Ex Parte Contag et al

Board of Patent Appeals and Interferences

Mar 21, 2012

11529807 (B.P.A.I. Mar. 21, 2012)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
11/529,807 09/29/2006 Christopher H. Contag STAN-441 (S05-194) 2044
77974 7590 03/21/2012
Stanford University Office of Technology Licensing
Bozicevic, Field & Francis LLP
1900 University Avenue
Suite 200
East Palo Alto, CA 94303
EXAMINER
HILL, KEVIN KAI
ART UNIT PAPER NUMBER
1633
MAIL DATE DELIVERY MODE
03/21/2012 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 CHRISTOPHER H. CONTAG and STEPHEN THORNE
__________

Appeal 2011-010910
Application 11/529,807
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to vaccinia
virus infected mammalian cells and methods of treating cancer. The
Examiner rejected the claims as obvious. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.

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Statement of the Case
Background
The Specification teaches “administration to a patient of an effector
cell population that is pre-infected with an oncolytic virus” (Spec. 3 ¶ 11).
According to the Specification, “[p]re-infection of effector cells with
oncolytic virus resulted in a prolonged eclipse period where the virus
remained within the cells until interaction with, and infiltration into, the
tumor” (Spec. 3 ¶ 12). The Specification teaches that “the effector cells
were shown to retain their ability to traffic to tumors. At the tumor site the
oncolytic virus was released deep in the tumor rather than merely at the
surface; thus the cell mediated delivery of the virus led to enhanced
biodistribution within the tumor” (Spec 3 ¶ 12).
The Claims
Claims 1, 2, 4, 5, 7, 8, 10-12, 14, 15, 17, 18, and 20-25 are on appeal.
Claims 1 and 11 are representative and read as follows:
1. An isolated mammalian T cell and/or natural killer cell
population, infected with an oncolytic vaccinia virus
comprising a genetic modification that substantially eliminates
an active viral gene necessary for replication in normal cells but
not tumor cells; and (ii) a genetic modification that substantially
eliminates active viral gene, which genetic modification
provides for tumor cell selectivity; and wherein replication of
said oncolytic virus is in an eclipse phase.

11. A method of treating cancer in a patient, the method
comprising:
administering to a cancer patient an effective amount of a
mammalian T cell and/or natural killer cell population, infected
with an oncolytic vaccinia virus comprising one or both of a (i)
genetic modification that substantially eliminates an active viral
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gene necessary for replication in normal cells but not tumor
cells; and (ii) a genetic modification that substantially
eliminates active viral gene, which genetic modification
provides for tumor cell selectivity; when replication of said
oncolytic virus is in an eclipse phase.

The issues

A. The Examiner rejected claims 1, 2, 4, 7, 8, 10-12, 14, 17, and 18 under
35 U.S.C. § 103(a) as obvious over Molnar-Kimber,1 McCart,2 Qin,3 Virus
Life Cycle,4 Virus Replication,5 Groene,6 Sanchez-Puig,7 and Chester8 (Ans.
4-9).

1 Molnar-Kimber et al., WO 99/45783 A1, published Sep. 16,
1999.
2 McCart et al., Systemic Cancer Therapy with a Tumor-selective
Vaccinia Virus Mutant Lacking Thymidine Kinase and Vaccinia
Growth Factor Genes, 61 CANCER RESEARCH 8751-8757 (2001).
3 Qin et al., Cancer Gene Therapy Using Tumor Cells Infected with
Recombinant Vaccinia Virus Expressing GM-CSF, 7 HUMAN GENE
THERAPY 1853-1860 (1996).
4 Virus Life Cycle, (web.archive.org/web/20030921205340/
http://www.ucalgary.ca/-cerilcmmb421prot/Virus+Life
+Cycle.html, last visited August 12, 2009)
5 Virus Replication, (http://www.microbiologybytes.com/virology/
3035Replication.html, last updated October 22, 2004, last visited
August 12, 2009)
6 Groene et al., US 2003/0077819 A1, published Apr. 24, 2003.
7 Sánchez-Puig et al., Susceptibility of different leukocyte cell types
to Vaccinia virus infection, 1 VIROLOGY J. 1-7 (2004).
8 Chester et al., Tumor antigen-specific induction of
transcriptionally targeted retroviral vectors from chimeric immune
receptor-modified T cells, 20 NATURE BIOTECHNOLOGY 256-263
(2002).
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B. The Examiner rejected claims 5, 15, and 20-25 under 35 U.S.C. §
103(a) as obvious over Molnar-Kimber, McCart, Qin, Virus Life Cycle,
Virus Replication, Groene, Sanchez-Puig, Chester, Smith,9 and Leemhuis10
(Ans. 9-10).
A. 35 U.S.C. § 103(a) over Molnar-Kimber, McCart, Qin, Virus Life
Cycle, Virus Replication, Groene, Sanchez-Puig, and Chester
The Examiner finds it obvious
to substitute a first oncolytic vaccinia virus with a second
vaccinia virus oncolytic vaccinia virus comprising
thymidine kinase-deleted (TK-) and vaccinia growth factor-
deleted (VGF-) mutations because McCart et al teach that
vaccinia virus is advantageous for using viral factors for
DNA and RNA synthesis, and thus is less dependent on
cellular factors than other viruses, the vaccinia promoters are
very strong and contribute to the vector efficiency

(Ans. 7). The Examiner finds it obvious “to administer a carrier
cell infected with an oncolytic virus . . .in an eclipse phase . . . because . . .
Qin et al successfully demonstrated the therapeutic efficacy towards the
treatment of cancer comprising administering a carrier cell infected with an
oncolytic virus when the replication of said oncolytic virus is in an eclipse
phase” (Ans. 8). The Examiner finds it obvious to “expand said cell
population in in vitro culture with a reasonable expectation of success
because Chester et al taught and successfully demonstrated that the oncolytic

9 Smith et al., US 2002/0031498 A1, published Mar. 14, 2002.
10 Leemhuis et al., A Phase I Trial of Autologous Cytokine-Induced
Killer Cells for the Treatment of Relapsed Hodgkin Disease and
Non-Hodgkin Lymphoma, 11 BIOLOGY BLOOD MARROW
TRANSPLANTATION 181-187 (2005).
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virus-infected T cell population may be exponentially grown, selected and
cultured in vitro, enriching for the cells containing the oncolytic virus” (Ans.
8).
Appellants contend that the invention “combines two biological
therapies in such a way that is able to harness the benefits of both and
produce a new combination therapy that far exceeds the effectiveness of
either alone” (App. Br. 6). Appellants contend that:
Immune effector cells are used to systemically deliver the
oncolytic vaccinia virus efficiently and specifically to the
site of the tumor. The oncolytic virus can then act to
increase the tumor cell killing potential of the CIK cells. In
addition to this however, it was found that the virus does not
affect CIK cell function, but can sensitize tumor cells to CIK
cell-mediated killing. Finally the CIK cells can transport the
virus deep within the tumor, producing a more uniform
biodistribution of viral infection of tumor cells within the
cancer.

(App. Br. 6).
Appellants “submit that Molnar-Kimber fail to teach the most
elemental aspects of the present invention, that is a combined therapeutic
that provides for both viral and cell based killing of tumor cells.” (App. Br.
8). Appellants contend that the “secondary references do not remedy the
deficiencies of the primary reference” (App. Br. 8).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Molnar-Kimber, McCart, Qin, Virus
Life Cycle, Virus Replication, Groene, Sanchez-Puig, and Chester render the
claims obvious?

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Findings of Fact
1. Molnar-Kimber teaches “a producer cell for administration to a
subject having tumor cells. The producer cell comprises an oncolytic virus
which is capable of replicating in the producer cell” (Molnar-Kimber 6, ll.
10-12).
2. Molnar-Kimber teaches that “the oncolytic virus is capable of
replicating in a tumor cell of the subject. For example, the oncolytic virus
may be less capable of replicating in a non-tumor cell of me subject than in
the tumor cell” (Molnar-Kimber 6, ll. 24-26).
3. Molnar-Kimber teaches that the “oncolytic virus may, for
example, be selected from the group consisting of . . . a vaccinia virus”
(Molnar-Kimber 8, ll. 6-8).
4. Molnar-Kimber teaches that
PA -1 human teratocarcinoma cells were exposed to ionizing
radiation at a single dose of 20 Gray and were then infected
with HSV-1716 at an MOI of 2. Two hours after infection,
cells were washed with PBS and harvested using a 0.05%
(w/v) 15 trypsin solution. Cells were washed twice in media
comprising 10% heat-inactivated FCS, centrifuged at 300xg
for 5 minutes, and re-suspended in RPMI media comprising
1% heat-inactivated FCS. About 5 x 106 cells were injected
intraperitoneally into tumor-bearing animals

(Molnar-Kimber 31, ll. 12-18).
5. Molnar-Kimber teaches that “delivery of oncolytic virus using
producer cells resulted in infection of larger areas of intraperitoneal tumors
by the virus and in deeper penetration of the virus within tumor nodules,
relative to virus administered by direct injection” (Molnar-Kimber 44, ll. 1-
4).
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6. McCart teaches that the “creation of a TK- and VGF-deleted
vaccinia virus offers several advantages for use as a tumor-directed vector
for cancer gene therapy” (McCart 8754, col. 1).
7. McCart teaches “decreased replication of this virus both in vitro
and in vivo in nondividing cells. Decreased viral pathogenicity was
demonstrated, including minimal recovery of vvDD-GFP from the brain
tissue of nude mice. As well, a significant antitumor effect was seen after
systemic injection because of selective replication of this virus in tumor
cells” (McCart 8754, col. 1).
8. Qin teaches that “Irradiated monolayers of cells were inoculated
with 3 X 108 pfu of rvv (moi, 10). After 2 hr at 37°C, the cells were
harvested by mild trypsin treatment, washed two times with PBS,
and resuspended in PBS at a desired concentration for inoculation” (Qin
1854, col. 2).
9. Virus Life Cycle teaches
ECLIPSE PHASE
• phase during which the virion has entered the cell
and before progeny virus are made. NO INFECTIOUS
VIRUS are present during this phase
• period in which virus gains control of host synthetic
machinery and produce components required to assemble
into virus
• defined as the period between addition of virus and
the appearance of assembled virus progeny inside the cell.

(Virus Life Cycle 1-2).
10. Virus Replication teaches that:
Shortly after infection and for several hours, only low
amounts of parental infectious material can be identified,
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this is the so called eclipse phase. Genome replication has
been initiated but progeny virus are not yet released. There
is then a maturation phase when viral material accumulates
exponentially in the cell or surrounding medium. After a few
hours cells infected with lytic viruses become metabolically
disordered and viral production ceases. Titres then slowly
drop.

(Virus Replication).
11. Groene teaches “a method of treating a human subject with
cancer, comprising administering . . .the pharmaceutical composition
comprising human cells infected with an oncolytic virus in suspension in a
physiologically acceptable solution, wherein the cells are leukocytes”
(Groene 1 ¶ 0012).
12. Groene teaches “leukocytes utilized in accordance with this
invention (e.g. monocytes, neutrophils and lymphocytes including tumor-
infiltrating lymphocytes)” (Groene 2 ¶ 0025).
13. Groene teaches “the oncolytic virus is selected from the group
consisting of . . . a Vaccinia Virus” (Groene 2 ¶ 0032).
14. Groene teaches that
Human Leukocytes (5x10+8 cells) are prepared by
leukophoresis or by gradient centrifugation employing
POLYMORPHPREP . . . The cells are mixed with 1x10+10
pfu of NDV (added aseptically) and allowed to sit for 30
minutes (with further brief mixings at 10 and 20 minutes).
The cells are centrifuged for 5 minutes at 1500 rpm and the
PBS removed. The cells are washed with 20 ml of 1XPBS
and centrifuged again. The cell pellet is diluted to 10 ml for
injection.

(Groene 4 ¶ 0060).
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15. Sanchez-Puig teaches “a significant preference of vaccinia virus
for certain cell types. In particular, monocytes were the most susceptible
cells, followed by B cells and NK cells. In contrast, T cells were infected at
very low rates” (Sanchez-Puig 5, col. 1).
16. Chester teaches that “we have shown that it is possible to use
human T cells as vector delivery and producer cells. In particular, systemic
delivery of CEA-targeted T-cell retroviral vector production generated
highly significant therapeutic effects in a model of metastatic disease”
(Chester 260, col. 2).
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’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Analysis
Molnar-Kimber teach isolated mammalian cells infected with
oncolytic viruses (FF 1) which preferentially replicate in tumor cells relative
to normal cells (FF 2) including an oncolytic vaccinia virus (FF 3). Molnar-
Kimber teaches harvesting and use of the infected producer cells at 2 hours
post infection, which is inherently during the eclipse phase (FF 4, 9, 10).
McCart teaches an oncolytic vaccinia virus with genetic modifications
which eliminate an active viral gene necessary for replication in normal but
not tumor cells, the TK gene, and which eliminate an active viral gene that
improves tumor cell selectivity, VGF (FF 6-7).
Qin teaches harvesting and use of the infected producer cells at 2
hours post infection, which is inherently during the eclipse phase (FF 8-10).
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Groene teaches using leukocytes infected with an oncolytic virus for
treatment of cancer (FF 11), including monocytes, neutrophils and
lymphocytes (FF 12), as well as vaccinia virus as the oncolytic virus (FF
13). Groene teaches harvesting and use of the infected producer cells at
about 1 hour post infection, which is inherently during the eclipse phase (FF
9, 10, 14). Sanchez-Puig teaches that vaccinia virus infects T cells and NK
cells (FF 15). Chester teaches that “that it is possible to use human T cells as
vector delivery and producer cells. In particular, systemic delivery of CEA-
targeted T-cell retroviral vector production generated highly significant
therapeutic effects in a model of metastatic disease” (Chester 260, col. 2; FF
16).
Applying the KSR standard of obviousness to the findings of fact, we
agree with the Examiner that the ordinary artisan in the field of cancer
treatment with oncolytic viruses would have reasonably found it obvious to
utilize the improved vaccinia virus of McCart in the producer cells of
Molnar-Kimber since McCart teaches that the “creation of a TK- and VGF-
deleted vaccinia virus offers several advantages for use as a tumor-directed
vector for cancer gene therapy” (McCart 8754, col. 1; FF 6). In particular,
McCart teaches selective replication in tumor cells (FF 7).
The ordinary artisan would also have reasonably found it obvious to
use cell populations including T-cells or NK cells since Chester teaches that
infected T-cells can assist in targeting of viruses (FF 15), Sanchez-Puig
teaches that vaccinia is capable of infecting NK cells and T-cells (FF 16),
and Groene teaches infecting leukocytic cells which include T-cells and NK
cells for oncolytic virus therapy (FF 11-13). Thus, we agree with the
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Examiner’s finding that “at the time of the instantly asserted invention, those
of ordinary skill in the art recognized that the use of immune effector
producer T cells infected with an oncolytic virus will achieve greater
efficacy than the use of immune effector T cells alone” (Ans. 7).
We also agree with the Examiner that in each of the references
teaching administration of producer cells, the administration occurred during
the eclipse phase, so Molnar-Kimber’s examples were administered during
eclipse phase (FF 4), as were Qin’s examples (FF 8) and Groene’s examples
(FF 14). Such a combination is merely a “predictable use of prior art
elements according to their established functions.” KSR, 550 U.S. at 417.
Appellants contend that the “present invention thus combines two
biological therapies in such a way that is able to harness the benefits of both
and produce a new combination therapy that far exceeds the effectiveness of
either alone” (App. Br. 6). Appellant contends that “the CIK cells can
transport the virus deep within the tumor, producing a more uniform
biodistribution of viral infection of tumor cells within the cancer” (App. Br.
6).
This result, while important, is not unexpected relative to the
teachings of the prior art. Molnar-Kimber expressly teaches that “delivery
of oncolytic virus using producer cells resulted in infection of larger areas of
intraperitoneal tumors by the virus and in deeper penetration of the virus
within tumor nodules, relative to virus administered by direct injection”
(Molnar-Kimber 44, ll. 1-4; FF 5). Thus, Molnar-Kimber recognizes the
benefit of the combination therapy identified by Appellants.
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In addition, while Appellants point to a comparison of vaccinia virus
alone with producer cells infected with virus to show the results of
combination therapy (see App. Br. 5-6), treatment with virus alone does not
represent the closest prior art. Instead, Qin teaches treatment of lung
metastases with producer cells infected with vaccinia virus (FF 8), and
Molnar-Kimber teach treatment of intraperitoneal tumors with producer cells
infected with HSV (FF 4) either of which represent closer prior art. See In re
Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen
unexpected results are used as evidence of nonobviousness, the results must
be shown to be unexpected compared with the closest prior art.”).
Appellants “submit that Molnar-Kimber fail to teach the most
elemental aspects of the present invention, that is a combined therapeutic
that provides for both viral and cell based killing of tumor cells.” (App. Br.
8). Appellants contend that the “secondary references do not remedy the
deficiencies of the primary reference” (App. Br. 8).
We are not persuaded. The Examiner reasonably relies upon the
teachings of multiple references to demonstrate that the claims are obvious.
We do not disagree with Appellants’ point that none of the references
anticipate the instant claims. Instead, we conclude that the ordinary artisan,
confronted with the combination of references, would have found the
claimed invention obvious for the reasons given above. 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.”)

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Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
Molnar-Kimber, McCart, Qin, Virus Life Cycle, Virus Replication, Groene,
Sanchez-Puig, and Chester render the claims obvious.
B. 35 U.S.C. § 103(a) over Molnar-Kimber, McCart, Qin, Virus Life
Cycle, Virus Replication, Groene, Sanchez-Puig, Chester, Smith, and
Leemhuis
The Examiner finds that Molnar-Kimber, McCart, Qin, Virus Life
Cycle, Virus Replication, Groene, Sanchez-Puig, and Chester do not
“disclose the producer cell population is a cytokine-induced killer (CIK)
cell” (Ans. 9). The Examiner finds that “at the time of the invention, Smith
et al disclosed that CIK cells are an art-recognized species of immune
effector cells within the same genus as T cells readily envisioned
for immunotherapy” (Ans. 9). The Examiner finds it obvious “to substitute
T cells for CIK cells in an immune effector cell population with a reasonable
expectation of success because the simple substitution of one known element
for another would have yielded predictable results” (Ans. 9-10).
The Examiner provides sound fact-based reasoning for combining
Smith and Leemhuis with the earlier prior art. We adopt the fact finding and
analysis of the Examiner as our own. Appellants argue the underlying
obviousness rejection, but Appellants do not identify any material defect in
the Examiner’s reasoning for combining Smith and Leemhuis. Since
Appellants only argue the underlying rejection which we affirmed above, we
affirm this rejection for the reasons stated by the Examiner.

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SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over Molnar-Kimber, McCart, Qin, Virus Life Cycle,
Virus Replication, Groene, Sanchez-Puig, and Chester. Pursuant to 37
C.F.R. § 41.37(c)(1), we also affirm the rejection of claims 2, 4, 7, 8, 10-12,
14, 17, and 18 as these claims were not argued separately.
We affirm the rejection of claims 5, 15, and 20-25 under 35 U.S.C. §
103(a) as obvious over Molnar-Kimber, McCart, Qin, Virus Life Cycle,
Virus Replication, Groene, Sanchez-Puig, Chester, Smith, and Leemhuis.

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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