Ex Parte Elledge et al

Patent Trial and Appeal Board

Jun 6, 2016

12528595 (P.T.A.B. Jun. 6, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/528,595 08/25/2009
66991 7590 06/06/2016
LAW OFFICE OF MICHAEL A, SANZO, LLC
15400 CALHOUN DR.
SUITE 125
ROCKVILLE, MD 20855
FIRST NAMED INVENTOR
Stephen Elledge
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.
7570/15400US 4985
EXAMINER
HIBBERT, CATHERINE S
ART UNIT PAPER NUMBER
1636
MAILDATE DELIVERY MODE
06/06/2016 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 PATENT TRIAL AND APPEAL BOARD
Ex parte STEPHEN ELLEDGE and HSUEH-CHI YEN
Appeal2013-009690
Application 12/528,595
Technology Center 1600
Before DONALD E. ADAMS, DEMETRA J. MILLS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to a
retrovirus vector. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants identify the Real Party in Interest as The Brigham and
Women's Hospital, Inc. (See App. Br. 2.)
Appeal2013-009690
Application 12/528,595
Statement of the Case
Background
"The present invention is directed to compositions and methods that
can be used to analyze the stability of proteins in vivo, to determine the
specificity of ubiquitin ligases and to screen for factors either inhibiting or
enhancing the activity of these enzymes and deubiquitinating enzymes"
(Spec. 1, 11. 10-13).
The Claims
Claims 1-6 and 30 are on appeal. Independent claim 1 is
representative and reads as follows:
1. A retrovirus vector comprising:
a) a promoter;
b) a sequence encoding a first marker protein lying 3 '
to said promoter;
c) an internal ribosome entry sequence (IRES) lying
3' to said sequence encoding said first marker
protein;
d) a sequence encoding a second marker protein,
wherein said second marker protein is different
from said first marker protein and lies 3 ' to said
internal ribosome entry sequence;
e) a sequence encoding a test protein lying 3' to said
sequence encoding said second marker protein and
wherein the sequence encoding the second marker
protein and the sequence encoding the test protein
are adjacent to one another so that they form a
single fusion protein when expressed;
and wherein both the sequence encoding said first marker
protein and the sequence encoding said second marker
protein are operably linked to said promoter.
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Appeal2013-009690
Application 12/528,595
The Issues
A. The Examiner rejected claims 1, 3---6 and 30 under 35 U.S.C. § 103(a)
as obvious over Martin2 and Rogers 3 (Ans. 2---6).
B. The Examiner rejected claim 2 under 35 U.S.C. § 103(a) as obvious
over Martin, Rogers, and Trono4 (Ans. 6-7).
C. The Examiner rejected claim 6 under 35 U.S.C. § 103(a) as obvious
over Martin, Rogers, and Baross5 (Ans. 7-8).
A. 35 US.C. § 103(a) over Martin and Rogers
The Examiner finds that Martin teaches
a retrovirus vector comprising: a CMV promoter; a sequence
encoding a first marker protein, DsRed, lying 3 ' to said
promoter; an internal ribosome entry sequence (IRES) lying 3'
to said sequence encoding DsRed; a sequence encoding a
second marker protein, GFP, wherein said second marker
protein is different from said first marker protein and lies 3' to
the IRES; wherein both the sequence encoding said first marker
protein ( dsRED) and the sequence encoding said second marker
protein (GFP) are operably linked to the promoter.
(Ans. 3).
2 Martin et al., Development of a new bicistronic retroviral vector
with strong IRES activity, 6 BMC BIOTECHNOLOGY 1-9 (2006).
3 Rogers et al., New Mammalian Expression Vectors Employ
Stable, High-Level Fluorescence Humanized Renilla GFP
Reporter, http://www.biocompare.com/Application-Notes/41982-
New-Mammalian-Expression-Vectors-Employ-Stable-High-Level-
Fluorescence-Humanized-Renilla-GFP-Reporter (accessed July 9,
2012), (2002)
4 Trono et al., US 2005/0014166 Al, published Jan. 20, 2005.
5 Baross et al., Systematic Recovery and Analysis of Full-ORF
Human cDNA Clones, 14 GENOME RESEARCH 2083-2092 (2004).
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Appeal2013-009690
Application 12/528,595
The Examiner acknowledges that Martin "does not teach a sequence
encoding a test protein lying 3' to said sequence encoding said second
marker protein and wherein the sequence encoding the second marker
protein and the sequence encoding the test protein are adjacent to one
another so that they form a single fusion protein when expressed" (id.).
The Examiner finds that Rogers teaches "GFP-fusion constructs
where a polypeptide/protein sequence of interest (i.e., which reads on a test
protein sequence) is fused to the 3' side of the GFP sequence" (id.).
The Examiner finds it obvious to "substitute into the bicistronic vector
disclosed by Martin et al the sequence encoding the vector element disclosed
by Rogers et al of the humanized GFP-test protein fusion ... for studies
which 'allow for the real-time monitoring ... in both transient and stable
applications"' (Ans. 5).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner's conclusion that Martin and Rogers render
claim 1 obvious?
Findings of Fact
1. Martin teaches
a new and convenient set of eukaryotic bicistronic expression
vectors that respects the original EMCV initiation environment
and fulfills several important needs: ease of cloning, sequencing
possibilities of the cloned inserts using universal primers, high
level of plasmid DNA production, possibility of epitope tagging
for immunological tracking of expressed inserts, possibility of
production of retro viral particles for retroviral transduction, and
easy monitoring of expression through the concomitant
synthesis of a fluorescent protein (GFP).
(Martin 2, col. 2.)
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Appeal2013-009690
Application 12/528,595
2. Figure 3 of Martin is reproduced below:
T\_ If a ,SP6 HimHU
\ i .! •. _"""""""-~ \if · ' -----------------, f'!K -1,'.i;;;};;~:---------- L TR
Fig:uro l
Figure 3 is a "[s]chematic representation of the pPRIG-HA-Red and pPRIG-
Hd-HA-Red retroviral vectors" (Martin 5) (emphasis omitted).
3. Figure 1 of Rogers is reproduced below:
Figure 1 depicts:
Em:::LJR~~~i$
~~Q;,'.;_~.@l~~
1;~~·1x:;m~~mr:c::_-_,~~i:-~•
~,~~~1mw~atmwML;u:• ~~
The pIRES-hrGFP-la and pIRES-hrGFP-2a expression vectors
(Figure 1) have a multiple cloning site upstream of three
contiguous copies of either the FLAG or hemagglutin (HA)
epitope tag sequence, respectively. In both vectors, duplicate
stop codons follow the final epitope tag sequence to ensure
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Appeal2013-009690
Application 12/528,595
termination of the inserted gene transcript and expression of an
epitope-tagged native protein. The stop codons are followed by
the coding region of an internal ribosome entry site (IRES) for
reentry of the ribosome and protein production of the
downstream hrGFP gene. In these bicistronic vectors,
translation of two open reading frames from one mRNA allows
expression of a gene of interest to be monitored at the single-
cell level by virtue of expression of hrGFP on the same
transcript. Expression of hrGFP can be detected visually, and
the FLAG- or HA-tagged fusion product is easily detected by
Western blot analysis.
(Rogers 2-3.)
4. Rogers teaches that using "the phrGFP-Nl vector, insertion of a
gene of interest into the multiple cloning site results in expression of hrGFP
fused to the N-terminus of the protein of interest" (Rogers 4).
5. Rogers teaches that"[ w ]e tested the protein fusion vectors by
fusing hrGFP to a series of genes that encode subcellularly localized
proteins .... These [sic] data confirm that phrGFP-Nl and phrGFP-G
protein fusion vectors provide convenient plasmid construction and high
level fluorescence ofhrGFP fusion proteins within the cell" (Rogers 4).
6. Rogers teaches that "each of the four subcellular localization
vectors ... are available as stand alone products. These vectors allow real-
time monitoring of the fate of peroxisomes, mitochondria, golgi and nuclei
in both transient and stable applications" (Rogers 4).
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'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
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Appeal2013-009690
Application 12/528,595
Analysis
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 2---6; FF 1---6) and agree that claim 1
is rendered obvious by Martin and Rogers. We address Appellants'
arguments below.
Appellants "contend that replacing the marker sequence at the second
cistronic site of Martin with a sequence such as that described by Rogers
(which is referred to below as a 'marker-protein fusion sequence')
constituted an act of invention" (App. Br. 11 ).
We do not find this argument persuasive. As the Examiner notes,
Martin teaches a bicistronic vector with the structure beginning at the 5' end
of a CMV promoter, a first DsRed marker, an IRES element, and a second
GFP marker (FF 2). Rogers teaches fusion of a GFP marker to the N-
terminus of a protein of interest (FF 4) in order to allow monitoring of
organelle fates (FF 6). We agree with the Examiner that it would have been
obvious to substitute known elements for one another, specifically Rogers
GFP - protein of interest fusion protein for the second GFP marker of
Martin in order to "allow real-time monitoring of the fate of peroxisomes,
mitochondria, golgi and nuclei in both transient and stable applications" (FF
6). See Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356,
1364 (Fed. Cir. 2012) ("This case presents a strong case of obviousness
based on the prior art references of record. [The claim] recites a combination
of elements that were all known in the prior art, and all that was required to
obtain that combination was to substitute one well-known ... agent for
another.")
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Application 12/528,595
Appellants contend that
a marker-protein fusion sequence and a marker sequence
differ substantially from one another. When fused to a
protein, a marker sequence allows one to follow the fate of
the protein in a way that cannot be done using either the
marker or protein alone. Thus, prima facie obviousness
cannot be based on an allegation that Appellants just
substituted one equivalent for another; some motivation for
combining elements must be established.
(App. Br. 11.)
We are not persuaded. We agree that in any case of substitution
where the equivalents are not identical, the issue becomes whether the
ordinary artisan would have had reason to make the substitution. Here,
Rogers provides such a reason to use the GFP - protein of interest fusion
protein, specifically in order to "allow real-time monitoring of the fate of
peroxisomes, mitochondria, golgi and nuclei in both transient and stable
applications" (FF 6). The ordinary artisan, interested in real-time
monitoring of organelle fate, would have had reason to incorporate the GFP
- protein of interest fusion into Martin's vector to permit such monitoring.
Appellants contend that "[ s ]ubstituting a marker-protein fusion
sequence for a marker sequence at the second cistronic site of Martin's
bicistronic vectors complicates the process of Martin without furthering its
objectives in any clear way" (App. Br. 12). Appellants further contend that
"using a bicistronic vector that includes the expression of a different marker
from the first cistronic site complicates Rogers' process of following the fate
of organelles by localizing marker-fused proteins without any clear
improvement in the process" (id.).
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Appeal2013-009690
Application 12/528,595
We are not persuaded because this argument fails to address the
combination of references. The issue is not whether the goal of Martin is
satisfied, but whether the incorporation of Roger's GFP - protein of interest
fusion provides additional functionality to the Martin vector, the ability to
monitor organelles in real time (FF 6). "Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references." In re Merck & Co., 800
F.2d 1091, 1097 (Fed. Cir. 1986). We remain in agreement with the
Examiner that
one of ordinary skill in the art of constructing mammalian
expression vectors would have been motivated to add the
GFP-test protein fusion protein feature of Rogers et al into
the successfully engineered vectors of Martin et al
(replacing the GFP feature of the Martin construct) for the
motivation provided by Rogers et al to add the benefit of
being able to localize test proteins of interest in the
mammalian cells.
(Ans. 10.)
Conclusion of Law
The evidence of record supports the Examiner's conclusion that
Martin and Rogers render claim 1 obvious.
B. and C. 35 US.C. § 103(a)
Appellants do not separately argue these obviousness rejections
including Trono and Baross. Having affirmed the obviousness rejection
over Martin and Rogers for the reasons given above, we also find that the
further obvious combination with Trono or Baross render the remaining
claims obvious for the reasons given by the Examiner (see Ans. 6-8).
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Application 12/528,595
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over Martin and Rogers. Claims 3---6 and 30 fall with
claim 1.
We affirm the rejection of claim 2 under 35 U.S.C. § 103(a) as
obvious over Martin, Rogers, and Trono.
We affirm the rejection of claim 6 under 35 U.S.C. § 103(a) as
obvious over Martin, Rogers, and Baross.
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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