Igor B. Roninson et al.

Patent Trials and Appeals Board

Aug 28, 2019

14153383 - (D) (P.T.A.B. Aug. 28, 2019)

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.
14/153,383 01/13/2014 Igor B. Roninson SEN-021US 9383
32254 7590 08/28/2019
Wayne A. Keown
Verrill Dana LLP
One Portland Square
Portland, ME 04112
EXAMINER
SWOPE, SHERIDAN
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
08/28/2019 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):
lhymel@verrilldana.com
patents@verrilldana.com
wkeown@verrilldana.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte IGOR B. RONINSON, DONALD C. PORTER, and
SERENA ALTILIA1
__________

Appeal 2018-0039412
Application 14/153,383
Technology Center 1600
__________

Before DONALD E. ADAMS, JOHN E. SCHNEIDER, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

SCHNEIDER, Administrative Patent Judge.

DECISION ON APPEAL
This is an Appeal under 35 U.S.C. § 134(a) involving claims to a
method for measuring the activity of a protein inhibitor, which have been
rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 Appellants identify the real party in interest as Senex Biotechnology, Inc.
Br. 1.
2 We have considered and herein refer to the Specification of Jan. 13, 2014
(“Spec.”); Final Office Action of Apr. 14, 2017 (“Final Act.”); Appeal Brief
of Nov. 13, 2017 (“Br.”); and Examiner’s Answer of Dec. 22, 2017
(“Ans.”).

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STATEMENT OF THE CASE
Potent and selective inhibitors of enzymes and other
bioactive proteins are used for numerous medical and
biotechnological applications, as well as for research. The
potency of a protein inhibitor is usually measured in cell-free
assays, using purified protein preparations. The selectivity of
the inhibitor is typically deduced by comparing its activities for
the inhibition of different proteins.

Spec. 2.
The utility of a protein inhibitor lies in its effect on the
target protein within a cell rather than in an artificial cell-free
assay. Therefore the most pertinent inhibitory activity is the
one measured in a cell-based assay, which measures directly the
effect of the inhibitor on the activity of the target protein in an
intact cell. However, direct cell-based assays are available for
only a small fraction of protein targets.

Id. at 3.
The Specification describes “a novel type of specific cell-based assays
suitable for many protein targets.” Id. at 4.
Claims 1, 2, 4, 8, 11–15, 18, and 21–23 are on appeal.3 Claim 1 is the
sole independent claim and reads as follows:
1. A method for determining the activity of an inhibitor of a
target protein, wherein the overexpression of the target protein
itself has a deleterious effect on cell growth, the method
comprising:
(a) providing a first population of cells that overexpress
the target protein and a second population of cells that do not
overexpress the target protein;
(b) determining that the second population of cells grows
faster than the first population of cells;

3 Claims 3, 5–7, 9, 10, 16, 17, 19, and 20 are pending in the Application but
have been withdrawn from consideration. Final Act. 1.
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(c) treating the first and second populations of cells with
different concentrations of an inhibitor of the activity of the
target protein;
(d) measuring either the growth rate of the first and
second populations of cells, or the amount of target protein
produced by the first and second populations of cells, or both,
(e) determining that the inhibitor causes, in a dose-
dependent manner, either an increase in the rate of growth of
the first population of cells, or in the amount of target protein
produced by the first population of cells, or both, and that the
inhibitor does not cause, in a dose-dependent manner, either an
increase in the rate of growth of the second population of cells
or the amount of target protein produced by the second
population of cells; and
(f) correlating the concentration of inhibitor with the
increase in growth rate of the first population of cells, or in the
amount of target protein produced by the first population of
cells, or both.

The claims stand rejected as follows:
Claims 1, 2, and 8 have been rejected under 35 U.S.C. § 103(a) as
unpatentable over Uhlmann4 in view of Crawford.5
Claims 1, 2, 4, 8, 11, 14, 15, 18, and 21 have been rejected under
35 U.S.C. § 103(a) as unpatentable over Li6 in view of Chen.7

4 Erik J. Uhlmann et al., A Potent Cell Death Activity Associated with
Transient High Level Expression of BCL-2, 273 J. BIOL. CHEM. 17926–932
(1998) (“Uhlmann”).
5 Anatasha Crawford & Rita Nahta, Targeting Bcl-2 in Herceptin-Resistant
Breast Cancer Cell Lines, 9 CURR PHARM. PERSON MED. 1–13 (2011)
(“Crawford”).
6 Li et al., US 2004/0018529 A1, published Jan. 29, 2004 (“Li”).
7 Yi-Hua Chen et al., Design, Synthesis, and Biological Evaluation of
Isoquinoline-1,3,4,-trione Derivatives as Potent Capase-3 Inhibitors, 49 J.
MED. CHEM. 1613–23 (2006) (“Chen”).
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Claims 1, 2, 11, and 12 have been rejected under 35 U.S.C. § 103(a)
as unpatentable over Sharma8 in view of Muruais.9
Claims 14, 21, and 22 have been rejected under 35 U.S.C. § 103(a) as
unpatentable over Sharma in view of Muruais in further view of Muller.10
Claims 1, 2, and 11–13 have been rejected under 35 U.S.C. § 103(a)
as unpatentable over Meikrantz11 in view of Chang.12
Claims 14, 18, and 21–23 have been rejected under 35 U.S.C.
§ 103(a) as unpatentable over Meikrantz in view of Chang in further view of
Luo.13

8 Monica Sharma et al., Cyclin dependent kinase 5 (Cdk5) mediated
inhibition of the MAP kinase pathway results in CREB down regulation and
apoptosis in PC12 cells, 358 BIOCHEM. BIOPHYS. RES. COMM. 379–84
(2007) (“Sharma”).
9 Gemma Muruais et al., The Cdk5 Inhibitor Roscovitine Strongly Inhibits
Glucose Uptake in 3T3-L1 Adipocytes Without Altering GLUT4
Translocation From Internal Pools to the Cell Surface, 220 J. CELL.
PHYSIOL. 238–44 (2009) (“Muruais”).
10 Susanne R. Muller et al., Laboratory Method: Efficient Transfection and
Expression of Heterologous Genes in PC12 Cells, 9 DNA CELL BIOL. 221
(1990) (“Muller”).
11 William Meikrantz & Robert Schlegel, Suppression of Apoptosis by
Dominant Negative Mutants of Cyclin-dependent Protein Kinases, 271 J.
BIOL. CHEM. 10205–209 (1996) (“Meikrantz”).
12 Chang et al., WO 2007/133772 A2, published Nov. 22, 2007 (“Chang”).
13 Kathy Q. Luo et al., Application of the Fluorescence Resonance Energy
Transfer Method for Studying the Dynamics of Caspase-3 Activation during
UV-Induced Apoptosis in Living HeLa Cells, 283 BIOCHEM. BIOPHYS. RES.
COMM. 1054–60 (2001) (“Luo”).
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UHLMANN COMBINED WITH CRAWFORD
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
claims 1, 2, and 8 would have been obvious over Uhlmann combined with
Crawford.
The Examiner finds that Uhlmann teaches a method for determining
the effect of Bcl-2 target protein over-expression on cell growth/viability
comprising the following steps:
(a) providing a first population of human cells that
overexpress the target protein Bcl-2 and a second population of
said cells that do not overexpress Bcl-2, as determined by
Western blotting (Fig[.] 7);
(b) determining that the second population of cells has
higher viability than the first population of cells (Fig[s.] 1&2);
(c) treating the first and second populations of cells with
an inhibitor of the Bcl-2- stimulated pathway (caspase inhibitor;
Fig. 6);
(d) measuring the cell viability of the first and second
populations of cells treated with the inhibitor, and
(e) determining that the inhibitor enhances viability of
the first population of cells but not the second population of
cells (Fig[.] 6).

Ans. 5.
The Examiner finds that while Uhlmann does no teach determining
the dose dependent effect on the Bcl-2 target protein, that step is taught by
Crawford. Id. The Examiner finds that the motivation to combine the
references stems from
the desire to examine the effect of direct inhibitors of the Bcl-2
target protein to reverse the cell death caused by Bcl-2 over
expression in human cells. The expectation of success is high,
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as Uhlmann teaches that over-expression of the target protein
Bcl-2 reduces cell viability (Fig[s.] 1,2,6), while Crawford
teaches the dose-response of the Bcl-2 inhibitor ABT- 737 on
the growth of breast cancer cells.

Id.
Appellants contend that Uhlmann does not teach or suggest the use of
an inhibitor for Bcl-2 but for caspase and does not assay for an inhibitor of a
target protein. Br. 5. Appellants also argue that Uhlmann is concerned with
the effect of 5’ and 3’ untranslated regions of Bcl-2 RNA on the expression
of Bcl-2 and not on assaying the effect of Bcl-2 inhibitors of cell growth. Id.
Appellants contend that Uhlmann’s focus on the untranslated regions belies
the motivation advanced by the Examiner. Id.
Principles of Law
[T]he examiner bears the initial burden, on review of the
prior art or on any other ground, of presenting a prima facie
case of unpatentability. If that burden is met, the burden of
coming forward with evidence or argument shifts to the
applicant.
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.

In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
“[N]ot unlike a determination of infringement, a determination of
anticipation, as well as obviousness, involves two steps. First is construing
the claim, . . . followed by, in the case of anticipation or obviousness, a
comparison of the construed claim to the prior art.” Key Pharms. v. Hercon
Labs. Corp., 161 F.3d 709, 714 (Fed. Cir. 1998).
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“[T]he specification is always highly relevant to the claim
construction analysis. Usually, it is dispositive; it is the single best guide to
the meaning of a disputed term.” Vitronics Corp. v. Conceptronic, Inc., 90
F.3d 1576, 1582 (Fed. Cir. 1996).

Analysis
We have considered the arguments advanced by the Examiner and
Appellants and conclude that the Examiner has failed to establish a prima
facie case of obviousness. We find that the Examiner has not demonstrated
that the references teach or suggest determining “an increase in the rate of
growth” as the term has been defined in the Specification. The first part of
any analysis for obviousness is to construe the claims. Key Pharms., 161
F.3d at 714. While claim terms are usually given their broadest reasonable
interpretation during prosecution, the specification should be consulted as a
guide to the meaning of a term. Vitronics, 90 F.3d at 1582. In the present
case, the Specification teaches that the term “growth rate” means “the
inverse of the doubling time of the cells or the transfection efficiency of the
cells.” Spec. at 10.
Applying this construction we find that the Examiner has not
established a prima facie case of obviousness. While Crawford teaches
measuring growth rate as that term is used broadly to include measuring cell
viability in a proliferation assay, the Examiner has not shown that the growth
rate reported in Crawford is measured in the same way as defined by the
Specification. Likewise while Uhlmann teaches measuring cell viability, the
Examiner has not shown that the viability measurement is a growth rate
measurement as defined by the Specification.
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We also find that the Examiner has not demonstrated a motivation to
combine the teachings of Uhlmann and Crawford. While the Examiner has
properly summarized the teachings of the references, the Examiner has not
explained how those teachings would lead one skilled in the art to combine
the teachings to arrive at the claimed invention. “Obviousness requires more
than a mere showing that the prior art includes separate references covering
each separate limitation in a claim under examination.” Unigene Labs., Inc.
v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir. 2011). “Rather, obviousness
requires the additional showing that a person of ordinary skill at the time of
the invention would have selected and combined those prior art elements in
the normal course of research and development to yield the claimed
invention.” Id.
Conclusion of Law
We conclude that a preponderance of the evidence does not support
the Examiner’s conclusion that the subject matter of claims 1, 2, and 8
would have been obvious over Uhlmann combined with Crawford.
LI COMBINED WITH CHEN
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter if
claims 1, 2, 4, 8, 11, 14, 15, 18, and 21 would have been obvious over Li
combined with Chen.
The Examiner finds that Li discloses a method for determining the
effect of caspase-3 overexpression on cell growth/viability comprising the
steps of
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(a) providing a first population of stably transfected cells
that overexpress a caspase-3 target protein and a second
population of said cells that do not overexpress caspase-3; and
. . .
(b) determining, by replicate plating, that the second
population of cells has higher viability than the first population
of cells.

Ans. 6 (citing Li ¶¶ 90, 161, 170, 171, 193, Figs. 28 B–D, 29D).
The Examiner acknowledges that Li does not teach determining dose-
dependent ability of a caspase-3 inhibitor to reverse the reduction of viability
of cells but finds that Chen teaches this limitation. Id.
The Examiner concludes:
It would have been obvious to a person of ordinary skill in the
art to use the cells of Li, expressing the caspase-3 target protein,
to determine dose-dependent ability of caspase-3 inhibitors of
Chen to reverse the reduction of viability in cells expressing the
caspase-3-target protein. Motivation to do so is provided by the
desire to determine the potency of Chen's inhibitors to affect
intact cell viability. The expectation of success is high, as Chen
teaches that at least some of their inhibitors were effective in
intact Jurkat T cells (Fig[.] 2).
Id.
Appellants contend that no one suggested the quantitation of the
activity of an inhibitor of a target protein before Appellants developed their
invention and that the motivation advanced by the Examiner was improperly
derived by Appellants’ invention. Br. 5. Appellants also contend that the
Examiner has misconstrued the teachings of Li. Id. at 6. Appellants contend
that Li is directed to the detection of ß-secretase which activates caspase not
inhibit it. Id. Appellants contend that this is the opposite of their invention.
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Analysis
Here again we find that the Examiner has not established a prima facie
case of obviousness. As with Uhlmann and Crawford discussed above, the
Examiner has not shown that the measurement of cell viability taught in Li
or Chen meets the definition of rate of growth defined by the Specification.
Absent such a showing we do not find that the references support a prima
facie case of obviousness.
Conclusion of Law
We conclude that a preponderance of the evidence does not support
the Examiner’s conclusion that the subject matter of claims 1, 2, 4, 8, 11, 14,
15, 18, and 21 would have been obvious to one of ordinary skill in the art at
the time the invention was made over Li combined with Chen.

SHARMA COMBINED WITH MURUAIS
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
claims 1, 2, 11, and 12 would have been obvious over Sharma combined
with Muruais.
The Examiner finds that Sharma teaches that over-expression of the
cdk5 target protein results in apoptosis of PC12 cells. Ans. 7. The
Examiner finds that Muruais teaches determining the dose dependent effect
of the cdk5 inhibitor roscovitine on glucose uptake in cells. Id. The
Examiner concludes:
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It would have been obvious to a person of ordinary skill in the
art to use the cdk5 inhibitor roscovitine to determine the dose-
dependent effect of inhibiting the cdk5 target protein on the
apoptosis of cells over-expressing cdk5. Motivation to do so is
provided by the desire to further characterize the role of cdk5 in
programmed cell death in PC 12 cells. The expectation of
success is high, as Sharma teaches that recombinant
overexpression of cdk5 target protein results in apoptotic cell
death of PC 12 cells and Muruais teaches the use of the cdk5
inhibitor roscovitine in cultured cells.

Id.
Appellants contend that Sharma does not teach comparing the growth
rate of cells overexpressing Cdk5 with cells that do not over-express the
protein. Br. 6. Appellants contend that it is not clear that Sharma can be
modified to measure the activity of roscovitine on cdk5. Id. Appellants also
contend that the motivation to combine the references is not clear.

Analysis
Here again we find that the Examiner has filed to establish a prima
facie case of obviousness. While we agree with the Examiner that Sharma
teaches measuring cell growth rate as that term is used broadly to include
measuring cell apoptosis, the Examiner has not shown that the rate of growth
described in Sharma meets the definition of rate of growth defined by the
Specification. See Ans. 6–7.

Conclusion
We conclude that a preponderance of the evidence does not support
the Examiner’s conclusion that the subject matter of claim 1, 2, 11, and 12
would have been obvious over Sharma combined with Muruais.
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SHARMA COMBINED WITH MURUAIS AND MULLER
The Examiner cites Muller for the limitation regarding the use of PC
12 cells stably transfected with the cdk5 target protein. Ans. 7. We discern
nothing in Muller that addresses the deficiency of Sharma and Muruais
discussed above. For this reason we reverse this rejection.

MEIKRANTZ COMBINED WITH CHANG
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
claims 1, 2, and 11–13 would have been obvious over Meikrantz combined
with Chang.
The Examiner finds that Meikrantz teaches that the overexpression of
cdk3 protein results in cell death of HB13 cells. Ans. 8. The Examiner
finds that Chang teaches determining the dose-dependent effect of a series of
cdk-3 inhibitors on cdk-3 kinase activity. Id. The Examiner concludes:
It would have been obvious to a person of ordinary skill in the
art to extend the method of Meikrantz by determining, in cells
over expressing the target protein cdk3, the dose-dependent
effect of the cdk3 inhibitors of Chang in apoptotic HB13 cell
death. Motivation to do so is provided by the desire to further
characterize the role of cdk3 in said cell death. The expectation
of success is high, as Meikrantz teaches that recombinant
overexpression of the cdk3 target protein results in apoptosis of
HB14 cells, Chang teaches the dose-dependent effect of a series
ofcdk3 inhibitors on enzyme activity in vitro, and Chang
teaches that at least some of their inhibitors are effective in
intact cells (e.g., Figs. 6- 10).

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Id.
Appellants contend that Meikrantz does not teach that over expression
of cdk-3 results in apoptosis but that the apoptosis observed as induced by
over expression of other proteins. Br. 7. Appellants also contend that
Meikrantz does not compare the growth rate of a population of cells
overexpressing cdk-3 with a population which does not overexpress cdk-3.
Id. Appellants argue there is no motivation to combine the references. Id.

Analysis
We find that the Examiner has gains failed to establish a prima facie
case of obviousness based on the teachings of these references. While
Meikrantz and Chang appear to teach measuring rate of growth as the term
in used broadly to include measuring apoptosis levels (Meikrantz) or growth
inhibition by measuring total cell number, the Examiner has not pointed to
anything in Meikrantz or Chang to show that Meikrantz or Chang measure
rate of growth in the manner prescribed by the Specification. See Ans. 8.

Conclusion
We conclude that a preponderance of the evidence does not support
the Examiner’s conclusion that the subject matter of claims 1, 2 and 11–13
would have been obvious over Meikrantz combined with Chang.

MEIKRANTZ COMBINED WITH CHANG AND LO
The Examiner cites to Lo as teaching the limitation of suing
transfected HB14 cells. Ans. 8–9. We discern nothing in the teachings of
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Lo which make up for the deficiencies in Meikrantz and Chang discussed
above. Therefore we reverse this rejection.
SUMMARY
We reverse the rejections under 35 U.S.C. § 103(a).

REVERSED