Ex Parte Barber

Patent Trial and Appeal Board

Oct 22, 2012

10194594 (P.T.A.B. Oct. 22, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte GLEN N. BARBER
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Appeal 2012-000238
Application 10/194,594
Technology Center 1600
__________

Before DONALD E. ADAMS, ERIC GRIMES, and LORA M. GREEN,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims related to a
recombinant viral vector. The Examiner has rejected the claims for
obviousness and for including new matter. We have jurisdiction under 35
U.S.C. § 6(b). We reverse the new matter rejection and affirm the
obviousness rejection.
STATEMENT OF THE CASE
Claims 103, 104, and 106-108 are on appeal. Claim 103 is
representative and reads as follows:
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103. A recombinant vesicular stomatitis virus (VSV) vector
comprising an interferon beta nucleic acid sequence, wherein the interferon
beta nucleic acid sequence is inserted between the vesicular stomatitis virus
vector genes, G and L and the VSV lacks G-protein function.
I.
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 112, first paragraph, on the basis that “[t]he limitation ‘wherein the
interferon beta nucleic acid sequence is inserted between the vesicular
stomatitis genes, G and L and the VSV lacks G-protein function’ . . . is not
supported by the as-filed specification” (Answer 5). The Examiner
acknowledges that the Specification exemplifies a vector in which the G
protein is removed but concludes that this example does not support the
claims, which “require the G protein to be present in the VSV viruses, but
lacking G-protein function” (id. at 6).
Appellant argues that the Specification describes insertion of an
interferon gene into a recombinant VSV virus between the G and L genes
(Appeal Br. 4) and describes VSV vectors that lack G protein function at
page 20, lines 5-8 (id. at 5).
We agree with Appellant that the Specification provides a description
adequate to show possession of viral vectors including the disputed
limitation. Figure 1A shows a “Foreign Gene” inserted between the G and L
genes, and flanked by Xho I and Nhe I restriction sites. Example 5 states
that an interferon beta (“IFN-β”) cDNA was “inserted into the Xho I-Nhe I
site of pVSV-XN2” (Spec. 54:30 to 55:4); in other words, between the G
and L genes. The Specification also states that “[i]n yet other examples, the
VSV vector lacks a protein function essential for replication, such as G-
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protein function” (id. at 20:5-7). These descriptions are adequate to support
the disputed claim limitation.
II.
Issue
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 103(a) for obviousness based on Schnell,1 Rose,2 Roberts,3 and Woo4
(Answer 7). Claims 104 and 106-108 stand or fall with claim 103 because
they have not been argued separately. 37 C.F.R. § 41.37(c)(1)(vii).
The Examiner finds that Schnell teaches that a foreign gene inserted
into a VSV vector between the G and L genes is stably expressed, but does
not specifically teach inserting an interferon beta gene in VSV (id.). The
Examiner finds that Rose teaches a VSV comprising an interferon gene,
Woo teaches a viral vector comprising a nucleic acid encoding interferon
beta, and Roberts teaches that a VSV vector lacking G protein function is
safe and effective as a vector (id.).
The Examiner concludes that it would have been obvious to make a
“VSV viral vector comprising a nucleic acid encoding interferon beta. One
of ordinary skill in the art would have been motivated to combine the
teaching[s] to study the expression of IFN-beta in cancer cells.” (Id. at 8.)

1 Matthias J. Schnell et al., The Minimal Conserved Transcription Stop-Start
Signal Promotes Stable Expression of a Foreign Gene in Vesicular
Stomatitis Virus, 70 J. VIROL. 2318-2323 (1996).
2 Rose et al., WO 96/34625, Nov. 7, 1996.
3 Anjeanette Roberts et al., Attenuated Vesicular Stomatitis Viruses as
Vaccine Vectors, 73 J. VIROL. 3723-3732 (1999).
4 Woo et al., US 6,217,860 B1, Apr. 17, 2001.
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The Examiner also concludes that it would have been obvious “to make the
VSV with a non-functional G protein. One of ordinary skill in the art would
have been motivated to combine the teaching[s] to make it safe but effective
as taught by Roberts.” (Id.)
Appellant contends that VSV is “is exquisitely sensitive to the
antiviral effects of type I interferon (IFN)” (Appeal Br. 6). Therefore,
Appellant argues, placing an interferon beta gene in the VSV genome is
counter-intuitive, because a skilled worker would have expected the
production of interferon by the virus to activate host antiviral defenses and
prevent replication of the virus (id. at 6-7).
The issue presented is: Does the evidence of record support the
Examiner’s conclusion that it would have been obvious to insert a nucleic
acid encoding interferon beta into a VSV vector lacking G protein function,
between the G and L genes?
Findings of Fact
1. Schnell discloses a VSV vector with a foreign gene encoding the
bacterial enzyme chloramphenicol acetyltransferase (CAT) inserted into it
(Schnell 2318, abstract).
2. In Schnell’s VSV vector, the CAT gene is inserted between the G
and L genes (id. at 2320, Fig. 1B).
3. Schnell discloses that “the unselected CAT gene is maintained
quite stably. Given this stability of expression, the ease with which VSVs
expressing foreign proteins can be constructed, and the very wide host range
of the virus, this system is likely to be an important vehicle for expression of
foreign genes in cells and in animals.” (Id. at 2318-2319.)
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4. Rose discloses “recombinant vesiculoviruses which are replicable
and capable of expressing foreign nucleic acid contained in their genome”
(Rose 1:9-11).
5. Rose discloses that the vesiculovirus is preferably VSV (id. at
10:22-24).
6. Rose discloses that the foreign nucleic acid inserted into its
recombinant viruses can encode a protein that is antigenic or immunogenic
(id. at 10:25-29).
7. Rose discloses that its recombinant viruses are useful as vaccines
(id. at 11:9-10); for example, “where the Antigen induces an immune
response against a tumor, the recombinant viruses of the invention have uses
in cancer immunoprophylaxis, immunotherapy, and diagnosis” (id. at 11:25-
28).
8. “In another specific embodiment, the foreign DNA can also
comprise a sequence encoding a cytokine capable of stimulating an immune
response. Such cytokines include . . . interferons.” (Id. at 12:3-7.)
9. Woo discloses that cytokine genes include “the interferons and
factors involved in the stimulation of helper and cytolytic T-lymphocytes to
mount an effective anti-tumoral response as well as macrophages and
monocytes to assist in the activation of B-lymphocytes to antibody-
producing cells. Cytokine genes include . . . interferon-β.” (Woo, col. 7,
ll. 13-23.)
10. Roberts discloses that “vaccination of mice with recombinant
VSV expressing influenza virus hemagglutinin (HA) protein (VSV-HA) was
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able to protect mice from lethal intranasal influenza virus challenge”
(Roberts 3724, left col.).
11. Roberts discloses that “[a]lthough the mice were completely
protected from influenza virus challenge, there was pathogenesis associated
with the initial VSV-HA vaccination. . . . The vector-associated patho-
genesis remained a significant concern in the development of a non-
pathogenic VSV-vectored vaccine.” (Id.)
12. Roberts discloses a “vector [that] has a truncation of the
cytoplasmic domain of the VSV G protein and expresses influenza virus HA
(CT1-HA). This nonpathogenic vector provides complete protection from
lethal influenza virus challenge after intranasal administration.” (Id. at 3723,
abstract.)
13. Roberts also discloses that a “second vector with VSV G deleted
and expressing HA (ΔG-HA) is also protective and nonpathogenic and has
the advantage of not inducing neutralizing antibodies to the vector itself”
(id.).
Analysis
We agree with the Examiner that the cited references would have
made obvious a VSV vector having an interferon beta gene inserted between
the VSV G and L genes, and lacking G protein function. Schnell discloses
that a CAT gene inserted into a VSV vector, between the G and L genes, is
stably maintained even without selection (FFs 2, 3), and suggests using its
system for expression of other foreign genes (FF 3). Rose discloses that
VSV vectors having an inserted cytokine gene, such as an interferon like
interferon beta (FF 9), are useful for stimulating an immune response (FFs 4,
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8) for, among other things, cancer immunoprophylaxis and immunotherapy
(FF 7). Roberts discloses that a VSV vector that encodes a functional G
protein retains some pathogenicity (FF 11), which is eliminated by
truncating (FF 12) or deleting (FF 13) the G protein gene.
Thus, it would have been obvious to substitute an interferon beta gene
for the CAT reporter gene in Schnell’s VSV vector and to truncate or delete
the G protein gene from the vector, in order to express the interferon beta
gene in cancer cells as part of an immunoprophylaxis or immunotherapy for
cancer, while eliminating potential pathogenicity caused by the viral vector
itself.
Appellant argues that VSV is “exquisitely sensitive to the antiviral
effects of type I interferon” (Appeal Br. 6), so expressing interferon beta
from a VSV vector would have been expected to “activate[ ] host antiviral
defense mechanisms which would have prevented the VSV’s own
replication” (id. at 6-7). Appellant argues that, therefore, “one of ordinary
skill in the art would not have inserted a gene which would inhibit the VSV
in vivo, thus defeating the intended purpose of inserting a foreign gene in a
vector” (id. at 7).
This argument is not persuasive. As the Examiner has pointed out
(Answer 12), Balachandran5 disclosed, prior to the effective filing date of
the claimed invention, that “although most tissue culture cell lines appear
permissive to VSV, the virus is extremely sensitive to the antiviral actions of
the interferons” (Balachandran 135, left col.). Balachandran states that the

5 Siddharth Balachandran et al., Vesicular Stomatitis Virus (VSV) Therapy of
Tumors, 50 IUBMB LIFE 135-138 (2000).
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fact “[t]hat VSV is capable of replicating in a majority of mammalian cell
lines, but not in primary cells unless PKR function or IFN signaling is
defective, implies that critical host defense mechanisms required to prevent
VSV replication are impaired in cells permissive to this virus, which
includes nearly all immortalized and malignant cells” (id. at 135, right col.,
emphasis added).
Thus, based on Balachandran, a skilled worker would have known
that VSV is capable of replication in nearly all immortalized or malignant
cells, which apparently have a defect in IFN signaling or in the function of
PKR, “the IFN-inducible double-stranded RNA-dependent protein kinase
. . . [that is] an essential and nonredundant component of antiviral host
defense” (Balachandran 135, right col.). Because Balachandran teaches that
VSV is capable of replication in nearly all immortalized or malignant cells, a
skilled worker would not have considered it counter-intuitive to express
interferon beta from Schnell’s VSV vector in cancer cells to aid in
stimulating an immune response in the course of developing a cancer
immunoprophylaxis or immunotherapy as suggested by Rose.
Appellant also argues that each of the cited references, considered
individually, fails to teach or suggest the claimed invention (Appeal Br. 7-9).
These arguments are unpersuasive because they are not addressed to what
the references, considered as a whole, would have suggested to a person of
ordinary skill in the art. See In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991)
(“The test for obviousness is what the combined teachings of the references
would have suggested to one of ordinary skill in the art.”).
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Conclusion of Law
The evidence of record supports the Examiner’s conclusion that it
would have been obvious to insert a nucleic acid encoding interferon beta
into a VSV vector lacking G protein function, between the G and L genes.
SUMMARY
We reverse the rejection of claims 103, 104, and 106-108 under 35
U.S.C. § 112, first paragraph. We affirm the rejection of claims 103, 104,
and 106-108 under 35 U.S.C. § 103(a) for obviousness based on Schnell,
Rose, Roberts, and Woo.
TIME PERIOD FOR RESPONSE
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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