Ex Parte Kinsella

Patent Trial and Appeal Board

Jun 29, 2017

13825542 (P.T.A.B. Jun. 29, 2017)

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.
13/825,542 05/28/2013 Todd M Kinsella RIGL-068 5724
83092 7590 07/03/2017
Rigel Pharmaceuticals, Inc.
Bozicevic, Field & Francis LLP
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
CHEN, SHIN LIN
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
07/03/2017 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte TODD M KINSELLA
Appeal 2016-001481
Application 13/825,542
Technology Center 1600
Before, DONALD E. ADAMS, DEMETRA J. MILLS, and
JOHN G. NEW, Administrative Patent Judges.
MILLS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse the pending obviousness rejections and enter a new ground of
rejection.
Appeal 2016-001481
Application 13/825,542
STATEMENT OF CASE
The following claim is representative.
1. A construct system for expressing a reporter protein,
comprising:
a) a reporter construct comprising:
i. an inducible promoter that is activated by a
transcription factor; and
ii. a coding sequence encoding a reporter protein,
wherein said coding sequence is in operable
linkage with said inducible promoter;
b) a first transcription factor construct comprising:
i. a first tissue-restricted promoter; and
ii. a coding sequence encoding a first fusion
protein comprising a first portion of a transcription
factor and a first subunit of a split intein, wherein
said coding sequence is in operable linkage with
said first promoter; and
c) a second transcription factor construct comprising:
i. a second tissue-restricted promoter; and
ii. a coding sequence encoding a second fusion
protein comprising a second portion of said
transcription factor and a
second subunit of said split intein, wherein the
second subunit of said split intein specifically
binds to the first subunit of the split intein and said
coding sequence is in operable linkage with said
second promoter;
wherein expression of said first and second fusion
proteins in a cell results in ligation, by a protein-splicing
reaction mediated by said first and second subunits of
said split intein, of said first and second portions of said
transcription factor to produce said transcription factor
and provides expression of the reporter protein only in
tissues in which expression of the promoters overlap.
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Application 13/825,542
Cited References
Manfredi et al. US 2002/0106699 A1 Aug. 8, 2002
Yadev et al. US 2004/0172688 Al Sept. 2, 2004
Kanno et al., Intefm-Mediated Reporter Gene Assay for
Detecting Protein-Protein Interactions in Living Mammalian
Cells, Analytical Chemistry, Vol. 78, No. 2 (2006).
Wikipedia definition of binding, including specific binding
Pending Grounds of Rejection
1. Claims 1—3, 6, 7, 10-12 and 14—17 are rejected
under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over
Kanno in view of Yadav.
2. Claims 1, 8, 9 and 13 are rejected under pre-AIA
35 U.S.C. § 103(a) as being unpatentable over Kanno and
Yadav in view of Manfredi.
Disposition of Pending Rejections
We reverse grounds of rejection 1 and 2 with respect to
claim 1, in favor of the following new grounds of rejection.
New Grounds of Rejection
Claims 1—3, 6, 7—9, 10—13 and 14—17 are rejected under
pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Kanno,
Yadav, Manfredi, and Wikipedia definition of binding site,
including specific binding.
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Application 13/825,542
FINDINGS OF FACT
1. Kanno, Fig. la is reproduced below.
[principle for the intein-mediated reporter gene assay.
DnaEn (amino acids 1-123) and DnaEc (amino acids 1-36) are
connected with mlexA (amino acids 1-229) and VP 16AD (amino
acids 411-456), respectively. Interested protein X and Y are linked
to the ends of DnaEs. Interaction between X and Y accelerates the
folding of DnaEn and DnaEc, and protein splicing results. mlexA
and VP16AD are linked together by a peptide bond to obtain a
transcriptional activity.
P. 558, col. 1.
2. Kanno discloses an intein-mediated reporter gene assay for
detecting protein-protein interactions in living mammalian
cells” (e.g. Title). Kanno discloses cDNA encoding fusion
protein, protein-DnaEn-mLexA (modified LexA DNA
binding domain), cDNA encoding fusion protein protein-
DnaEc-VP 16AD and the cDNA encoding each fusion
protein are inserted into pcDNA3.1( + ). Kanno also
discloses a reporter construct comprising a major late
promoter of adenovirus, eight-repeated LexA operators, and
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Application 13/825,542
DNA sequence encoding Firefly Luciferase (e.g. Figure la,
lb, p. 558, right column, 2nd paragraph). Kanno teaches
“the principle of the present method is shown in Figure la.
When X interacts with Y, the DnaEs are brought in
proximity and undergo correct folding, which induces
protein splicing. Consequently, mLexA and VP 16AD
directly linked to each other by a peptide bond. Until
mLexA is ligated with VP 16AD, the firefly luciferase
reporter gene is not transcribed into mRNA” (e.g. bridging
pages 558 and 559). CHO-EGFR cells were transfected
with 0.5 ug of pmLDn_Ras and pDcv_Raf-l and all cells to
be assayed were transfected with 0.5 ug of pX81uc. The
luminescence from firefly luciferase was measured (e.g.
Figure lb and Figure 3). The pcDNA3.1(+) plasmid contains
T7 promoter and CMV immediately early promoter. The
DnaEn and DnaEc are subunit of intein protein. The CHO-
EGFR cells are mammalian cells. When both the promoters
in pmLDn_Ras and pDcv Raf-1 are stimulated, those
promoters have overlapping expression pattern. The T7 or
CMV promoter is constitutive promoter (claim 4). The
major late promoter of adenovirus is conditionally inducible
and promoters containing LexA operators are inducible by
LexA containing transcription factor (claim 6).
3. Kanno does not specifically teach the promoters on both
transcription factor constructs are tissue-restricted/tissue
specific, and expression of the reporter protein only in tissue
in which expression of the promoters overlap.
4. Yadav discloses an isolated polynucleotide comprising a
nucleotide sequence that encodes a polypeptide comprising
an N terminal portion of the polypeptide (ExtN), a C-
terminal portion of the polypeptide (ExtC), an intein (Int)
interposed between the ExtN and the ExtC (e.g. 119). The
polynucleotide further comprises a regulatory sequence,
such as a constitutive plant promoter or a plant tissue
specific promoter. || 95, 96, 126.
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5. Manfredi discloses:
A method for detecting protein-protein interactions ..., in
which two fusion proteins are prepared and allowed to
interact with each other. The interaction between the two
fusion proteins leads to protein trans-splicing, generating an
active and detectable reporter.
Abstract.
6. Manfredi discloses that:
Suitable transcription activators include, but are not limited
to, GAL4, GCN4, ARD1, the human estrogen receptor, E.
coli LexA protein, herpes simplex virus VP 16 (Triezenberg
et al., Genes Dev. 2:718-729 (1988)), the E. coli B42 protein
(acid blob, see Gyuris et al., Cell, 75:791- 803 (1993)), NF-
KB p65, and the like. In addition, hybrid transcriptional
activators composed of a DNA binding domain from one
transcriptional activator and an activation domain from
another transcriptional activator are also useful. ... The
corresponding transcriptional elements specifically
interacting with the transcriptional activators or repressors
are well known in the art. See e.g., Hanna-Rose and Hansen,
Trends. Genet., 12:229-234 (1996).
199.
7. Manfredi further discloses that
a transcriptional activator or repressor protein
can be divided into an N-terminal portion and a C-terminal
portion which are fused to the N-terminus of N-intein and
C-terminus of C-intein, respectively. Upon protein trans­
splicing, a full-length protein emerges as a functional
transcriptional activator or repressor which subsequently
activates or represses the expression of the detectable gene
in the reporting vector.
1100.
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8. Manfredi discloses that:
[M]any . . . reporters can be used in a similar manner in the
present invention. Such other reporters include, for example, the
green fluorescent protein (GFP), which can be detected by
fluorescence assay and sorted by flow-activated cell sorting
(FACS) (See Cubitt et al., Trends Biochem. Sci., 20:448-455
(1995)), secreted alkaline phosphatase, horseradish peroxidase, the
blue fluorescent protein (BFP), and luciferase photoproteins such
as aequorin, obelin, mnemiopsin, and berovin ....
195.
9. Manfredi discloses that:
[T]he fusion constructs are designed such that intein mediated
trans-splicing produces an active reporter that is a transcriptional
activator or repressor capable of activating or repressing the
expression of a detectable gene. Thus, the trans-splicing event will
be detected based on the expression or suppression of the
detectable gene. In this embodiment, a “reporting vector”
containing the detectable gene operably linked to a transcriptional
regulatory sequence is also introduced into the host cells.
198.
10. Figure 2A of Manfredi is reproduced below.
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Figure 2A, top two scheme lines of Manfredi show an example of
an N-intein and C-intein pairing or specific binding. When the
inteins pair and interact with each other, an active reporter will be
detectable in the host cell.
148.
11. Manfredi teaches introducing into an yeast cell a first chimeric
gene and a second chimeric gene, said first chimeric gene
encoding a first fusion protein having a first test polypeptide, an
N-intein, and a first inactive reporter polypeptide fused to the
N-terminus of the N-intein, said second chimeric gene encoding
a second fusion protein having a second test polypeptide, a C-
intein, and a second inactive reporter polypeptide fused to the
C-terminus of the C-intein, wherein ligation between the C-
terminus of said first inactive reporter polypeptide and the N-
terminus of said second inactive reporter polypeptide forms an
active reporter protein (e.g. claim 12). The reporter protein can
be luciferase, green fluorescence protein or blue fluorescence
protein (e.g. claim 18). The fusion constructs can be designed
such that intein mediated trans-splicing produces an active
reporter that is a transcriptional activator or repressor capable of
activating or repressing the expression of a detectable gene (e.g.
[0098]). The suitable transcription activator includes GAL4,
GCN4 and herpes simplex virus VP 16 etc. (e.g. [0099]).
12. “In biochemistry, a binding site is a region on a protein or
piece of DNA or RNA to which ligands (specific molecules
and/or ions) may form a chemical bond.” “A more specific
type of binding site is the transcription factor binding site
present on DNA. Short, recurring patterns in DNA often
indicate sequence-specific binding sites for proteins such as
nucleases and transcription factors; ribosome binding, mRNA
processing, and transcription termination are also signaled by
these sequence motifs.”
See, https://en.wikipedia.org/wiki/Binding site
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PRINCIPLES OF LAW
In making our determination, we apply the preponderance of the
evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427
(Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings
before the Office).
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Claim interpretation
Claim 1 uses the transitional phrase “comprising” and, therefore, does
not exclude other claim elements, for example, Protein X and Protein Y of
Kanno, Fig. 1.
The Specification does not define the term “specifically binds,” as
used in claim 1. During ex parte prosecution, claims are to be given their
broadest reasonable interpretation consistent with the description of the
invention in the specification. See In re Zletz, 893 F.2d 319, 321 (Fed. Cir.
1989). See also, Cuozzo Speed Technolgies, LLC v. Lee, 136 S. Ct. 2131,
2144 (2016). “Without evidence in the patent specification of an express
intent to impart a novel meaning to a claim term, the term takes on its
ordinary meaning.” Optical Disc Corp. v. Del Mar Avionics, 208 F.3d 1324,
1334 (Fed. Cir. 2000). We find that the ordinary meaning of the term
“specifically binds” means, “In biochemistry, a binding site is a region on a
protein or piece of DNA or RNA to which ligands (specific molecules
and/or ions) may form a chemical bond.” FF 10. “A more specific type of
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binding site is the transcription factor binding site present on DNA. Short,
recurring patterns in DNA often indicate sequence-specific binding sites for
proteins such as nucleases and transcription factors; ribosome binding,
mRNA processing, and transcription termination are also signaled by these
sequence motifs.” FF10. Thus, we read the term “specific binding” in the
claims to mean a specific association, attraction between molecules.
Prima Facie Case
Kanno discloses a construct system for expressing a reporter protein,
(Fig la and b). Fig lb of Kanno shows construct pX81uc which is an
inducible promoter that is activated by a transcription factor. | 66 of Kanno
discloses, “In the case of a polypeptide reporter or polypeptide test agent
fused to the C-terminus of the C-intein, it may also be preferred that the first
amino acid of the polypeptide immediately following the C-terminus of the
C-intein is cystenine, serine, or threonine.” Thus, Kanno discloses a coding
sequence encoding a reporter protein, wherein said coding sequence is in
operable linkage with said inducible promoter. Kanno also discloses a
reporter construct comprising a major late promoter of adenovirus, eight-
repeated LexA operators, and DNA sequence encoding Firefly Luciferase
reporter (e.g. Figure la, 1 b, p. 558, right column, 2nd paragraph).
Fig. la of Kanno, second line of scheme, further discloses a first
transcription factor construct comprising a promoter, and a second promoter;
and a coding sequence encoding a second fusion protein comprising a
second portion of said transcription factor and a second subunit of said split
intein. Kanno Fig. la and b discloses a coding sequence encoding a first
fusion protein comprising a first portion of a transcription factor and a first
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subunit of a split intein, wherein said coding sequence is in operable linkage
with said first promoter.
The principle of the method of Kanno, and as claimed, is shown in
Figure la. When X interacts with Y, the DnaEs are brought in proximity and
undergo correct folding (specific binding), which induces protein splicing.
P. 558, col. 2. To yield an efficient splicing reaction,
two particular amino acid sequences (KFAEY fused to DnaEn
and CFNLSH fused to DnaEc) were inserted at the splicing
junctions of each cDNA These two cDNAs were separately
inserted into multiple cloning sites of pcDNA3.1(+) expression
vectors, and we named these plasmids as pmLDn (encoding a
mLexA-DnaEn fusion protein) and pDcV (encoding a
VP16AD-DnaEc fusion protein) (Figure lb).
P. 558, col. 2. Claim 1 and its transitional claim language “comprising,”
does not exclude the additional X-Y protein interaction or drawing together
of the intein molecules for their specific binding/folding interaction.
Kanno does not disclose that the promoter of the intein construct is a
tissue specific promoter. Yadav makes up for this deficiency in Kanno.
Yadav discloses it is well known in the art to include a tissue specific
promoter in an intein mediated protein splicing construct. 1195, 96, 126.
Kanno discloses that the second subunit of said split intein specifically
binds to the first subunit of the split intein and the coding sequence is in
operable linkage with the second promoter. Expression of the first and
second fusion proteins in a cell results in ligation, by a protein-splicing
reaction mediated by the first and second subunits of said split intein, of the
first and second portions of the transcription factor to produce the
transcription factor and provides expression of the reporter protein only in
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tissues in which expression of the promoters overlap. One of ordinary skill
in the art would have recognized that the folding reactions between split
inteins in Kanno, and Manfredi Fig. 2A, are specific binding reactions well
known in the art and within the definition of “specific binding” of record,
and which are generally useful configurations in split intein mediated protein
and reporter constructs within their technical grasp.
Appellant’s Previous Position
Appellant previously contended that:
[T]he Examiner has erred in interpreting the cited art and, in
fact, the cited references do not teach or suggest all the
limitations of the claims. Furthermore, the Examiner's proposed
modification of the system of Kanno to arrive at the instantly
claimed system would not have been obvious to the ordinary
skilled artisan at least in part because such modification would
render the system of Kanno unable to be used for its intended
purpose.
App. Br. 5—6. In particular, Appellant argues that:
[T]he method of Kanno requires that, to detect a protein-protein
interaction, the test proteins and not the intein subunits
specifically bind to one another. If the intein subunits of Kanno
were to specifically bind with one another the reporter would be
activated in the absence of binding of the test proteins, making
the system incapable of indicating whether or not a protein-
protein interaction of the test proteins has occurred. Thus,
Kanno clearly fails to teach or suggest intein subunits that
specifically interact with one another.
App. Br. 6.
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ANALYSIS
We entertain, but are not persuaded by, Appellant’s previous
arguments of record. As indicated herein, the additional protein-protein
interaction of the test proteins X-Y in Kanno is not excluded from the scope
of the pending claims. In addition, Manfredi teaches that the use of split
inteins and their specific binding are well known in the art of reporter
expression. See, Fig. 2A. Manfredi also teaches that:
Hybrid transcriptional activators composed of a DNA binding
domain from one transcriptional activator and an activation
domain from another transcriptional activator are also useful.
... The corresponding transcriptional elements specifically
interacting with the transcriptional activators or repressors are
well known in the art. See. e.g., Hanna-Rose and Hansen,
Trends. Genet., 12:229-234 (1996).
Manfredi 99 and 100, Fig. 5.
It would have been prima facie obvious for one of ordinary skill in the
art at the time of the invention to use tissue-restricted promoter in the vector
taught by Kanno because Yadav teaches intein-mediated protein splicing,
particularly trans-splicing, in plants, microbial, yeast and animal systems,
the use of regulatory sequence and the regulatory sequence (promoter) can
be tissue-specific, developmental stage-specific or inducible promoter.
Yadav teaches that tissue-specific promoters were well known in the use of
intein reporter systems. One of ordinary skill in the art would have
substituted the promoter taught by Kanno with tissue-specific promoter
taught by Yadav in order to provide tissue-specific expression of the fusion
proteins. Since the intein-mediated protein splicing system taught by Yadav
requires expression of IntN (N-terminal portion of intein) and IntC (C-
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terminal portion of intein) and the IntN and the IntC together forms a
naturally split intein to bring together ExtN and ExtC to form a functional
protein, one of ordinary skill in the art at the time of the invention would
have used a tissue-restricted promoter (for example, same type of tissue-
restricted promoter) that promotes expression of both IntN and IntC in the
same cell. Thus, it would have been obvious to one of ordinary skill that
expression of the reporter protein (ExtN+ExtC) would be in tissue in which
expression of both tissue-restricted promoters overlap. One having ordinary
skill in the art at the time the invention was made would have been
motivated to do so in order to form fused transcription factor containing
mLexA and VP 16AD so as to activate expression of reporter gene as taught
by Kanno with reasonable expectation of success. One of ordinary skill in
the art would have recognized that the folding reactions between split inteins
in Kanno, and Manfredi are specific binding reactions within the definition
of record.
We find that the cited prior art, in combination, teaches each element
claimed. Thus we find that the preponderance of the evidence supports that
the combination of the cited references teaches the invention, as claimed.
CONCLUSION OF LAW
The Examiner’s obviousness rejections are reversed in favor of the
above new ground of rejection. All pending, rejected claims fall.
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). 37 C.F.R. § 41.50(b) provides “[a] new ground of
rejection pursuant to this paragraph shall not be considered final for judicial
review.” 37 C.F.R. § 41.50(b) also provides that Appellant, WITHIN TWO
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MONTHS FROM THE DATE OF THE DECISION, must exercise one of
the following two options with respect to the new grounds of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment of
the claims so rejected or new evidence relating to the claims so
rejected, or both, and have the matter reconsidered by the
examiner, in which event the proceeding will be remanded to
the examiner....
(2) Request rehearing. Request that the proceeding be reheard
under § 41.52 by the Board upon the same record....
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(l)(iv).
REVERSED: and 37 C.F.R, $ 41.50(b)
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