the presence or approximate quantity of at least one
analyte in a liquid sample." (Ly 1 i-f 8.)
2. Ly's Figure 7A is reproduced below:
Absorbent
Sample application site
(sample entry port)
Immohiliz.·e-0
capwre A.bi
I \
Porous material \\
\ ,, ,,
'-·,,~Label (biotin
coupled latex beads) Tag (Ab~-Avidm
conjug:ate)
Figure 7 A shows a cross-section of one embodiment of Ly's invention
that includes a non-enzymatic label and a tagging zone. (Id. at 4 i-f 34.)
3. Ly states that the device of Figure 7 A includes a sample
application site where a sample is applied, a non-enzymatic label (biotin-
labeled colored beads) located in a secondary flow path, a tagging zone that
includes antibody to the analyte of interest (Ab2) conjugated to avidin, and
immobilized capture antibodies (Ab1) that capture antibody-bound, avidin-
labeled analyte, which produces a visually detectable signal when contacted
with the biotin-coupled beads. (Id. at 4, i-fi-134--35.)
4. Ly states that the materials used for its device are selected to be
compatible "without undesired interference by components within a bodily
fluid sample containing the analyte( s) of interest such as whole blood, whole
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Application 13/205,095
blood-derived specimens (e.g., plasma or serum), urine," etc. (Id. at 12
ii 101.)
5. Johnson "report[s] on the differential expression and detection of
survivin, Bcl-2, and telomerase in the urine of women with benign and
ovarian cancer compared to healthy controls." (Johnson 1.)
6. Johnson states that "twice the number of cancer patients had
detectable Bcl-2 levels in their plasma than that of normal or benign disease
patients. Further, greater than 53% of cancer patients had detectable levels
of Bcl-2 in their urine, compared to 7% and 23% in urine from normal and
benign disease patients, respectively." (Id.)
7. Zymed discloses the "Zymed® Bcl-2 ELISA Kit ... an enzyme-
linked immunosorbent sandwich assay for the quantitative detection of
human Bcl-2 in cell lysates, supematants, whole blood, and serum." (Zymed
1.)
8. Zymed states that "Bcl-2 protein plays a critical role in
oncogenesis and resistance to cancer therapy." (Id.)
9. Zymed states that
prognostic significance of Bcl-2 expression has been shown for
several malignancies such as Non-Hodgkin's Lymphoma,
squamous cell carcinomas, breast carcinoma, gallbladder
carcinoma, and thymoma. Deregulated Bcl-2 expression has
been shown in Multiple Myeloma patients and in acute myeloid
leukemia (AML). Bcl-2 has been suggested as a useful marker
for adequate IL-2 therapy in AIDS patients.
(Id., reference citations omitted.)
10. Bender discloses an "enzyme-linked immunosorbent assay for
quantitative detection of human Bcl-2." Bender 2.
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Application 13/205,095
11. Bender shows that "[t]ypical data using the Bcl-2 ELISA" for
samples containing 0.5 ng/ml Bcl-2 provides a mean optical density (O.D.)
reading of0.058, compared to 0.018 for a blank lacking Bcl-2. (Id. at 21.)
12. Bender states that "[t]he limit of detection of Bcl-2 ... was
determined to be less than 0,5 ng/ml." (Id. at 23.)
Analysis
Claim 1 is directed to a "device for the rapid detection of Bcl-2 in a
sample of urine." "[A] claim preamble has the import that the claim as a
whole suggests for it." Bell Commc 'ns Research Inc. v. Vitalink Commc 'ns
Corp., 55 F.3d 615, 620 (Fed. Cir. 1995). In this case, the preamble of claim
1 states that the device is intended for use in detecting Bcl-2 in a urine
sample, and therefore requires that the device be capable of being used with
a urine sample.
Claim 1 also states that the device comprises three specific zones and
is configured so that a sample with a Bcl-2 level below a threshold gives a
signal different from that of a sample with a Bcl-2 level above the threshold,
where the threshold is in the range of 0-2.0 ng/ml.
Ly discloses a device for detecting an analyte in a liquid sample
(FFl), which can be urine (FF4). Ly's device includes a sample application
site for receiving a sample (FF3), a labeling zone ("Tag") that contains an
analyte-binding agent (Ab2) conjugated to avidin (FF3), and a detection zone
("capture") where analyte-Ab2-avidin complex is retained by capture
antibody Ab1 and gives a detectable signal when exposed to biotin-coupled
colored beads (FF3). Ly's device therefore includes each of the three zones
recited in claim 1 on appeal, albeit not specifically for detecting Bcl-2.
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Application 13/205,095
Johnson discloses that least twice as many patients with ovarian
cancer had detectable levels of Bcl-2 in their plasma or urine, as compared
to normal patients or patients with benign disease (FF6). Both Zymed and
Bender disclose immunoassays for detecting Bcl-2 (FF7, FFlO). Zymed
states that Bcl-2 expression has been shown to have prognostic significance
for a number of different cancers (FF9). Bender discloses that its
immunoassay can detect Bcl-2 at a level of less than 0.5 ng/ml (FF12).
We agree with the Examiner that, based on these disclosures, it would
have been obvious to modify Ly's device to include Bcl-2-specific
antibodies, as taught by Zymed or Bender, with the expectation of achieving
a device capable of detecting Bcl-2 at a level of 0.5 ng/ml. A skilled artisan
would have had a reason to make this modification based on Johnson's
disclosure that a detectable level of Bcl-2 in plasma or urine indicates a
higher likelihood of the patient having ovarian cancer, as well as Zymed's
disclosure that Bcl-2 has prognostic significance in a number of cancers.
Appellant argues that the cited references do not suggest any threshold
concentration for Bcl-2. (Appeal Br. 2-5.) Appellant argues that "a skilled
artisan would have had no reason or motivation to select a target threshold
concentration between 0 ng/ml and 2.0 ng/ml out of the standard ranges of
32-0.5 ng/ml" disclosed by Bender. (Id. at 5.)
This argument is not persuasive because claim 1 is directed to a
device, not a method. "[A]pparatus claims cover what a device is, not what
a device does." Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d
1464, 1468 (Fed. Cir. 1990). As long as the prior art would have made
obvious the structural limitations of the device of claim 1, it need not
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Application 13/205,095
suggest using the claimed device in a particular way in order to make the
device itself obvious, and therefore unpatentable.
The "threshold" limitation of claim 1 requires that the device is
configured so as to provide a different signal for a sample with a Bcl-2
concentration below a threshold than for a sample with a Bcl-2 concentration
above a threshold, where the threshold is between 0 ng/ml and 2.0 ng/ml.
The antibodies used in Bender's immunoassay provide the recited function,
since the assay provides increasing optical density (O.D.) readings for
samples with increasing Bcl-2 concentrations; e.g., 0.058 at a Bcl-2
concentration of 0.5 ng/ml compared to 0.018 for a blank with no Bcl-2 in it
(FFll).
Appellant argues that Johnson would not have provided a reason to
make the claimed device:
In the view of a skilled artisan, Johnson presents at most an
extremely \'l/eak correlation bet\'l/een the urinary Bcl=2 level and
the existence of ovarian cancer, of virtually no predictive value.
Because of its very low predictive value, showing 53% accuracy,
with 7% false positive and 23% false negative, Johnson does not
suggest nor present a reasonable expectation of success to
motivate a skilled artisan to use urinary Bcl-2 levels for detection
of ovarian cancer.
(Appeal Br. 3, quoting Kruk Declaration9 ,-r 2.)
This argument is unpersuasive. First, claim 1 is directed to a device
that can be used with a urine sample, but Appellant has pointed to no
structural feature of the device that would require using urine as a sample.
9 Declaration under 37 C.F.R. § 1.132 of Patricia A. Kruk, signed Aug. 19,
2009.
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Application 13/205,095
In addition to its findings regarding Bcl-2 in urine, Johnson also reports that
"twice the number of cancer patients had detectable Bcl-2 levels in their
plasma than that of normal or benign disease patients" (FF6). The Kruk
Declaration provides no basis for concluding that it would not have been
obvious to use the device made obvious by the cited references to assay
Bcl-2 levels in blood or plasma samples.
In addition, successfully using the claimed device does not require
"detection of ovarian cancer" (Kruk Deel. i-f 2), but only using it to
determine whether the Bcl-2 level in a sample is above or below a threshold
in the range of 0-2.0 ng/ml. Bender demonstrates that Bcl-2-specific
immunoassays are capable of the required level of discrimination (FF 11,
FF12) and therefore provides a basis for a reasonable expectation of success.
Appellant also argues that she has provided evidence of unexpected
results. (Appeal Br. 5.) Appellant cites evidence provided in the
Specification and in the Kruk Declaration. Specifically, Appellant argues
that she "discovered that urinary Bcl-2 concentrations within a threshold
range provided an almost 100% correlation between levels of Bcl-2
concentration and ovarian cancer ... (see, specification page 11, lines 8-9;
see also Kruk Declaration paragraph 3)." (Id. at 5---6.)
We have considered the cited evidence but are not persuaded that it
shows that the claimed device would have been nonobvious. The
Specification states that urine samples were collected from healthy
volunteers and patients with either ovarian or peritoneal cancer, and the
samples were "measured in triplicate for Bcl-2 using commercially available
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Application 13/205,095
ELISA kits (BenderMedSystems, catalog #BMS244/3) according to the
manufacturer's instructions." (Spec. 11 :3-5.)
The Specification states that the amount of Bcl-2 in urine from
patients with cancer was significantly higher than those in healthy
volunteers. (Id. at 11: 5-7.) That finding, however, lacks a nexus with the
presently claimed device, since the claimed device was not used to generate
the evidence that allegedly shows unexpected results. See In re GPAC, Inc.,
57 F.3d 1573, 1580 (Fed. Cir. 1995) ("For objective evidence [of
nonobviousness] to be accorded substantial weight, its proponent must
establish a nexus between the evidence and the merits of the claimed
invention."); In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011) ("Where the
offered secondary consideration actually results from something other than
what is both claimed and novel in the claim, there is no nexus to the merits
of the claimed invention.").
The evidence cited in the Kruk Declaration likewise lacks a nexus to
the presently claimed device. Dr. Kruk states that "my claimed invention is
a method for detecting ovarian cancer by measuring the urinary Bcl-2 level
with the ELISA assay." (Kruk Deel. i-f 3, emphasis added.) The Kruk
Declaration cites the Specification's evidence regarding levels of Bcl-2 in
healthy patients and cancer patients and concludes that the "extremely high
correlation between levels of urinary Bcl-2 and ovarian cancer is a surprising
discovery that could not have been predicted from Johnson." (Id.)
As with the Specification's evidence, however, the Kruk Declaration
provides no basis for concluding that the allegedly unexpected results
derived from using the device defined by claim 1, which is not an ELISA
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Application 13/205,095
assay. Dr. Kruk does not say which "ELISA assay" was used to generate the
cited urinary Bcl-2 levels, and the Kruk Declaration's citation to the
Specification implies that the cited results are those that were generated by
the BenderMedSystems ELISA kit (Spec. 11 :3--4), rather than the device of
claim 1.
Conclusion of Law
A device meeting the limitations of claim 1 would have been prima
facie obvious based on the cited references. Appellant has not provided
evidence of unexpected results that, when weighed with the evidence
favoring obviousness, shows that the claimed device would have been
nonobvious.
Claims 3-5, 7-10, and 14 have not been argued separately and
therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
II
Issue
The Examiner has rejected claims 1, 3-10, and 14 based on any one of
de Zoeten, Remington, or Goodell, combined with Johnson and either of
Zymed or Bender. The Examiner finds that Remington discloses a device
for detecting a protein in a body fluid comprising the three zones recited in
claim 1. (Ans. 8. 10) The Examiner cites Johnson, Zymed, and Bender for
10 The Examiner relies on de Zoeten and Goodell for disclosures similar to
that of Remington. (Ans. 8.) Because we conclude that de Zoeten and
Goodell are not necessary to support a prima facie case of obviousness, we
will not discuss them further.
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Application 13/205,095
their Bcl-2-related teachings that have already been discussed. (Id.) The
Examiner concludes that it would have been obvious to modify Remington's
device to include the anti-Bcl-2 antibodies taught by Zymed or Bender,
motivated by Johnson's teaching of detecting Bcl-2 in urine for non-invasive
detection of ovarian cancer. (Id. at 9.)
Appellant contends that the cited references do not teach or suggest
any target threshold concentration of Bcl-2 in a urine sample. (Appeal Br.
6-7.)
The issue with respect to this rejection is whether device meeting the
limitations of claim 1 would have been prima facie obvious based on the
cited references.
Findings of Fact
13. Remington discloses "methods, kits and reagents that can be
directly used to detect cerebrospinal fluid leakage." (Remington 1 i-f 5.)
14. Remington states that in a preferred embodiment, "an
immunoassay is accomplished using an apparatus that is capable of
producing rapid results, such as a strip test." (Id. at 8 i-f 87 .)
15. Remington's Figure 4 is reproduced below:
. 440
Figure 4 shows an embodiment of a strip test. (Id. at 8 i-f 90.)
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Application 13/205,095
16. The device of Remington's Figure 4 includes an application pad
410 that holds the sample and allows flow-through of proteins and other
molecules to be tested while filtering out large particulate matter. (Id. at 8
i-f91.)
17. Remington states that "a sample can include one or more of the
following fluids: serous fluid, urine," etc. (Id. at 2 iT 34.)
18. The device of Remington's Figure 4 includes a conjugate release
pad 420 that "contains a detector antibody conjugated to a detectable
reagent. A detector antibody can be any antibody that specifically binds to
the antigen." (Id. at 9 iT 92.)
19. The device of Remington's Figure 4 also includes one or more
testing regions 450, which "comprise [ ] immobilized capture antibodies or
secondary antibodies. The capture antibodies can specifically bind the
antigen ... or the antigen-detector antibody complex." (Id. at 9 iT 94.)
20. Remington states that "[b ]y binding to the antigen or antigen-
detector antibody complex, the capture antibody triggers a change in
appearance in testing region 450 which can be visualized and preferably
quantified." (Id.)
Analysis
Remington discloses a strip test for detecting a protein or other
molecule in a sample (FF14-FF16), which can be urine (FFl 7).
Remington's device includes a sample application site for receiving a
sample (FF 16), a labeling zone ("conjugate release pad") that contains an
agent that binds to the antigen of interest (FF 18), and a detection zone
("testing region[]") where capture antibodies bind the antigen or antigen-
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Application 13/205,095
antibody complex and provide a signal that can be visualized (FF19).
Remington's strip test therefore includes each of the three zones recited in
claim 1 on appeal. The disclosures of Johnson, Zymed, and Bender relating
to Bcl-2 are discussed above in regard to the§ 103 rejection based on Ly.
We agree with the Examiner that, based on the disclosures of
Remington, Johnson, Zymed, and Bender, it would have been obvious to
modify Remington's device to include Bcl-2-specific antibodies, as taught
by Zymed or Bender, with the expectation of achieving a device capable of
detecting Bcl-2 at a level of 0.5 ng/ml. A skilled artisan would have had a
reason to make this modification based on Johnson's disclosure that a
detectable level of Bcl-2 in plasma or urine indicates a higher likelihood of
the patient having ovarian cancer, as well as Zymed's disclosure that Bcl-2
has prognostic significance in a number of cancers.
Appellant argues that none of Remington, Johnson, Z ymed, or Bender
suggests any threshold concentration ofBcl-2 in a urine sample. (Appeal
Br. 6-7.)
As previously discussed, however, claim 1 is directed to a device, and
"apparatus claims cover what a device is, not what a device does." Hewlett-
Packard, 909 F.2d at 1468. Therefore, the cited references support a prima
facie case of obviousness as long they would have made obvious the
structural limitations of the device of claim 1. As also discussed above, the
evidence supports a conclusion that the device made obvious by the prior art
would be configured to provide different signals for samples with Bcl-2
concentrations below or above a threshold that is between 0 ng/ml and 2.0
ng/ml because Bender shows that its immunoassay provides increasing
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Application 13/205,095
optical density (O.D.) readings for samples with increasing Bcl-2
concentrations (FF 11).
Conclusion of Law
A device meeting the limitations of claim 1 would have been prima
facie obvious based on the cited references.
Claims 3-10, and 14 have not been argued separately and therefore
fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm both of the rejections on appeal.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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