Ex Parte Lewisch et al

Patent Trial and Appeal Board

Jun 17, 2016

12103245 (P.T.A.B. Jun. 17, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/103,245 04/15/2008
28524 7590 06/21/2016
SIEMENS CORPORATION
INTELLECTUAL PROPERTY DEPARTMENT
3501 Quadrangle Blvd Ste 230
Orlando, FL 32817
FIRST NAMED INVENTOR
Sandra A. Lewisch
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.
2008P59106US 1591
EXAMINER
YAKOVLEV A, GALINA M
ART UNIT PAPER NUMBER
1678
NOTIFICATION DATE DELIVERY MODE
06/21/2016 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):
ipdadmin.us@siemens.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SANDRA A. LEWISCH, PRATAP SINGH, VIRAL DESAI,
KAREN L. KRAKOWSKI, and JAMES E. DUFFY
Appeal2014-005132
Application 12/103,245
Technology Center 1600
Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and
JOHN G. NEW, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a method for designing an
antibody reagent for use in an assay for the detection of an analyte to obtain
optimum assay sensitivity. Appellants appeal from the Examiner's final
rejection of claims 1, 3-11, and 13-19 as obvious under 35 U.S.C. § 103.
We have jurisdiction under 35 U.S.C. § 134. The rejection is affirmed.
STATEMENT OF CASE
Claims 1, 3-11, and 13-19 stand rejected under 35 U.S.C. § 103(a)
(pre-AIA) as obvious in view of Pierce (Applications Handbook and
Catalog 200512006, pages 266-268, 277, 279-280, 282, 285) and Rong
Appeal2014-005132
Application 12/103,245
("Two-site imnmno-tluorometric assay of intact salmon calcitonin with
improved sensitivity, Clinical Chem., 1997, vol. 43(1): 71-75).
Claims 1 and 11 are independent claims. Appellants did not argue the
claims separately. We select claim 1 as representative for deciding all issues.
Claim 1 is reproduced below:
1. A method for designing an antibody reagent for use in an
assay for the detection of an analyte to obtain an optimum assay
sensitivity wherein the antibody reagent is a conjugate of a
small molecule attached by a spacer group to an antibody for
the analyte, the method comprising:
preparing two or more of the conjugates by selecting a
set of reaction parameters for each conjugate wherein the set of
reaction parameters is different for each conjugate and wherein
the set of reaction parameters is selected from the group
consisting of the hydrophobicity or hydrophilicity of the spacer
group, the length of the spacer group, the number of molecules
of the small molecule attached to the antibody and the point of
attachment of the small molecule to the antibody;
conducting an assay for the analyte employing each
conjugate; and
selecting for use in the assay the conjugate that provides
an optimum assay sensitivity in an assay for the detection of the
analyte wherein assay sensitivity is monitored by monitoring a
difference in the amount of signal obtained for calibrators
spanning a suspected concentration range of interest of the
analyte and wherein a difference in the signal detected between
a calibrator of lowest concentration and next lowest
concentration is at least about 50%, and signal detected for a
calibrator of highest concentration is at least about 10 times
greater than the signal detected for the calibrator of lowest
concentration.
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Appeal2014-005132
Application 12/103,245
REJECTION
Rong describes an immunoassay for salmon calcitonin ("SCT")
utilizing 1) a biotinylated capture antibody to "catch" the calcitonin and 2)
an antibody labeled with a Eu chelate as signaling marker to detectably label
the captured calcitonin. Rong 71 (Abstract; col. 2).
The Examiner found that Rong tested various combinations of
antibodies to determine the best combination with the highest sensitivity in
detecting salmon calcitonin. Final Rej. 13. The Examiner found that Figure
1 of Rong summarizes the test results ofbiotinylated antibodies 309, 8A4,
5G9, and 3G4 (B-309, B-8A4, B-5G9, and B-3G4) and Eu-labeled
antibodies 309 and 3G4 (Eu-309 and Eu-3G4) using salmon calcitonin as a
calibrator in concentration ranges that read on the claimed calibrator
concentrations. Id. The Examiner found that the combination of B-5G9/Eu-
309 resulted in the best sensitivity with low background. Id.
Figure 1 of Rong is reproduced below:
Salmon Ca!citonin (prnol/L)
···<'.!··· SCT v 8"'309#/Eu.'.3G4
···O··· SCT v B-5G9!Eu<3G4
... 41.... SCT v 8-5G9!Eu-·309# i
···V··· SCT v 8-3G4/EU··3iJ9#
···¢··· SGT v B-309#iE.u~309# .
·"-¢-"· SCT v B-8.A.4/Eu-:~O':i#
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Appeal2014-005132
Application 12/103,245
Figure 1 is a graph showing different conjugates tested at a range of
calcitonin concentrations ("calibrators"). The combination of B-5G9/Eu-309
(represented by a triangle in the figure) resulted in the best sensitivity.
With respect to the claimed limitation that a "signal detected for a
calibrator of highest concentration is at least about 10 times greater than the
signal detected for the calibrator of lowest concentration" as recited in claim
1, the Examiner found that it would have been obvious to have chosen the
calibrators for optimal assay sensitivity and calcitonin range to be detected.
Final Rej. 15, 20. The Examiner acknowledged that Figure 1 does not show
the signal being 10-fold different between the lowest and highest calibrator
concentrations, but found that Figures 3 and 4 of Rong show linearity using
biotinylated 5G9 and Eu-labeled 309# with over an 18-fold signal
difference. Id. at 16-17; 18-19. The Examiner further found that Rong
teaches linearity until at least 300 pmol/L and that linearity over a wide
calibrator concentration range is desirable to improve accuracy when it is
desired to detect the analyte calcitonin over a broad range. Answer 9.
Appellants contend that Figure 1 of Rong shows a signal difference of
about 7.9, which is only about 7 times greater than that for the lowest
calibrator. Appeal Br. 7. Appellants also contend that Figures 3 and 4 show
"only the conjugate B-5G9 (biotinylated 5G9 antibody) and its separate use
in an assay for salmon calcitonin." Id. Appellants state that only Figure 1
shows a "side by side comparison of conjugates," and in this experiment the
calibrator concentrations do not meet the claimed requirement for a signal of
10 times great between the lowest and highest concentrations. Id. at 7-8.
Appellants also state:
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Appeal2014-005132
Application 12/103,245
[The] results depicted in Figs. 3 and 4 of Rong represent the use
of a single conjugate in the determinations of salmon calcitonin
concentrations and have no relationship to the results of assays
on several conjugates, the results of which are summarized in
Fig. 1 of Rong.
Id. at 8.
In the Reply Brief, Appellants state that Figure 1 shows results of
calibrator concentrations between 0 and 10 pmol/L. Reply Br. 6. Appellants
conclude: "To impute more into the disclosure of Fig. 1 is speculation.
Appellant submits that the Office's interpretation of the above teaching of
Rong is based on Appellant's disclosure and does not represent what a
person of ordinary skill in the art would have been fairly taught by Rong."
Id.
Appellants also argue that the spacer in Rong was the same for all
conjugates, while the claims require different reaction parameters which
include using different spacers. Id.
DISCUSSION
The main dispute in this Appeal is whether Rong teaches or suggests
that the signal detected for the highest concentration of calibrator is "at least
about 10 times greater" than the signal detected for the lowest concentration
of calibrator as required by independent by claims 1 and 11, and all the
claims which depend from them. The Examiner cited Figs. 1, 3, and 4 of
Rong as making this signal range obvious to one of ordinary skill in the art.
Final Rej. 13-14.
Claim 1 requires "preparing two or more of the conjugates by
selecting a set of reaction parameters for each conjugate," "conducting an
assay for the analyte employing each conjugate," and "selecting for use in
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Appeal2014-005132
Application 12/103,245
the assay the conjugate that provides an optimum assay sensitivity." Fig. 1
of Rong shows "two or more conjugates" being tested, as required by the
claims, to determine which combination of capture and labeling antibody
gave the best sensitivity. Rong 72 ("Tests of Antibody Combinations.").
Calcitonin serves as the calibrator. As explained in the Specification, a
calibrator is a known amount of analyte. Spec i-f 8. Calibrators are tested
over a range of concentrations, as shown in Rong' s Fig. 1 (0 to 10 pmol/L
calcitonin), to monitor and calibrate the performance of the assay. Id. The
dispute arises because Fig. 1 does not show a signal difference of 10-fold
between the lowest and highest concentrations, but rather the difference is
less than 8-fold. The Examiner found it would have been obvious to
optimize the assay to achieve high sensitivity (Final Rej. 15, 20) and pointed
to Figs. 3 and 4 of Rong where an about 18-fold difference in detected signal
was observed between the lowest and highest concentrations of calibrator,
providing evidence that a signal difference of greater than 10 is described by
Rong (id. at 17).
Appellants argue that Figs. 3 and 4 only look at one conjugate, not
two or more as required by the claim, and state the skilled worker would not
have imputed the information from Figs. 3 and 4 into Fig. 1. Appeal Br. 7-
8.
Appellants' arguments are not supported by adequate evidence. Fig. 1
of Rong is a "calibration curve." Rong 72 ("Tests of Antibody
Combinations"). The calibration curve, as reproduced above, shows that as
the calibrator is increased for the combination of B-5G9/Eu-309 (represented
by a triangle in the figure), the fluorescence increased linearly. Such a curve
allows unknown amounts of calcitonin in samples to be determined by
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Appeal2014-005132
Application 12/103,245
matching the measured fluorescence of an unknown sample to a point on the
calibration curve. Rong teaches that its assay can be used to monitor
calcitonin levels in patients.
Our studies (Fig. 5) demonstrate that the assay has clinical
applications. We can readily monitor the serum concentrations
of SCT in patients who have received the drug. Since the assay
is linear over the wide range of 0.3 to 300 pmol/L, high and low
concentrations can be measured in the same assay and without
the need for sample dilution. Both of these assay characteristics
improve its accuracy.
Id. at 74.
Thus, while Fig. 1 is conducted over a limited range of 0 to 10 pmol/L
with a less than 10 fold difference in signal between the lowest and highest
concentrations, Rong teaches that for clinical applications it is desirable to
test for low and high concentrations in the same assay, providing a reason to
have used a broader range of calibrator which would be reasonably expected
to result in a greater difference in fluorescent signal than depicted in Fig. 1.
Figs. 3 and 4 of Rong show that a greater than 10-fold difference in signal
can be achieved. When the assay is to be designed for high and low analyte
concentrations as taught by Rong (id. at 74), it would have been obvious to
have optimized different conjugates, as Rong did in Fig. 1, but over the
broader concentration range to identify the antibody conjugate pair with the
best sensitivity. Appellants' arguments focus on Fig. 1, but do not
adequately address the obviousness of performing Fig. 1 over a broader
concentration as motivated by Rong's teachings.
Appellants in the Reply Brief argue that the spacers are the same in
Rong, while the claim requires them to be different. Reply Br. 6. We have
not been pointed to where this argument was made in the Appeal Brief.
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Appeal2014-005132
Application 12/103,245
Nonetheless, Appellants have not identified language in the claim which
requires the spacers to be different. The limitation in claim 1 at issue reads
(underlining added):
selecting a set of reaction parameters for each conjugate
wherein the set of reaction parameters is different for each
conjugate and wherein the set of reaction parameters is selected
from the group consisting of the hydrophobicity or
hydrophilicity of the spacer group, the length of the spacer
group, the number of molecules of the small molecule attached
to the antibody and the point of attachment of the small
molecule to the antibody
The limitation only requires that one parameter is different, and such
parameter could be something other than the spacer, e.g., "the number of
molecules of the small molecule attached to the antibody and the point of
attachment of the small molecule to the antibody." The Examiner addressed
these differences on, e.g., page 14 of the Final Rejection.
For the foregoing reasons, we affirm the rejection of claims 1 and 11.
Dependent claims 3-10 and 13-19 fall with claims 1 and 11 because
separate reasons for their patentability were not provided. 37 C.F.R. §
41.37(c)(l)(iv).
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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