Ex Parte Yilmaz et al

Board of Patent Appeals and Interferences

Dec 5, 2011

11397974 (B.P.A.I. Dec. 5, 2011)

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.
11/397,974 04/05/2006 Omer H. Yilmaz UM-10907 6083
72960 7590 12/05/2011
Casimir Jones, S.C.
2275 DEMING WAY, SUITE 310
MIDDLETON, WI 53562
EXAMINER
YAO, LEI
ART UNIT PAPER NUMBER
1642
MAIL DATE DELIVERY MODE
12/05/2011 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte OMER H. YILMAZ and SEAN J. MORRISON
__________

Appeal 2011-010891
Application 11/397,974
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for identifying a test compound useful for cancer treatment. The Examiner
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

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Statement of the Case
Background
“The present invention relates to . . . methods for the identification of
cancer therapeutics” (Spec. 1, ll. 8-9).
The Claims
Claims 1-4, 12 and 13 are on appeal. Claim 1 is representative and
reads as follows:
1. A method of identifying a test compound useful
for treating cancer comprising:
a) providing isolated cancer stem cells harvested
from a subject, and isolated normal stem cells;
b) administering said test compound to said
isolated cancer stem cells and said isolated normal stem
cells;
c) monitoring the response of both said isolated
cancer stem cells and said isolated normal stem cells to
said test compound; and
d) identifying a test compound that alters said
isolated cancer stem cells without harming said isolated
normal stem cells.

The issues

A. The Examiner rejected claims 1-4, 12 and 13 under 35 U.S.C. §
103(a) as obvious over Kondo,
1
and Jamieson
2
or Singh
3
(Ans. 5-7).
B. The Examiner rejected claims 1-4, 12 and 13 under 35 U.S.C. §
103(a) as obvious over Clarke
4
(Ans. 7-8).

1
Kondo, T., US 2008/0132423 A1, published Jun. 5, 2008.
2
Jamieson et al., US 2004/0018531 A1, published Jan. 29, 2004.
3
Singh et al, Identification of a Cancer Stem Cell in Human Brain
Tumors, 63 CANCER RESEARCH 5821-5828 (2003).
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A. 35 U.S.C. § 103(a) over Kondo, and Jamieson or Singh
The Examiner finds that Kondo teaches
a method of identifying a compound useful for treating
cancer comprising the steps of providing cancer stem cell
that is a cancer cell line, administering (contacting) the test
compound to the isolated cancer stem cell and normal stem
cell, and then monitoring and identifying a test compound
that alters proliferation or survival of the cancer cells

(Ans. 5).
The Examiner finds that Kondo teaches “a method of isolating and
identifying cancer stem cell and normal stem cells from cultured cancer cells
. . . Kondo et al teach that non cancer stem cell or normal stem cells are used
as control cells” (id.).
The Examiner finds that Jamieson teaches a “method of screening and
identifying a test compound that acts on the cancer stem cell only for
treating a cancer comprising the steps of harvesting (isolating) the cancer
stem cell from a cancer tissue of a subject and isolating the normal
hematopoietic stem cell” (id. at 6). The Examiner finds that Singh teaches
“a method of isolating tumor stem cell[s] and normal stem cell[s] from brain
tumor and normal brain tissues” (id.).
The Examiner finds it obvious “to one of ordinary skill in the art at the
time the claimed invention was made to combine the methods to screen and
identify a compound that alters the primary cancer stem cell” (id.).
Appellants contend that “neither Jamieson nor Singh teach or suggest
the use of primary cancer stem cells in compound screening assays” (App.

4
Clarke et al., US 2004/0037815 A1, published Feb. 26, 2004.
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Br. 5). Appellants contend that the “Examiner has not pointed to one
teaching or suggestion in Jamieson of using primary cancer cells in a drug
screening assay” (id. at 6). Appellants contend that “Kondo lacks any
teaching suggesting the use of primary cancer stem cells in drug screening
assays. By simply teaching the existence of primary cells, and not their use
in screening assays, Jamieson and Singh fail to adequately overcome the
deficiencies of Kondo.” (Id.)
Appellants contend that “Kondo does not simply teach the use of a
cell line instead of primary cancer cells. Rather, Kondo goes further and
actively teaches that primary solid tumor cells should not be used for drug
screening assays.” (Id. at 7).
Appellants contend that “there is no indication in Kondo, Jamieson, or
Singh that primary cancer stem cells should be used in drug screening
assays” (id.). Appellants contend that there “is no teaching in Kondo, or any
other reference cited, that the use of primary stem cells is routine procedure.
One cannot simply assume that because Kondo provides numerous
advantages for cell lines over primary cells, that primary cells must be the
„norm‟” (id. at 9).
The issue with respect to these rejections is: Does the evidence of
record support the Examiner‟s conclusion that Kondo, and Jamieson or
Singh render claim 1 obvious?
Findings of Fact
1. Kondo teaches that “[c]ancer stem cells are shown herein to be
[sic] play a significant role in the malignancy of cancer conditions.
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Therefore, compounds that specifically target these cells may be useful as
anti-cancer therapeutics” (Kondo 5 ¶ 0090).
2. Kondo teaches the use of
cell line-derived cancer stem cells identified from cancer
cell lines, as described herein, to screen test compounds to
identify candidate compounds having anti-cancer stem cell
activity. The screening of test compounds for anti-cancer
stem cell activity overcomes many of the limitations
associated with classic drug screening, which tests
compounds only for activity against the entire cell line (i.e.,
with no cell line-derived cancer stem cell readout).

(Kondo 5 ¶ 0090.)
3. Kondo teaches that the “use of cell lines overcomes many of the
limitations associated with testing drugs using primary tissue since primary
cancer tissue is of finite supply for a given experiment. Accessing additional
primary tissues interrupts the reproducibility of an experiment which is not
the case when cell lines are used” (Kondo 5 ¶ 0090).
4. Kondo teaches:
A method of identifying and/or obtaining an anti-
cancer compound comprises contacting a cell isolated by a
method described herein with a test compound, and;
determining the growth, proliferation, viability, and/or
differentiation status of the cell in the presence of the
compound. The growth, proliferation, viability, and/or
differentiation status of the cell may be determined relative
to binding to a non-stem cell, for example a cancer cell or a
normal non-cancer cell, or a normal stem cell. A decrease in
the growth, proliferation, and/or viability or a change in the
differentiation status of the cell in the presence relative to
the absence of test compound is indicative that the test
compound is a candidate compound for the treatment of a
cancer condition.
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(Kondo 6 ¶¶ 0105-0109.)
5. Kondo teaches that “[c]ancer cell lines are initially derived
from cancerous tissue, for example primary or metastatic tumours, but have
been maintained in a culture for an extended period. Such cells can be
reproduced indefinitely in vitro (i.e., they are continuous cell lines) and have
a potentially unlimited lifespan in culture” (Kondo 3 ¶ 0035).
6. Jamieson teaches “[m]ethods and compositions are provided for
the identification of stem cells and cancer stem cells. . . . In the presence of
active, nuclear -catenin, the detectable marker is expressed, and indicates
that a cell is a stem cell” (Jamieson 1 ¶ 0007).
7. Jamieson teaches that “the population of cells is a mixed
population of stem cells and non-stem cells . . . Stem cells, for these
purposes, may include normal stem cells . . . or may be tumor stem cells.”
(Jamieson 1 ¶ 0008.)
8. Singh teaches that “[r]egardless of pathological subtype, within
24-48 h of primary culture all of the brain tumors yielded a minority fraction
of cells that demonstrated growth into clonally derived neurosphere-like
clusters, termed tumor spheres . . . The frequency of the stem cell population
within the tumor was determined by primary sphere formation assays”
(Singh 5822, col. 2).
Principles of Law
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
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nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
The Supreme Court has recently emphasized that “the [obviousness] analysis
need not seek out precise teachings directed to the specific subject matter of
the challenged claim, for a court can take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” KSR
Int'l v. Teleflex Inc., 550 U.S. 398, 418 (2007).
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
Id. at 416. “If a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability.” Id. at 417. Moreover, an
“[e]xpress suggestion to substitute one equivalent for another need not be
present to render such substitution obvious.” In re Fout, 675 F.2d 297, 301
(CCPA 1982). As noted by the Court in KSR, “[a] person of ordinary skill is
also a person of ordinary creativity, not an automaton.” 550 U.S. at 421.
Analysis
The Examiner finds that “replacing the cancer stem cell line of Kondo
with primary cell stem cells of Jamieson or Singh would be prima facie
obvious to one of ordinary skill in the art at the time the claimed invention
was made” (Ans. 10). The Examiner finds that one “skilled in the art would
be motivated to do so because the primarily isolated cancer stem cell has the
closer in vivo characteristics than that of the established cancer stem cell line
used in the Kondo‟s reference” (id.).
Appellants contend that the “fact that methods to isolate primary
cancer stem cells existed, does not indicate that these cells should be used in
assays to screen for cancer therapeutics, and the Examiner has not provided
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any reference teaching or suggesting their use therein” (App. Br. 6).
Appellants contend that “[o]ne of skill in the art would clearly avoid the use
of primary cancer cells based on this teaching of Kondo” (id. at 7).
We find that the Examiner has the better position. We acknowledge
that Kondo teaches that the “use of cell lines overcomes many of the
limitations associated with testing drugs using primary tissue since primary
cancer tissue is of finite supply for a given experiment. Accessing additional
primary tissues interrupts the reproducibility of an experiment which is not
the case when cell lines are used” (Kondo 5 ¶ 0090; FF 3). However, the
person of ordinary skill in the art would have weighed the teachings of the
prior art and dealt with such trade-offs as the prior art taught. The fact that
Kondo taught that primary tissue is finite in supply may represent a
limitation on the use of primary tissue, but it does not mandate a finding that
a person of ordinary skill would have been too discouraged to consider using
primary tissue in a drug screening assay where the improved accuracy of
primary tissue would have been important (see, e.g., Ans. 10). Also see, e.g.,
Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006):
obviousness must be determined in light of all the facts, and
there is no rule that a single reference that teaches away will
mandate a finding of nonobviousness. Likewise, a given
course of action often has simultaneous advantages and
disadvantages, and this does not necessarily obviate
motivation to combine. See [Winner Int’l Royalty Corp. v.
Wang, 202 F.3d 1340,] 1349 n. 8 [(Fed.Cir.2000)] (“The fact
that the motivating benefit comes at the expense of another
benefit, however, should not nullify its use as a basis to
modify the disclosure of one reference with the teachings of
another. Instead, the benefits, both lost and gained, should
be weighed against one another.”).
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Appellants contend that “Kondo does not simply teach the use of a
cell line instead of primary cancer cells. Rather, Kondo goes further and
actively teaches that primary solid tumor cells should not be used for drug
screening assays.” (Id. at 7).
We are not persuaded. Our reviewing court has specifically rejected
the notion that the prior art‟s mere disclosure of more than one alternative is
a teaching away. In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004).
Moreover, the court specifically clarified that Gurley did not require a
contrary result. See id. (“Indeed, in the case cited by appellants, In re
Gurley, [27 F.3d 551 (Fed. Cir. 1994)] we held that the invention claimed in
the patent application was unpatentable based primarily on a prior art
reference that disclosed two alternatives, one of which was the claimed
alternative. Accordingly, mere disclosure of alternative designs does not
teach away.”).
In the instant case, while Kondo recognizes advantages of the cancer
cell lines over primary tissue (FF 3), it is equally clear that primary tissue is
a viable alternative as the Examiner finds that “primary cells are art-
equivalent to cell lines cells for screening useful compounds” (Ans. 12).
Appellants contend that there “is no teaching in Kondo, or any other
reference cited, that the use of primary stem cells is routine procedure. One
cannot simply assume that because Kondo provides numerous advantages
for cell lines over primary cells, that primary cells must be the „norm‟” (id.
at 9).
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We are not persuaded. We agree with the Examiner that “[r]eading
Kondo, one of ordinary skill in the art would be motivated to use primary
stem cells if they are available abundantly . . . Kondo use the cancer stem
cell line because Kondo considers that the primary cancer stem cell presents
in very small number and is difficult to isolate at the time filing his
application” (Ans. 12). The Examiner finds that “Kondo would prefer use
[of] primary cancer stem cell[s] if the resource of the primary cancer stem
cell[s] becomes unlimited” (Ans. 12). The Examiner has relied upon Singh
and Jamieson to show reliable isolation of stem cells from primary tissues
(FF 6-8), addressing the concern of Kondo.
Conclusion of Law
The evidence of record supports the Examiner‟s conclusion that
Kondo, and Jamieson or Singh render claim 1 obvious.
B. 35 U.S.C. § 103(a) over Clarke
The Examiner finds that Clarke teaches “a method of screening and
identifying a test compound for treating a cancer comprising the steps of
providing isolated cancer stem cell obtained from a subject” (Ans. 7). The
Examiner finds that Clarke teaches “contacting or injecting the test
compound with the isolated cancer stem cells and normal stem cells as
control, and then monitoring and identifying the test compound that alters
the gene expression, proliferation or survival of the cancer stem cells” (id.).
The Examiner finds that Clarke “did not teach that the identified compound
does not harm the normal stem cell, but did suggest the identified compound
having [a] different effect on the cancer stem cell vs. the normal stem cells”
(Ans. 8).
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The Examiner finds it obvious “to modify the method of Clarke et al
to screen and identify a compound that inhibits or works on the cancer stem
cell, but is not harmful to the normal stem cell in order to lower the risk of
cancer treatment by decreasing the side effect on the normal stem cell” (id).
Appellants “submit that Clark et al. does not teach the use of normal
stem cells in such an assay” (App. Br. 10). Appellants contend that “Dr.
Morrison indicates, as both one skilled in the art and as an inventor on the
Clarke et al. reference, that Clarke et al. teaches the use of untreated cancer
stem cells, not normal stem cells” (id.).
The issue with respect to these rejections is: Does the evidence of
record support the Examiner‟s conclusion that Clarke renders claim 1
obvious?
Findings of Fact
9. Clarke teaches that to “determine the effect of a potential test
compound on solid tumor stem cells, a culture of precursor cells derived
from tumor stem cells can be obtained from tissue of a subject, such as a
patient with a tumor or other cancerous disease, such as an epithelial cancer
or breast cancer” (Clarke 12 ¶ 0113).
10. Clarke teaches that the
ability of various biological agents to increase, decrease, or
modify in some other way the number and nature of the
solid tumor stem cells and solid tumor stem cell progeny can
be screened. For example, it is possible to screen for test
compounds that decrease the proliferative ability of the solid
tumor stem cells, which would be useful for identifying anti-
cancer therapeutic agents. In these assays, the relevant cells
are cultured in the presence of the test compounds of interest
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and assayed for the degree of proliferation or cell death that
occurs.

(Clark 12 ¶ 0114.)
11. Clarke teaches that the “effects of the test compounds or
biological agents are identified on the basis of significant difference relative
to control cultures” (Clark 12 ¶ 0118).
12. Clarke teaches that the “the assays measure a response the
target cells (solid tumor stem cells or genetically modified solid tumor stem
cells) that provides detectable evidence that the test compound may be
efficacious. The detectable signal is compared to control cells and the
detectable signal identified by subtraction analysis” (Clarke 22-23 ¶ 0205).
13. Clarke teaches that these “results demonstrate that these assays
also provide a means for detecting multipotent progenitors from normal
breast epithelium. This assay may be used for the purification of normal
breast stem cells” (Clarke 26 ¶ 0236).
14. Dr. Morrison
5
states that “I believe that the context of the
Clarke et al. reference makes it clear that untreated cancer stem cells, not
normal stem cells, are used as the control cells in this reference” (Morrison
Dec. ¶ 7).
15. Dr. Morrison states that
it is noted that the cancer stem cells used in the cited
Examples of Clarke et al. were breast cancer stem cells.
This is important because at the time the Clarke et al.
reference was filed, to my knowledge, the art had not
identified a way to identify normal breast epithelial stem

5
Declaration of Sean J. Morrison, Ph.D., filed Jan. 26, 2010.
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cells, so we could not have compared (and did not compare)
breast cancer stem cells to normal breast epithelial cells

(Morrison Dec. ¶ 7).
Principles of Law
“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).
Analysis
The Examiner acknowledges that “Clarke does not specify the normal
stem cell as a control” (Ans. 18). The Examiner finds that “one of ordinary
skilled in the art would arrive at current invention by using normal stem cell
as control for screening and identifying a compound that shows different
effect on the cancer stem cell from the normal stem cell” (id.).
Appellants “submit that Clark et al. does not teach the use of normal
stem cells in such an assay” (App. Br. 10). Appellants contend that “Dr.
Morrison indicates, as both one skilled in the art and as an inventor on the
Clarke et al. reference, that Clarke et al. teaches the use of untreated cancer
stem cells, not normal stem cells” (id.).
We find that Appellants have the better position. The evidence of
record, and in particular the Morrison Declaration, clarify that Clarke did not
use normal stem cells in the comparison assay (FF 14-15). While Clarke
does teach the use of controls (FF 11), the Examiner has provided no
evidence or reason to select normal stem cells as a control in the place of the
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untreated cancer stem cells used in Clarke (FF 14). Without such evidence,
we are constrained to reverse this rejection.
Conclusion of Law
The evidence of record does not support the Examiner‟s conclusion
that Clarke renders claim 1 obvious.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over Kondo, and Jamieson or Singh. Pursuant to 37
C.F.R. § 41.37(c)(1), we also affirm the rejection of claims 2-4, 12, and 13
as these claims were not argued separately.
We reverse the rejection of claims 1-4, 12 and 13 under 35 U.S.C. §
103(a) as obvious over Clarke.

AFFIRMED

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