Ex Parte Kinsella et al

Patent Trial and Appeal Board

Aug 1, 2018

13825543 (P.T.A.B. Aug. 1, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/825,543 06/07/2013
83092 7590 08/03/2018
Rigel Pharmaceuticals, Inc.
Bozicevic, Field & Francis LLP
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
FIRST NAMED INVENTOR
Todd M. Kinsella
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
RIGL-054 8472
EXAMINER
LEA VITT, MARIA GOMEZ
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
08/03/2018 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 and DONALD G. PAY AN
Appeal2017-007990 1
Application 13/825,543
Technology Center 1600
Before FRANCISCO C. PRATS, JEFFREYN. FREDMAN, and
JOHN G. NEW, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims to a mouse or
rat model for monitoring muscle cell atrophy. The Examiner rejected the
claims for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b)(l).
We affirm.
STATEMENT OF THE CASE
The following rejections are before us for review:
(1) Claims 1, 2, 11-14, 17, and 19-26, under 35 U.S.C. § 103(a) for
obviousness over Cardozo, 2 Nishijo, 3 Capecchi, 4 and Tong5 (Ans. 3-8); and
1 Appellants state that the "Real Party in Interest is Rigel Pharmaceuticals,
Inc." Br. 3.
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Application 13/825,543
(2) Claims 6-10, under 35 U.S.C. § I03(a) for obviousness over
Cardozo, Nishijo, Capecchi, Tong, Watson, 6 de Felipe,7 and Kim8 (Ans. 14--
16).
Claim 1 is representative and reads as follows:
1. A mouse or rat model for monitoring muscle cell
atrophy, wherein the mouse or rat has a nuclear genome
compnsmg:
(a) a biologically active atrogen gene that is endogenous
to the mouse or rat, comprising an atrogen promoter and coding
sequence for an atrogen protein, and
(b) a reporter construct comprising:
i. a first coding sequence for an optically
detectable protein; and
ii. a second coding sequence for a secreted reporter
enzyme;
wherein the reporter construct is operably linked to the
atrogen promoter, and wherein said atrogen protein, said
secreted reporter enzyme and said first optically detectable
protein are induced by muscle cell atrophy, thereby allowing
muscle cell atrophy in the mouse or rat to be measured by in
2 US 2006/0166324 Al (published Jul. 27, 2006).
3 Koichi Nishijo et al., Biomarker system for studying muscle, stem cells,
and cancer in vivo, 23 FASEB J. 2681-2690 (2009).
4 US 2005/0149998 Al (published Jul. 7, 2005).
5 Chang Tong et al., Production of p53 gene knockout rats by homologous
recombination in embryonic stem cells, 467 NATURE 211-213 (2010).
6 JAMES A. WATSON ET AL., RECOMBINANT DNA, GENES AND GENOMES-A
SHORT COURSE (3d ed. 2007).
7 Pablo de Felipe, Skipping the co-expression problem: the new 2A
'CHYSEL' technology, 2 GENETIC VACCINES AND THERAPY 13 (2004).
8 Jin Hee Kim et al., High Cleavage Efficiency of a 2A Peptide Derived from
Porcine Teschovirus-1 in Human Cell Lines, Zebrafish and
Mice, 6 PLoS ONE 1-8 (2011).
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vivo imaging and by testing for said secreted reporter enzyme in
the blood of the mouse or rat.
Br. 12.
DISCUSSION
The Examiner's Prima Facie Case
In determining that the mouse/rat model recited in representative
claim 1 would have been obvious, the Examiner cited Cardozo as describing
a reporter construct in which the promoter of a human atrogen gene having
an activity encompassed by claim 1, Muscle Atrophy F-box (MAFbx), was
operably linked to a sequence coding for an optically detectable protein.
Ans. 3-5.
The Examiner conceded that Cardozo' s reporter construct differs
from the construct recited in claim 1 in that Cardozo "does not teach a
second marker for a secreted reporter enzyme." Id. at 5.
As evidence that the reporter construct recited in claim 1 nonetheless
would have been obvious, the Examiner cited Nishijo as disclosing that a
reporter construct, having "an optically detected reporter gene functionally
linked to a gene encoding a human placental phosphatase that is secreted
into the serum[,] ... permit[ s] both spatial localization and accurate
quantification of biological processes in vivo, even when the tissue of
interest is deep within an animal (abstract)." Id.
The Examiner conceded that Cardozo and Nishijo's combined
suggestion of preparing a reporter construct with both a visually detectable
reporter and a secreted enzyme reporter differs from Appellants' claim 1 in
that the combined references "do not teach the generation of transgenic
knock-in mice and rats for testing muscle loss under the control of an
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endogenous mouse or rat atrogen promoter ( e.g., mouse or rat MAFbx
promoter)." Id.
As evidence that an ordinary artisan would have considered it obvious
to prepare a mouse or rat model encompassed by representative claim 1, in
which the endogenous mouse or rat MAFbx promoter drives expression of
the two-reporter construct suggested by Cardozo/Nishijo, the Examiner
found:
Id.
the generation of knock-in transgenic mice homozygous
and heterozygous having a genome comprising a modification
of said genome and produced by inserting into the mice
embryonic stem cells a target vector of interest which is capable
of homologous recombination comprising endogenous
promoters able to drive transgene expression was routine in the
art at the time the invention was made, as evidenced by the
teachings of Capecchi et al. (full document). Likewise, ...
prior to the effective filing date of the instant application, ES
[ embryonic stem] cells had been successfully isolated and used
to develop transgenic animals other than mice, including rats as
evidenced by the disclosure of Tong et al.
Based on the references' combined teachings, the Examiner reasoned
that, "[i]n view of the benefit of using a secreted reporter enzyme for
accurate quantification in vivo," an ordinary artisan would have considered it
obvious to employ a second polypeptide reporter, "such as a human
placental phosphatase, as taught by Nishijo et al., in the vector construct of
Cardozo et al., for accurate quantification in vivo of a biological process
induced by regulation of the MAFbx promoter vector with a reasonable
expectation of success .... " Id. at 5---6.
The Examiner further reasoned that it would have been obvious to
prepare a mouse or rat model encompassed by representative claim 1, in
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which the endogenous mouse or rat MAFbx promoter drives expression of
the two reporter construct suggested by Cardozo/Nishijo,
for further testing of MAFbx transcription regulatory sequence
in muscle-specific expression of trans genes during or after
development under the control of a mouse endogenous
promoter to permit developmental expression under the control
of a mouse MAFbx endogenous promoter to permit muscle-
specific expression of trans genes during or after development or
monitoring pathways leading to cellular muscular dysfunctions.
Id. at 6.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
primafacie case ofunpatentability ....
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 the present case, having carefully considered the arguments and
evidence advanced by Appellants and the Examiner, Appellants do not
persuade us that the preponderance of the evidence fails to support the
Examiner's conclusion of obviousness as to claim 1.
In particular, we find that Appellants' arguments are in large part
directed to the alleged deficiencies of the cited references individually,
rather than addressing the combination of references as advanced by the
Examiner. See In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir.
1986) ("Non-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references. . . . [The reference] must be read, not in
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Application 13/825,543
isolation, but for what it fairly teaches in combination with the prior art as a
whole.").
For example, we acknowledge, as Appellants contend (Br. 7), that in
describing a reporter construct composed of an optically detectable protein
operably linked to the regulatory sequences of the Muscle Atrophy F-box
(MAFbx) gene, Cardozo discusses the use of human sequences rather than
an endogenous mouse or rat sequence, as recited in Appellants' claim 1. See
Cardozo ,r 58.
We acknowledge also that, when using its reporter construct for
assaying potential muscle-building agents or potential agents for inhibiting
muscle loss (see id. ,r 61 ), Cardozo does not appear to disclose its integration
into a mouse model, as claim 1 also requires. See id. ,r,r 13 0, 131 ( describing
transgenic cells generally).
Nishijo, however, teaches the desirability of using genetically
engineered mice, incorporating reporter genes, as models for studying
physiological processes, including in the context of muscle tissue. See
Nishijo 2681 ("GENETICALLY ENGINEERED MICE are emerging as
critical tools to study tissue physiology, stem cell dynamics, and tumor
progression because of the reporter genes that can be incorporated into these
preclinical models." ( citation omitted)); see also id. ( describing
"[b]iomarker system for studying muscle" (title)).
Nishijo, moreover, teaches that when using a mouse model, it is
advantageous to use a reporter construct composed of both an optically
detectable protein and a secreted reporter enzyme, as recited in Appellants'
claim 1:
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Id.
In this study, we introduce a mouse reporter system that
facilitates dual spatial detection and quantification for cells of
interest in conditional genetic models that use Cre/LoxP
technology. Our engineered allele strongly expresses firefly
luciferase and a human placental secreted alkaline phosphatase
as tandem cistrons from a modified Rosa26 promoter. These
reporters are amenable to noninvasive optical imaging and
minimally invasive serum microtiter assays, respectively ....
This dual-modality bioreporter system promises to have a wide
range of application in preclinical models of disease where
higher precision and a shorter time to study end point are
desirable.
Therefore, Cardozo differs from Appellants' claim 1 in not disclosing
the use of its reporter construct in a mouse model, and in not combining its
reporter construct's optically detectable protein with a secreted reporter
enzyme. Nevertheless, given the teachings in Nishijo noted above,
Appellants do not persuade us that the Examiner erred in finding that an
ordinary artisan had good reason for, and a reasonable expectation of
success in, combining the optically detectable protein of Cardozo' s reporter
construct with a secreted reporter enzyme, and using that construct in a
mouse model, as recited in claim 1.
As to the use of the endogenous mouse MAFbx sequences required by
Appellants' claim 1 in relation to the reporter construct, we note, as the
Examiner pointed out, that the core promoter of the mouse and human
MAFbx genes is highly conserved. See Ans. 11 (citing Cardozo ,r,r 7, 56-
58, Fig. 5). We note also Cardozo's disclosure that expression of the mouse
MAFbx gene had previously been evaluated in relation to muscle loss.
Cardozo ,r 7. Accordingly, Appellants do not persuade us that the Examiner
erred in finding that, when preparing an MAFbx promoter sequence
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operably linked to an optically detectable protein and a secreted reporter
enzyme, for use in a mouse model of muscle loss as suggested by the
combination of Cardozo and Nishijo, an ordinary artisan would have
recognized that the mouse MAFbx promoter sequence would be useful in the
reporter construct.
We acknowledge, as Appellants contend, that Capecchi and Tong
might only "provide ways to make transgenic mice and rats," and include no
specific disclosures relating to the constructs required by claim 1. Br. 9.
The Examiner, however, cited those references as evidence that
techniques for preparing transgenic mice and rats including reporter genes
linked to endogenous regulatory sequences were known in the art (see, e.g.,
Ans. 5), a fact Appellants do not dispute. Moreover, that Capecchi and Tong
might not include specific disclosures relating to the constructs required by
claim 1 does not negate the combined teachings in Cardozo and Nishijo,
discussed above, suggesting the preparation of a mouse model for muscle
atrophy including the dual reporter proteins required by claim 1, or the fact
that, based on the teachings in Capecchi and Tong, an ordinary artisan would
have known how to prepare those models for muscle atrophy.
We acknowledge, but are unpersuaded by, Appellants' contention that
" [ c] ombining the MAFbx promoter of Cardozo with the dual-reporter
construct ofNishijo would result in a construct that would not allow for in
vivo monitoring of muscle atrophy, let alone constant in vivo measurement
thereof." Br. 8.
We first note that claim 1 does not require the claimed model to allow
constant in vivo measurement of muscle atrophy. Rather, claim 1 recites that
the model need only allow "muscle cell atrophy in the mouse or rat to be
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measured by in vivo imaging and by testing for said secreted reporter
enzyme in the blood of the mouse or rat." Br. 12 (claim 1). As Nishijo
explains, its construct provides precisely that capability. Nishijo 2681
("These reporters are amenable to noninvasive optical imaging and
minimally invasive serum microtiter assays, respectively.").
Moreover, Appellants do not direct us to disclosures in any of the
cited references explaining why, in the context of analyses such as
Cardozo's muscle atrophy, Nishijo suggests preparation of a model that
would be constitutively inducible. Again, such an interpretation ignores the
suggestion of the combined references. Further, even if the combination of
Nishijo and Cardozo were to suggest only a constitutively inducible mouse
model of muscle atrophy, Appellants do not persuasively explain why
representative claim 1 would fail to encompass such a model.
In sum, for the reasons discussed, Appellants do not persuade us that
the preponderance of the evidence fails to support the Examiner conclusion
of obviousness as to claim 1. We, therefore, affirm the Examiner's rejection
of claim 1 over Cardozo, Nishijo, Capecchi, and Tong. Because they were
not argued separately, claims 2, 11-14, 17, and 19-26, fall with claim 1. See
37 C.F.R. § 4I.37(c)(l)(iv).
As noted above, the Examiner also rejected claims 6-10 for
obviousness over Cardozo, Nishijo, Capecchi, Tong, Watson, de Felipe, and
Kim. Ans. 14--16.
As to this rejection, Appellants contend only that "as Watson, De
Felipe and Kim are cited merely for allegedly teaching an IRES and a
FMDV2A self-processing polypeptide, the additional references cannot
remedy the above described deficiencies of the primary cited art.
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Accordingly, Applicants respectfully submit that this rejection may be
withdrawn." Br. 10.
As discussed above, however, Appellants do not persuade us that the
combined teachings of Cardozo, Nishijo, Capecchi, and Tong are deficient
in demonstrating the obviousness of the subject matter recited in claim 1.
Because Appellants, therefore, do not identify, nor do we discern, error in
the Examiner's conclusion that the models recited in claims 6-10 would
have been obvious to an ordinary artisan, we also affirm the Examiner's
rejection of claims 6-10 for obviousness over Cardozo, Nishijo, Capecchi,
Tong, Watson, de Felipe, and Kim.
SUMMARY
We affirm the Examiner's rejection of claims 1, 2, 11-14, 17, and 19-
26, under 35 U.S.C. § 103(a) for obviousness over Cardozo, Nishijo,
Capecchi, and Tong.
We also affirm the Examiner's rejection of claims 6-10, under 35
U.S.C. § 103(a) for obviousness over Cardozo, Nishijo, Capecchi, Tong,
Watson, de Felipe, and Kim.
TIME PERIOD
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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