Ex Parte Feng

Board of Patent Appeals and Interferences

Jan 10, 2011

10460577 (B.P.A.I. Jan. 10, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte GEN-SHENG FENG
__________

Appeal 2010-000611
Application 10/460,577
Technology Center 1600
__________

Before TONI R. SCHEINER, ERIC GRIMES, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of maintaining stem cells in an undifferentiated state. The Examiner
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 The two-month time period for filing an appeal or commencing a
civil action, as recited in 37 C.F.R. § 1.304, or for filing a request
for rehearing, as recited in 37 C.F.R. § 41.52, begins to run from
the “MAIL DATE” (paper delivery mode) or the
“NOTIFICATION DATE” (electronic delivery mode) shown on
the PTOL-90A cover letter attached to this decision.
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Statement of the Case
The Specification teaches that the “invention relates to modulation of
Shp-2 tyrosine phosphatase activity within embryonic, and preferably
hematopoietic, stem cells to modulate stem cell self-renewal, survival and
differentiation” (Spec. 1 ¶ 0003).
The Claims
Claims 6, 7, 9, 14, 17, and 18 are on appeal. Since the claims have not
been argued separately, they stand or fall together. 37 C.F.R. §
41.37(c)(1)(vii). Independent claim 6 is representative and reads as follows:
6. A method of maintaining stem cells in an
undifferentiated state, comprising contacting said stem
cells with an antisense nucleic acid that reduces
functional Shp-2 levels in said stem cells.

The issues2
A. The Examiner rejected claims 6, 7, 9, 14, and 17 under 35 U.S.C. §
103(a) as obvious over Burdon,3 Qu,4 Bennett,5 and Morley6 (Ans. 5-7).
B. The Examiner rejected claims 6, 7, 9, 14, and 18 under 35 U.S.C. §
103(a) as obvious over Burdon, Qu, Andrews,7 and Morley (Ans. 7-8).

2 The Examiner withdrew the 35 U.S.C. § 112, first paragraph
enablement rejection (Ans. 4).
3 Burdon et al., Suppression of SHP-2 and ERK Signalling
Promotes Self-Renewal of Mouse Embryonic Stem Cells, 210
DEVELOPMENTAL BIOLOGY 30-43 (1999).
4 Qu et al., Shp-2 has a positive regulatory role in ES cell
differentiation and proliferation, 17 ONCOGENE 433-439 (1998).
5 Bennett et al., US 6,200,807 B1, issued Mar. 13, 2001.
6 Morley, Katherine, Embryonic Stem Cells, Office of Public
Policy and Ethics, Institute for Molecular Bioscience, The
University of Queensland, Australia (2002).
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Because the same issue is dispositive with respect to both rejections,
we will consider them together.
The Examiner finds that “while both Burdon et al and Qu et al show
that decreased functional Shp-2 levels, due to mutant forms of Shp-2,
suppressed differentiation, neither teach methods for reducing or inhibiting
functional Shp-2 present in wild-type cells” (Ans.8 6). The Examiner finds
that “Bennett et al teach a variety of anti-sense oligonucleotides that can
reduce the functional level of Shp-2 in cells” (id.). The Examiner finds that
“Andrews et al disclose use of specific siRNA molecules to selectively
inhibit expression of genes which play a role in stem cell differentiation”
(Ans. 7-8).
The Examiner finds it obvious to “use the antisense oligonucleotides
of Bennett et al to inhibit Shp-2 expression in embryonic stem cells (thereby
reducing the level of functional Shp-2 in ES cells), to suppress
differentiation of the embryonic stem cells” (id.). The Examiner finds that
suppression of differentiation “to maintain embryonic stem cells in an
undifferentiated state for a prolonged period of time would be highly
desirable in the field of stem cell research and therapy. Undifferentiated
embryonic stem cells are used for generation of organs and tissues for
transplantation, cell therapies, gene therapies and toxicology testing” (id.).
Appellant contends that “the cited references do not teach or suggest
reducing the functional levels of Shp-2 in stem cells” (App. Br. 11). In

7 Andrews et al., WO 02/16620 A2, published Feb. 28, 2002.
8 We will use Answer when we refer to the Examiner’s Answer
filed July 18, 2007.
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particular, Appellant contends that the “cell line in Burdon not only
contained normal levels of intact Shp-2, but also contained an
overabundance of mutant Shp-2 that lacked phosphatase activity” (id.).
Appellant contends that “Qu teaches stem cells that are homozygous for a
specific mutation in the shp-2 gene . . . However, the Shp-2 gene still
maintained the second SH-2 domain, as well as the catalytic domain, the site
of phosphorylation, and cytoplasmic tail which presumably retain activity”
(App. Br. 11-12).
Appellant also contends that “neither Burdon nor Qu would lead the
skilled artisan to use the compounds of Bennett to maintain cells in an
undifferentiated state” (id. at 13).
The issue with respect to both rejections is: Does the evidence of
record support the Examiner’s conclusion that it would have been obvious to
contact “stem cells with an antisense nucleic acid that reduces functional
Shp-2 levels” as required by claim 1?
Findings of Fact
1. Burdon teaches that
we confirm that activation of gp130 does stimulate the
phosphorylation of SHP-2 and activation of ERK1 and
ERK2 in ES cells. Surprisingly, however, these signals are
not required for the efficient propagation of stem cells. On
the contrary, elimination of the phosphotyrosine binding site
for SHP-2 from gp130 or inhibition of ERK activation
enhanced ES cell self-renewal.

(Burdon 31, col. 1-2.)
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2. Burdon teaches that “expression of the SHP-2 (C-S) mutant
increased stem cell self-renewal compared with cells transfected with control
vector” (Burdon 36, col. 1).
3. Burdon teaches that both “SHP-2 (WT) or (Y-F) slightly
inhibited self-renewal. This result supports the notion that the phosphatase
activity of SHP-2 can suppress ES cell self-renewal” (Burdon 36, col. 1).
4. Burdon teaches that “these results suggest that SHP-2 activity
suppresses or antagonises [sic] mechanisms that promote ES cell self-
renewal” (Burdon 40, col. 1).
5. Qu teaches that the “data presented here suggest strongly that
Shp-2 acts as a positive regulator of ES cell differentiation as well as
proliferation” (Qu 434, col. 1).
6. Qu teaches that the “totipotency of ES cells is maintained by
addition of LIF in the culture medium. Thus, an ES cell clone with
decreased differentiation capacity may require lower levels of LIF for
maintenance of stem cell status” (Qu 435, col. 1).
7. Qu teaches that to “compare the response to LIF treatment,
wild-type and mutant ES cells were cultured in media supplemented with . . .
LIF for 96 h. . . . a significantly elevated proportion of mutant ES cells
maintained the morphologically undifferentiated status at concentrations of
60 and 15 U/ml of LIF, as compared to the wild-type ES cells” (Qu 435, col.
1-2).
8. Qu teaches that “a targeted Shp-2 mutant allele was generated
by a homologous recombination in mouse embryonic stem (ES) cells, which
results in an internal deletion of 65 amino acid residues in the N-terminal
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SH2 (SH2-N) domain” (Qu 433, col. 2). Qu teaches that “it appears that the
Shp-2 mutation decreases rather than completely blocks ES cell
differentiation” (Qu 435, col. 2).
9. Qu teaches that “decreased cell division rate was observed for
Shp-2 mutant ES cells . . . consistent with previous observations that
microinjection of anti-Shp-2 antibody or truncated Shp-2 mutant proteins
blocked mitogenic stimulation of DNA synthesis” (Qu 438, col. 1).
10. Bennett teaches “compositions and methods for modulating the
expression of SHP-2. In particular, this invention relates to antisense
compounds, particularly oligonucleotides, specifically hybridizable with
nucleic acids encoding human SHP-2” (Bennett, col. 1, ll. 5-9).
11. Bennett teaches that “[a]ntisense technology is emerging as an
effective means for reducing the expression of specific gene products and
may therefore prove to be uniquely useful in a number of therapeutic,
diagnostic, and research applications for the modulation of SHP-2
expression.” (Bennett, col. 3, ll. 1-5.)
12. Bennett teaches treatment of human embryonic keratinocytes
with SHP-2 antisense oligonucleotides (see Bennett, Example 9, col. 36, ll.
15-67).
13. The Examiner finds that Morley teaches that “[u]ndifferentiated
embryonic stem cells are used for generation of organs and tissues for
transplantation, cell therapies, gene therapies and toxicology testing” (Ans.
6).
14. Andrews teaches “contacting a stem cell with at least one
inhibitory RNA (RNAi) molecule comprising a sequence of a gene, or the
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effective part thereof, which mediates at least one step in the differentiation
of said cell” (Andrews, 7, ll. 7-9).
15. The Examiner finds that “Andrews et al further provides
guidance on how to produce siRNA molecules specific to the gene of
interest” (Ans. 8).
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.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “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
Both Burdon and Qu teach that lower amounts of functional SHP-2
result in less differentiation by stem cells (FF 1-9). In particular, Burdon
teaches that “expression of the SHP-2 (C-S) mutant increased stem cell self-
renewal compared with cells transfected with control vector” (Burdon 36,
col. 1; FF 2). Burdon also teaches that “these results suggest that SHP-2
activity suppresses or antagonises [sic] mechanisms that promote ES cell
self-renewal” (Burdon 40, col. 1; FF 4). Similarly, Qu teaches that “it
appears that the Shp-2 mutation decreases rather than completely blocks ES
cell differentiation” (Qu 435, col. 2; FF 8). Qu also teaches that a
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“decreased cell division rate was observed for Shp-2 mutant ES cells . . .
consistent with previous observations that microinjection of anti-Shp-2
antibody or truncated Shp-2 mutant proteins blocked mitogenic stimulation
of DNA synthesis” (Qu 438, col. 1; FF 9).
Thus, Burdon and Qu teach that whether relative amounts of SHP-2
are reduced by mutation of the phosphotyrosine binding site (FF 1), deletion
of an SH2 domain (FF 8), microinjection of an anti-Shp-2 antibody (FF 9) or
injection of truncated Shp-2 mutant proteins (FF 9), the result is reduced
differentiation of the embryonic stem cells and reduced stimulation of DNA
synthesis (FF 1-9).
Bennett teaches that “[a]ntisense technology is emerging as an
effective means for reducing the expression of specific gene products and
may therefore prove to be uniquely useful in a number of therapeutic,
diagnostic, and research applications for the modulation of SHP-2
expression.” (Bennett, col. 3, ll. 1-5; FF 11.) The Examiner finds that
Morley teaches that “[u]ndifferentiated embryonic stem cells are used for
generation of organs and tissues for transplantation, cell therapies, gene
therapies and toxicology testing” (Ans. 6; FF 13). Andrews teaches
“contacting a stem cell with at least one inhibitory RNA (RNAi) molecule
comprising a sequence of a gene, or the effective part thereof, which
mediates at least one step in the differentiation of said cell” (Andrews, 7, ll.
7-9; FF 14).
Applying the KSR standard of obviousness to the findings of fact, we
conclude that the person of ordinary creativity would have predictably
applied Bennett’s antisense method for reduction of SHP-2 expression to
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reduce ES cell differentiation since Burdon and Qu both teach that reduction
in SHP-2 functions in cells using a variety of SHP-2 mutations and a variety
of other techniques correlates with reduced embryonic cell differentiation.
Similarly, it would have been obvious to combine the RNAi method of
Andrews with Burdon and Qu to reduce SHP-2 activity.
Appellant contends that “the cited references do not teach or suggest
reducing the functional levels of Shp-2 in stem cells” (App. Br. 11). In
particular, Appellant contends that the “cell line in Burdon not only
contained normal levels of intact Shp-2, but also contained an
overabundance of mutant Shp-2 that lacked phosphatase activity” (id.).
Appellant contends that “Qu teaches stem cells that are homozygous for a
specific mutation in the shp-2 gene . . . However, the Shp-2 gene still
maintained the second SH-2 domain, as well as the catalytic domain, the site
of phosphorylation, and cytoplasmic tail which presumably retain activity”
(id. at 11-12).
We are not persuaded. While we understand Appellant’s essential
contention that there is no evidence that Burdon and Qu teach stem cells
with reduced functional SHP-2 levels, this contention is inconsistent with the
central point taught by both Burdon and Qu. Burdon compares stem cells
transfected with wild-type SHP-2 and mutant SHP-2 and finds that the
reduced activity of the mutant permits increased stem cell renewal relative to
the full activity of the wild-type (FF 2-3). Burdon therefore is showing that
more SHP-2 activity results in differentiation and less SHP-2 activity results
in stem cell self-renewal (FF 2-4).
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Qu similarly teaches that reduced levels of SHP-2 wild-type activity
resulted in reduced differentiation and that “a significantly elevated
proportion of mutant ES cells maintained the morphologically
undifferentiated status at concentrations of 60 and 15 U/ml of LIF, as
compared to the wild type ES cells” (Qu 435, col. 1-2; FF 7).
Appellant contends that “neither Burdon nor Qu would lead the
skilled artisan to use the compounds of Bennett to maintain cells in an
undifferentiated state” (App. Br. 13).
We are not persuaded. “[W]hen the question is whether a patent
claiming the combination of elements of prior art is obvious,” KSR directs
that “a court must ask whether the improvement is more than the predictable
use of prior art elements according to their established functions.” KSR, 550
U.S. at 417. Here, the Examiner reasonably finds that the ordinary artisan
would expect that use of the anti-sense oligonucleotides of
Bennett et al would suppress differentiation of ES cells, as
taught by Burdon et al and Qu et al. Suppression of
differentiation to maintain embryonic stem cells in an
undifferentiated state for a prolonged period of time would
be highly desirable in the field of stem cell research and
therapy.

(Ans. 6.)
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that it
would have been obvious to contact “stem cells with an antisense nucleic
acid that reduces functional Shp-2 levels” as required by claim 1.
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SUMMARY
In summary, we affirm the rejection of claim 6 under 35 U.S.C. §
103(a) as obvious over Burdon, Qu, Bennett, and Morley. Pursuant to 37
C.F.R. § 41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 7, 9,
14, and 17 as these claims were not argued separately.
We affirm the rejection of claim 6 under 35 U.S.C. § 103(a) as
obvious over Burdon, Qu, Andrews, and Morley. Pursuant to 37 C.F.R. §
41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 7, 9, 14, and 18
as these claims were not argued separately.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

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