Ex Parte Martuza et al

Board of Patent Appeals and Interferences

May 7, 2012

10788410 (B.P.A.I. May. 7, 2012)

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.
10/788,410 03/01/2004 Robert L. Martuza 066683-0198 4953
22428 7590 05/07/2012
FOLEY AND LARDNER LLP
SUITE 500
3000 K STREET NW
WASHINGTON, DC 20007
EXAMINER
SHEN, WU CHENG WINSTON
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
05/07/2012 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ROBERT L. MARTUZA, SAMUEL D. RABKIN,
and TOSHIHIRO MINETA
__________

Appeal 2011-012085
Application 10/788,410
Technology Center 1600
__________

Before ERIC GRIMES, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
modified herpes simplex virus. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

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Statement of the Case
The Specification teaches “the present invention relates to a mutated,
replication-competent Herpes Simplex Virus-l (HSV-l) which contains
mutations in two genes, is hypersensitive to antiviral agents such as
acyclovir, is not neurovirulent and does not replicate in non-dividing cells,
yet can kill nervous system tumor cells” (Spec. 1, ll. 4-10).
The Claims
Claims 16, 18-20, and 28-32 are on appeal. Claim 16 is representative
and reads as follows:
16. A herpes simplex virus with a genome that
comprises (i) an expressible non-herpes simplex virus
nucleotide sequence encoding a cytokine capable of
eliciting an immune response against a tumor cell, and
(ii) an alteration in the 34.5 gene such that no functional
34.5 gene product is made, wherein the neurovirulence
of said herpes simplex virus is attenuated.

The issues

A. The Examiner rejected claims 16, 28, and 29 under 35 U.S.C. § 103(a)
as obvious over Roizman
1
and Vile
2
(Ans. 4-7).
B. The Examiner rejected claims 18-20 under 35 U.S.C. § 103(a) as
obvious over Roizman, Vile, and Chang
3
(Ans. 7-11).

1
Roizman et al., US 6,172,047 B1, issued Jan. 9, 2001.
2
R. G. Vile & I. R. Hart, Targeting of cytokine gene expression to
malignant melanoma cells using tissue specific promoter
sequences, 5 ANN. ONCOL. SUPP. 559-565 (1994).
3
Chang et al., A Gene Delivery/Recall System for Neurons Which
Utilizes Ribonucleotide Reductase-Negative Herpes Simplex
Viruses, 185 VIROLOGY 437-40 (1991).
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C. The Examiner rejected claims 30-32 under 35 U.S.C. § 103(a) as
obvious over Roizman, Vile, McKay,
4
and Wright, Jr.
5
(Ans. 11-14).
A. 35 U.S.C. § 103(a) over Roizman and Vile
The Examiner finds that Roizman teaches the “use of the HSV -1
virus with a null mutation in the 34.5 gene provides a method of therapeutic
treatment of tumorogenic diseases both in the CNS and in all other parts of
the body” (Ans. 5). The Examiner finds that “given the ability to target
tumors within the CNS, the 34.5 minus virus has proven a powerful
therapeutic agent for hitherto virtually untreatable forms of CNS cancer”
(id.). The Examiner finds that Vile teaches that “constitutively producing
cytokines such as IL-2, IL-4, and GM-CSF could be use[d] as [a] „cancer
vaccine‟ by activation of immune system” (id. at 6).
The Examiner finds it obvious to “combine the teachings of Roizman
et al. with the teachings of Vile et al. (1994) because (i) the 34.5 gene
mutation would result in a non-pathogenic vector, as taught by Roizman . . .
and (ii) the exogenous expression of a cytokine gene would result in
diminishing or eliminating tumorigenicity of tumor cells, as taught by Vile”
(id. at 7).
Appellants contend that “the skilled artisan would not have combined
a modality of oncolytic therapy, which aimed at killing host cells in vivo,
with cytokine expression, which the prior art advanced as a therapeutic goal
unto itself” (App. Br. 9). Appellants also contend that “it would have been
the understanding of the skilled artisan that cytokine expression, per se,

4
McKay et al., WO 92/14821 A2, published Sep. 3, 1992.
5
Wright, Jr., G., US 5,639,656, issued Jun. 17, 1997.
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would counteract oncolytic therapy, which requires the HSV vector to infect
and replicate serially in host cells” (App. Br. 9).
Appellants contend that “there would have been no principled way of
predicting a priori the outcome, in terms of cancer treatment, of combining
the presently recited features, drawn from oncolytic therapy and gene
therapy (cytokine expression)” (id. at 11).
Appellants contend that the Examiner “discounted the declaration
evidence, however, (i) by substituting his own judgment, without basis, for
an expert's opinion and (ii) by asserting that the declaration evidence is not
commensurate in scope with the claimed invention” (id. at 13).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner‟s conclusion Roizman and Vile render it obvious to
express a cytokine in an HSV virus with a nonfunctional 34.5 gene?
Findings of Fact
1. Roizman teaches “methods for blocking or delaying
programmed cell death, for delivery of gene therapy to specific cells, and for
treatment of cancer and other tumorgenic diseases, as well as treatment of
viral infections” (Roizman, col. 1, ll. 20-24).
2. Roizman teaches that:
The function of the gene 134.5 in its ability to enable
the virus to replicate, multiply and spread in the central
nervous system (CNS) was demonstrated by a set of
recombinant viruses and by testing their abilities to cause
fatal encephalitis in the mouse brain. The mutant viruses
lacking the gene therefore lost their ability to multiply and
spread in the CNS and eyes and therefore is non-pathogenic.

(Roizman, col. 4, ll. 35-41.)
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3. Roizman teaches that the “the HSV-1 virus, appropriately
modified so as to be made non-pathogenic, can serve as a vehicle for
delivery of gene therapy to neurons” (Roizman, col. 5, ll. 31-33).
4. Roizman teaches that the “„ 134.5 minus‟ virus can induce
apoptosis and thereby cause the death of the host cell, but this virus cannot
replicate and spread. Therefore, given the ability to target tumors within the
CNS, the 134.5 minus virus has proven a powerful therapeutic agent for
hitherto virtually untreatable forms of CNS cancer” (Roizman, col. 5, ll. 61-
66).
5. Roizman teaches that “the brains of animals inoculated with the
viruses that failed to make ICP34.5 contained very little virus” (Roizman,
col. 17, ll. 51-52).
6. Roizman teaches that “it was discovered that infection of cells
of neuronal origin with mutants incapable of expressing the 134.5 gene
resulted in shutoff of cellular protein synthesis” (Roizman, col. 17, l. 67 to
col. 18, l. 3).
7. Vile teaches that “[t]ransduction of tumour cells in vitro with
cDNAs encoding various cytokines and/or immune accessory molecules has
been shown to diminish or eliminate tumorigenicity when such cells are
returned in vivo to syngeneic animals” (Vile 59, col. 1).
8. Vile teaches that the “5‟ flanking region of this gene has been
shown to direct expression of heterologous genes both in human and murine
melanocytes and melanoma cells, while not permitting expression in a range
of other cell types” (Vile 59, col. 2).
9. Vile teaches that
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a significant anti-tumour effect on the growth of the injected
tumours using cytokine cDNAs has not been observed. This
is not wholly unexpected. Although transfer of the IL-2
gene to B16 cells has been shown to abrogate
tumorigenicity, both in this study and in others . . . a high
percentage of the tumour cells (at least 50%) must express
the gene at the time of injection for these effects to be
observed.

(Vile 64, col. 1.)
Principles of Law
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993).
“‟[R]ejections on obviousness grounds cannot be sustained by mere
conclusory statements; instead, there must be some articulated reasoning
with some rational underpinning to support the legal conclusion of
obviousness.‟” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
Analysis
The Examiner reasons that it would have been obvious to combine
Roizman and Vile “to arrive at the claimed HSV with disrupted both 34.5
that exhibits no neurovirulence, and expressing a cytokine gene that elicit an
immune response against a tumor cell” (Ans. 7).
However, Roizman teaches that HSV with a disrupted 34.5 gene
“can induce apoptosis and thereby cause the death of the host cell, but this
virus cannot replicate and spread” (Roizman, col. 5, ll. 61-66; FF 4).
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Roizman teaches that “the brains of animals inoculated with the viruses that
failed to make ICP34.5 contained very little virus” (Roizman, col. 17, ll. 51-
52; FF 5). Roizman teaches that “it was discovered that infection of cells of
neuronal origin with mutants incapable of expressing the 134.5 gene
resulted in shutoff of cellular protein synthesis” (Roizman, col. 17, l. 67 to
col. 18, l. 3; FF 6).
While Roizman suggests that the modified HSV deliver gene therapy
(FF 1), Roizman‟s own teachings demonstrate that the mutated HSV with a
disrupted 34.5 gene does not produce virus and shuts off protein synthesis
(FF 4-6), and thus would be expected to prevent expression of a gene
therapy protein.
Vile teaches that cytokines can be transduced into tumor cells (FF 7),
but Vile teaches that
a significant anti-tumour effect on the growth of the injected
tumours using cytokine cDNAs has not been observed. This
is not wholly unexpected. Although transfer of the IL-2
gene to B16 cells has been shown to abrogate
tumorigenicity, both in this study and in others . . . a high
percentage of the tumour cells (at least 50%) must express
the gene at the time of injection for these effects to be
observed.

(Vile 64, col. 1; FF 9.)
Consequently, since Roizman teaches that the mutant virus shuts
down protein synthesis and Vile teaches that a high percentage of cells must
express the cytokine gene and protein for anti-tumor effects to be observed,
Roizman and Vile do not support a finding that gene therapy using the HSV
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mutated virus and a cytokine would have had a reasonable expectation of
success.
We therefore agree with Appellants that “there would have been no
principled way of predicting a priori the outcome, in terms of cancer
treatment, of combining the presently recited features, drawn from oncolytic
therapy and gene therapy” (App. Br. 11).
The Examiner finds that “the claims . . . [are] directed to a product,
not a method of using said product in cancer gene therapy that results a
statistically significant reduction in tumor growth” (Ans. 19).
We are not persuaded. Whether the claims are product or method
claims, there must be a reasonable expectation of success regarding the use
of the product or method, in order for a skilled worker to have a reason to
combine prior art teachings. Here, the evidence of Roizman and Vile
supports the conclusion that the gene therapy vector would not have been
expected to function to express the cytokine required by the claim to elicit an
immune response.
The Examiner finds that “a skilled person in the art would be
motivated to make the claimed HSV based on the combined references and
to test how effective the claimed HSV may be in a given cancer gene
therapy of interest” (id.).
We are not persuaded. This is the essence of an impermissible
obvious to try argument, since there is no evidence that the combination had
a reasonable expectation of success in treating cancer. Therefore, we see the
invention as, at best, an improper use of an obvious to try rationale. In re
O’Farrell, 853 F.2d 894, 904 (Fed. Cir. 1988). We have considered the
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Rabkin Declaration
6
but, since we have concluded that the Examiner has not
made out a prima facie case of obviousness, we do not need to address the
sufficiency of the declaration as rebuttal evidence.
Conclusion of Law
The evidence of record does not support the Examiner‟s conclusion
Roizman and Vile render it obvious to express a cytokine in an HSV virus
with a nonfunctional 34.5 gene.
B. 35 U.S.C. § 103(a) over Roizman, Vile, and Chang
This rejection relies upon the underlying obviousness rejection over
Roizman and Vile which we reversed above. Having reversed the
obviousness rejection over Roizman and Vile for a failure to present a prima
facie case of obviousness, we necessarily reverse this obviousness rejection
further including Chang as Chang does not resolve the issue of reasonable
expectation of success.
C. 35 U.S.C. § 103(a) over Roizman, Vile, McKay, and Wright, Jr.
This rejection relies upon the underlying obviousness rejection over
Roizman and Vile which we reversed above. Having reversed the
obviousness rejection over Roizman and Vile for a failure to present a prima
facie case of obviousness, we necessarily reverse this obviousness rejection
further including McKay and Wright, Jr., as McKay, and Wright, Jr. do not
resolve the issue of reasonable expectation of success.

6
Declaration by Samuel D. Rabkin, filed May 5, 2008.
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SUMMARY
In summary, we reverse the rejection of claims 16, 28, and 29 under
35 U.S.C. § 103(a) as obvious over Roizman and Vile.
We reverse the rejection of claims 18-20 under 35 U.S.C. § 103(a) as
obvious over Roizman, Vile, and Chang.
We reverse the rejection of claims 30-32 under 35 U.S.C. § 103(a) as
obvious over Roizman, Vile, McKay, and Wright, Jr.

REVERSED

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