Ex Parte Gaitanaris

Patent Trial and Appeal Board

Sep 18, 2012

10974603 (P.T.A.B. Sep. 18, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte GEORGE A. GAITANARIS
__________

Appeal 2012-000158
Application 10/974,603
Technology Center 1600
__________

Before DEMETRA J. MILLS, ERIC GRIMES, and FRANCISCO C.
PRATS, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
transgenic mouse, which the Examiner has rejected for obviousness. We
have jurisdiction under 35 U.S.C. § 6(b). We reverse.
STATEMENT OF THE CASE
Claims 23-33 and 37-41 are on appeal. Claim 23 is the only
independent claim and reads as follows:
23. A transgenic mouse comprising:
(a) a first transgene comprising (i) a regulatory gene encoding a
regulatory protein, and (ii) a transcription terminator at which site
Appeal 2012-000158
Application 10/974,603

2
transcription terminates, said transcription terminator situated 3' to said
regulatory gene, wherein said first transgene has integrated into an
endogenous gene of said mouse such that said endogenous gene is mutated
and said regulatory gene is positioned for expression under control of the
promoter of said endogenous gene, said promoter being operably linked to
said regulatory gene upon integration of said transgene into said endogenous
gene, and said first transgene mutagenizes said endogenous gene; and
(b) a second transgene comprising a gene operably linked to
regulatory sequence regulated by said regulatory protein, wherein said
second transgene is integrated into the genome of said mouse,
wherein said regulatory protein modulates expression of said gene
operably linked to said regulatory sequence.

The claims stand rejected under 35 U.S.C. § 103(a) as follows:
• Claims 23-27, 37, 38, 40, and 41 based on Furth,1 Friedrich,2 and
Ashfield3 (Answer 5);
• Claims 28-31 based on Furth, Friedrich, Ashfield, and Zhang4
(Answer 9);
• Claim 32 based on Furth, Friedrich, Ashfield, and Bremer5 (Answer
10);

1 Priscilla A. Furth et al., Temporal control of gene expression in transgenic
mice by a tetracycline-responsive promoter, 91 PROC. NATL. ACAD. SCI.
USA 9302-9306 (1994).
2 Glenn Friedrich et al., Promoter traps in embryonic stem cells: a genetic
screen to identify and mutate developmental genes in mice, 5 GENES AND
DEVELOPMENT 1513-1523 (1991).
3 Rebecca Ashfield et al., Transcriptional termination between the closely
linked human complement genes C2 and Factor B: common termination
factor for C2 and c-myc?, 110 EMBO J. 4197-4207 (1991).
4 Guohong Zhang et al., An Enhanced Green Fluorescent Protein Allows
Sensitive Detection of Gene Transfer in Mammalian Cells, 227 BIOCHEM.
BIOPHY. RES. COMM. 707-711 (1996).
Appeal 2012-000158
Application 10/974,603

3
• Claim 33 based on Furth, Friedrich, Ashfield, and Smith6 (Answer
11); and
• Claim 39 based on Furth, Friedrich, Ashfield, and Borrelli7 (Answer
12).
Thus, each of the Examiner’s relies on the combination of Furth,
Friedrich, and Ashfield. The Examiner finds that Furth discloses a
transgenic mouse that includes in its genome a first transgene encoding a
regulatory protein and a second transgene encoding a reporter gene, the
expression of which is regulated by the regulatory protein of the first
transgene (Answer 5-6). The Examiner acknowledges that Furth’s first
transgene is not under the control of an endogenous promoter and does not
include a transcriptional terminator, as required by the claims (id. at 6).
The Examiner finds that Friedrich discloses “a transgenic mouse
comprising in its genome a transgene comprising a fusion of β-gal and
neomycin phosphotransferase gene under the control of a promoter of an
endogenous gene” (id.), and teaches that “such promoter traps combine the
ability to select for insertions within genes with the ability to follow the
activity of the tagged gene by β-gal expression, and perform functional
analysis of the gene” (id. at 7). The Examiner finds that Ashfield discloses

5 Meire C. D. Bremer, VDE endonuclease cleaves Saccharomyces cerevisiae
genomic DNA at a single site: physical mapping of the VMA1 gene, 20
NUCLEIC ACIDS RESEARCH 5484 (1992).
6 Smith et al., US 6,150,169, Nov. 21, 2000.
7 Emiliana Borrelli et al., Targeting of an inducible toxic phenotype in
animal cells, 85 PROC. NATL. ACAD. SCI. USA 7572-7576 (1988).
Appeal 2012-000158
Application 10/974,603

4
the identification of a transcription terminator between human complement
genes (id.).
The Examiner concludes that it would have been obvious
to make a transgenic mouse comprising the binary temporal
control system as taught by Furth et al. and modif[y] the
transgenic mouse by replacing the promoter that controls the
first transgene with a promoter from an endogenous gene such
that it provides a gene regulatory system that can study tissue
specific and/or developmental stage specific expression of an
endogenous gene.
(Id.) The Examiner reasons that Friedrich’s teachings would have provided
a reasonable expectation of success in modifying Furth’s system to put the
first transgene under the control of an endogenous promoter (id. at 7-8). The
Examiner also concludes that it would have been obvious to include a
transcription terminator to prevent transcriptional read-through to
neighboring sequences (id. at 8).
Appellant argues that the Examiner has not provided a reason that a
person of ordinary skill in the art would have combined the references in the
manner proposed (Appeal Br. 10). Appellant argues that “[n]either
reference . . . provides any objective teaching that would lead an individual
to combine them in a manner so as to result in the claimed invention.
Indeed, combining the references as proposed by the Examiner would
further the goal of neither Furth nor Friedrich.” (Id. at 11.)
We agree with Appellant that the Examiner has not persuasively
explained why a skilled worker would have modified the prior art in the
manner required by the claims. Claim 23 recites a first transgene that
encodes a regulatory protein and is under the control of an endogenous
promoter.
Appeal 2012-000158
Application 10/974,603

5
Furth discloses a method of making transgenic mice in which
expression of a gene of interest can be turned off or on by administering or
withholding tetracycline (Furth 9302, abstract). Furth describes two types of
transgenic mice, one that includes a regulatory gene in its genome and a
second that includes a gene of interest (e.g., a reporter gene) under the
control of a promoter controlled by the regulatory gene (id.). When the two
types of mice are mated, the double-transgenic offspring express the gene of
interest in a tetracycline-dependent manner (id.).
Furth’s system depends on the protein encoded by its regulatory gene
to drive transcription of the gene of interest when tetracycline is absent (id.
at 9302, right col.). In Furth’s construct, the regulatory gene is “under the
control of the hCMV IE1 promoter/enhancer” (id. at 9302, right-hand col.),
and Furth discloses that the “hCMV IE1 promoter/enhancer was chosen
because it is expressed in a broad spectrum of tissues in transgenic mice”
(id. at 9303, right col.).
Furth concludes that “the tetracycline regulatory system can provide
temporal control of transgene expression” (id. at 9306, left col.) and that the
“induction of transgenes through the withdrawal of tetracycline can have
specific advantages for some experiments,” such as analyzing the roles of
oncogenes, growth factors, or tumor suppressor genes on tumor formation
(id.). Furth also states that “temporal control of the induction of growth
modulators, oncoproteins, and other proteins participating in developmental
processes could provide further definition to their roles in normal growth
and tumorigenesis” (id.).
Appeal 2012-000158
Application 10/974,603

6
Friedrich discloses a system for “selecting insertion mutations in
mice” (Friedrich 1513, abstract). Friedrich describes its system as a
“[p]romoter trap[ ] . . . based on the integration of a reporter gene lacking a
promoter into the genome and its expression from a tagged endogenous
promoter” (id. at 1514, left col.). Furth uses a “reporter gene encod[ing] a
protein, β-geo, with both β-galactosidase (β-gal) and neomycin phospho-
transferase (neo) activities” (id.). Furth discloses that the reporter gene
allows selection of cells with promoter trap events because the neo gene
confers resistance to the antibiotic G418, and the β-gal gene allows assay of
spatial and temporal patterns of expression of the trapped promoter (id.).
We agree with Appellant that the Examiner has not provided any
persuasive reason for concluding that it would have been obvious to modify
either Furth or Friedrich as required by the claims on appeal. Furth discloses
that its system requires expression of its regulatory protein in order to
control expression of a gene of interest, and it states that the hCMV IE1
promoter/enhancer was specifically chosen because it is expressed in a
variety of tissues. The Examiner has not provided adequate evidence or
sound reasoning to support the conclusion that it would have been obvious
to modify Furth’s system to put the regulatory gene under the control of a
random endogenous promoter, as in Friedrich, when there is no way of
knowing whether the endogenous promoter would provide a pattern of
expression that would make it useful in Furth’s system.
The Examiner reasons that it would have been obvious to make the
required modification to Furth’s system to “provide[ ] a gene regulatory
system that can study tissue specific and/or developmental stage specific
Appeal 2012-000158
Application 10/974,603

7
expression of an endogenous gene” (Answer 7). Furth’s system, however,
already allows study of expression of any gene of interest – endogenous or
otherwise – by including it in the system under the control of the promoter
regulated by Furth’s regulatory protein. The Examiner has not provided an
adequate reason for concluding that a skilled worker would have found it
obvious to integrate Furth’s regulatory protein into the genome under the
control of an endogenous promoter.
Friedrich’s system does rely on endogenous promoters to drive
expression of its transgene. However, Friedrich’s transgene includes a
selectable marker (neo) that allows selection, based on antibiotic resistance,
of insertion events that put the transgene under the control of an endogenous
promoter, as well as a β-galactosidase gene that allows colorimetric
screening for activity of the promoter under different conditions. Furth does
not disclose that its regulatory protein allows either selection based on its
expression or an easy method of screening for its expression. Thus, to the
extent the Examiner may have been relying on this rationale as a basis of
obviousness, the references do not support it either.
In short, we agree with Appellant that the Examiner’s proposed
modification of the prior art “would further the goal of neither Furth nor
Friedrich” (Appeal Br. 11). Obviousness under § 103 requires “identify[ing]
a reason that would have prompted a person of ordinary skill in the relevant
field to combine the [known] elements in the way the claimed new invention
does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). The
Examiner has not provided a persuasive reason for combining the elements
Appeal 2012-000158
Application 10/974,603

8
of Furth and Friedrich, and therefore the rejection of claim 23, and
dependent claims 24-27, 37, 38, 40, and 41, must be reversed.
Each of the other rejections on appeal also relies on the combination
of Furth and Friedrich (see Answer 9-12), and suffers from the same
deficiency discussed above. Therefore, we also reverse the rejections of
claims 28-33 and 39.
SUMMARY
We reverse all of the rejections on appeal.

REVERSED

lp