Ex Parte Curran et al

Board of Patent Appeals and Interferences

Feb 28, 2011

10078927 (B.P.A.I. Feb. 28, 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.
10/078,927 02/19/2002 Thomas Curran SJ-01-0032 6357
28258 7590 02/28/2011
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
OFFICE OF TECHNOLOGY LICENSING
332 N. LAUDERDALE
MEMPHIS, TN 38105
EXAMINER
STEADMAN, DAVID J
ART UNIT PAPER NUMBER
1656
MAIL DATE DELIVERY MODE
02/28/2011 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 THOMAS CURRAN and LAKHU KESHVARA
__________

Appeal 2010-005812
Application 10/078,927
Technology Center 1600
__________

Before DEMETRA J. MILLS, FRANCISCO C. PRATS, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL1

This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).

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 CASE
The following claims are representative:
36. A method for detecting cyclin dependent kinase 5 (Cdk5) serine kinase
activity in a biological sample, which method comprises determining
whether the carboxy terminal domain of Disable 1 protein (Dab1) in said
sample is phosphorylated on a serine within a candidate sequence, wherein
phosphorylation of Dab1 on said serine indicates the presence of active
Cdk5 in said sample.

38. A method for detecting cyclin dependent kinase 5 (Cdk5) serine kinase
activity in a biological sample, which method comprises
immunoprecipitation of Dab1 from said biological sample; contacting the
immunoprecipitated Dab1 with a phosphoantibody generated using SEQ ID
NO:3 as an antigen; detecting binding of the phosphoantibody to a serine
within a candidate sequence in the carboxy terminal domain of said Dab1,
wherein binding of the phosphoantibody to said serine of said Dab1 in such
biological sample indicates the presence of Cdk5 serine kinase activity in
said sample.

Cited References

Curran et al. US 6,323,177 B1 Nov. 27, 2001

Carr et al., Selective Detection and sequencing of Phosphopeptides at the
Femtomole Level by Mass Spectrometry, 239 ANALYTICAL BIOCHEMISTRY
180-192 (1996).

GenBank GI:1771281, M. musculus mRNA for mDab555 protein, February
1997.

GenBank GI:3288851, Homo sapiens disbled-1 (DAB1) mRNA, November
1998.

Michalewski et al., Immunoblotting with Antiphosphoamino Acid
Antibodies: Importance of the Blocking Solution, 276 ANALYTICAL
BIOCHEMISTRY 254-257 (1999).

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Niethammer et al., NUDEL Is a Novel Cdk5 Substrate that Associates with
LIS1 and Cytoplasmic Dynein, 28 NEURON 697-711 (2000).

Keshvara et al., Identification of Reelin-induced Sites of Tyrosyl
Phosphorylation on Disabled 1, 276 J. BIO. CHEM. 16008-16014 (2001).

Fu et al., Cdk5 is involved in neuregulin-induced AChR expression at the
neuromuscular junction, 4 NATURE NEUROSCIENCE 374-381 (2001).

Zhen et al., Prenatal Exposure to Cocaine Disrupts D1A Dopamine Receptor
Function Via Selective Inhibition of Protein Phosphatase 1 Pathway in
Rabbit Frontal Cortex, 21 J. NEUROSCIENCE 9160-9167 (2001).

Grounds of Rejection
1. Claims 4-8 and 36-37 are rejected under 35 U.S.C. § 103(a) for
obviousness over Curran in view of Keshvara, Niethammer, Carr, GenBank
and GenBank.
2. Claims 10-11, 13-15 and 38 are rejected under 35 U.S.C. § 103(a) for
obviousness over Curran in view of Keshvara, Niethammer, Carr, GenBank
and GenBank, Howard, Fu and Michalewski.

FINDINGS OF FACT
The findings of fact relevant to all rejections are set forth below.
1. The reference of Curran teaches "In vitro cdk5 can also phosphorylate
Dabl on serine residues" (col. 4, ll. 46-47) and "In particular, identification
of the site of Dabl phosphorylation may permit its use as a potential target
for agonists and antagonists. Cdk5 phosphorylates Dabl in vitro. We can
screen for inhibitors and agonists of this activity in connection with Reelin
binding to VLDLR, and map the phosphorylation sites. Cdk5 has been
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implicated as a kinase associated with increased phosphorylation of
neurofibrillary tangles in AD [Alzheimer’s Disease]. Thus, this area of
exploration has significant relevance" (col. 23, l. 63 to col. 24, l. 4).
2. The Examiner finds that
The differences between Curran and the claimed methods
are: Curran does not teach those residues of Dab1 that are
phosphorylated by Cdk5; Curran does not teach Dab1 is
phosphorylated in biological sample e.g., brain and blood, from
a mouse or human; and Curran does not teach methods of
measuring Cdk5 activity by determining whether or not Dab1 is
phosphorylated at these residues.

(Ans. 5.)
3. According to the Examiner
The references of Niethammer, Keshvara, and Carr are
cited as showing various methods for analyses of a
phosphoprotein. Regarding the limitations of claims 4-5, 7-8,
and 36-37, the reference of Niethammer teaches a method for
determining the sites of phosphorylation of a substrate
polypeptide of Cdk5. For example, the method involves
immunoprecipitation of the substrate polypeptide from mouse
brain extracts with or without catalytically active Cdk5 activity
and determining whether or not the substrate protein has altered
electrophoretic mobility (p. 704, Figures 7A, 7D, and 7E and p.
709, column 1); teaches identifying those amino acids that are
potentially phosphorylated by Cdk5 kinase in the primary
sequence of the polypeptide, which have serine-proline (p. 703,
column 2, bottom and p. 698, Figure IA); individually and
combinatorially mutating the potential Cdk5-phosphorylated
serine residue to an alanine; comparing the electrophoretic
mobility shift in migration of immunoprecipitated wild-type
and mutant proteins in the presence and absence of catalytically
active Cdk5 in COS7 cells; and identifying those residues that
are phosphorylated by Cdk5 by comparing the Cdk5
phosphorylation of the wild-type, individual mutants, and
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combinatorial mutants (p. 704, Figure 7F and p. 708, column 1
to p. 709, column 2).

(Ans. 5-6.)
4. The Examiner finds
[r]egarding the limitations of claims 6-7 and 36-37, the
reference of Keshvara teaches a method of identifying sites of
tyrosine phosphorylation of Dab1 by Src, using a method
similar to that of Niethammer, wherein the tyrosine residues
phosphorylated by Src are identified by mutating each potential
Src-phosphorylated tyrosine to phenylalanine and analyzed by
autoradiography and tryptic phosphopeptide analysis (p. 16009,
Figure 1A-B and column 1 under Kinase Reactions and
Phosphopeptide Mapping; p. 16010, Figure 2A-B). Keshvara
teaches an expression vector encoding Dab1 for use in
expressing Dab1 in a eukaryotic cell (p. 16009, under Cell
Culture and Immunoprecipitations).

(Id. at 6-7.)
5. The Examiner concludes that
at the time of the invention it would have been obvious
to one of ordinary skill in the art at the time of the invention to
combine the teachings of Curran, Niethammer, Keshvara, and
GenBank Accession Numbers 1771281 and 3288851 to
immunoprecipitate Dab1 from a mouse brain extract with and
without catalytically active Cdk5 (as taught by Niethammer)
and analyze its electrophoretic mobility and to determine
whether or not serine at positions 260, 400, 481, 491, and 515
are phosphorylated in accordance with the methodology of
Niethammer and Keshvara. One would have been motivated to
do this because of the teachings of Curran that Cdk5
phosphorylates Dab1; the sites of Cdk5 phosphorylation of
Dab1 can be identified; and may have "significant relevance" to
screen for agonists and antagonists because Cdk5 has been
implicated as a kinase associated with increased
phosphorylation of neurofibrillary tangles in AD.
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(Ans. 7.)
6. The Examiner further concludes that
[o]ne would have had a reasonable expectation of success to
immunoprecipitate Dab1 from a mouse brain extract with and
without catalytically active Cdk5 (as taught by Niethammer)
and analyze its electrophoretic mobility and to determine
whether or not serine at positions 260, 400, 481, 491, and 515
are phosphorylated in accordance with the methodology of
Niethammer and Keshvara because of the results of Curran,
Niethammer, Keshvara, and GenBank Accession Numbers
1771281 and 3288851.

(Id. at 7-8.)
7.
Alternatively, it would have been obvious to one of
ordinary skill in the art at the time of the invention to combine
the teachings of Curran, Keshvara, and Carr to
immunoprecipitate Dab1 from mouse brain extract with
catalytically active Cdk5 to determine its potential site(s) of
phosphorylation according to the phosphopeptide analysis
method of Carr. By doing this, one of ordinary skill in the art
would have practiced the active method step(s) as recited in the
claims. One would have been motivated to do this because of
the teachings of Curran that Cdk5 phosphorylates Dab1; the
sites of Cdk5 phosphorylation of Dab1 can be identified; and
may have "significant relevance" to screen for agonists and
antagonists because Cdk5 has been implicated as a kinase
associated with increased phosphorylation of neurofibrillary
tangles in AD.

(Id. at 8.)

8. The Examiner concludes that
[o]ne of ordinary skill in the art would have had a reasonable
expectation at the time of the invention to combine the
teachings of Curran, Keshvara, and Carr to immunoprecipitate
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Dab1 from mouse brain extract with catalytically active Cdk5
to determine its potential site(s) of phosphorylation according
to the phosphopeptide analysis method of Carr.

(Ans. 8.)

Discussion
ISSUE
Appellants argue that none of the prior art cited by the Examiner
teaches or suggests that the candidate sequence within the carboxy terminal
domain of Dab1 is selectively serine phosphorylated by Cdk5, as claimed.
(App. Br. 4). Appellants argue that there is no motivation to combine the
cited references (id. at 5) and that there is no suggestion in the cited
references that Cdk5 selectively phosphorylates Dab1 in a biological (in
vivo) sample, nor do they teach which serines might be selectively
phorphorylated by Cdk5. (Id. at 6.)
The issue is: Does the prior art disclose or suggest to one of ordinary
skill in the art the detection of Cdk5 activity in a sample by phosphorylation
of Dab1? Does the prior art disclose or suggest which serines on Dab1 are
phosphorylated by Cdk5?

PRINCIPLES OF LAW
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993) (citations omitted). In order to determine whether a prima facie
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case of obviousness has been established, we consider the factors set forth in
Graham v. John Deere Co., 383 U.S. 1, 17 (1966): (1) the scope and content
of the prior art; (2) the differences between the prior art and the claims at
issue; (3) the level of ordinary skill in the relevant art; and (4) objective
evidence of nonobviousness, if present.
“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).

ANALYSIS
Upon review of the evidence of record, we agree that the Examiner
has presented a prima facie case that the method of claim 36 would have
been obvious. The Examiner provides evidence, Curran, that Dab1 is
phosphorylated by Cdk5 at serine residues, thus revealing the presence of
Cdk5 upon detection of phosphorylation of Dab1 in a sample. This process
is suggested to be an important pathway, as Cdk5 has been implicated as a
kinase associated with increased phosphorylation of neurofibrillary tangles
in the brain in Alzheimer’s disease. (Curran, col. 23 and 24.) The GenBank
references provide evidence of the location of serine residues in Dab1.
Niethammer evidences that there is a well known method to determine
phosphorylation of a substrate by Cdk5 in brain lysates by mutation of serine
residues. (Niethammer, p. 704.) Thus, one of ordinary skill in the art with
this knowledge would have been led to determine which residues of Dab1
are phosphorylated by Cdk5 in brain tissue because Cdk5 has been
implicated as a kinase associated with increased phosphorylation of
neurofibrillary tangles in the brain in Alzheimer’s disease. One of ordinary
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skill in the art would have been provided with the means to determine
phosphorylation by the well known methods disclosed in Niethammer. One
of ordinary skill in the art determining the phosphorylation of Dab1 by Cdk5
inherently detects cyclin dependent kinase 5 (Cdk5).
Appellants argue that none of the prior art cited by the Examiner
teaches or suggests that the candidate sequence within the carboxy terminal
domain of Dab1 is selectively serine phosphorylated by Cdk5, as claimed.
(App. Br. 4.) Appellants argue that the prior art does not teach which serines
might be selectively phorphorylated by Cdk5. (Id. at 6.) However, the cited
prior art provides the location of serine residues in Dab1. One of ordinary
skill in the art determining which serines are phosphorylated in Dab1 by the
well known methods of Niethammer would determine phosphorylation of
the serine at the carboxy terminal domain of Dab1 as well as other
phosphorylated serine residues. (Ans. 12-13.)
Even though the Examiner stated that he would read the preamble and
wherein clause in claim 36 as intended use of language having no bearing on
patentability (id. at 13), the motivating disclosure in Curran states that Cdk5
phosphorylates Dab1 at serine residues and this important pathway has been
implicated in the brain disorder, Alzheimer’s disease. Thus the motivating
disclosure cited by the Examiner actually provides a reason to detect Cdk5
phosphorylation of Dab1 in a brain sample, consistent with the preamble
language, as claimed.
Appellants argue that there is no suggestion in the cited references
that Cdk5 selectively phosphorylates Dab1 in a biological (in vivo) sample.
For the reasons given herein, Curran provides a reason to detect Cdk5
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phosphorylation of Dab1 in a brain sample, in vivo, through its implication
of its association with an important pathway found in Alzheimer’s disease.
Patentability determinations are based on a preponderance of the
evidence. “After evidence or argument is submitted by the applicant in
response, patentability is determined on the totality of the record, by a
preponderance of the evidence with due consideration to persuasiveness of
argument.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
Upon review of the evidence of record, Appellants have failed to rebut
the Examiner’s prima facie case of obviousness, and a preponderance of the
evidence supports the obviousness rejection. The obviousness rejection is
affirmed.

2. Claims 10-11, 13-15 and 38 are rejected under 35 U.S.C. § 103(a)
for obviousness over Curran in view of Keshvara, Niethammer, Carr,
GenBank and GenBank, Howard, Fu and Michalewski.
Appellants argue that this rejection suffers from the same deficiencies
as the first rejection. (App. Br. 7.) For the reasons given for rejection 1, the
obviousness rejection is affirmed.

CONCLUSION OF LAW
The cited references support the Examiner’s obviousness rejections.
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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cdc

ST. JUDE CHILDREN'S RESEARCH HOSPITAL
OFFICE OF TECHNOLOGY LICENSING
332 N. LAUDERDALE
MEMPHIS, TN 38105