Ex Parte Xiang et al

Patent Trial and Appeal Board

Nov 26, 2013

10807897 (P.T.A.B. Nov. 26, 2013)

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.
10/807,897 03/24/2004 Rong Xiang TSRI 874.1 6550
7590 11/27/2013
OLSON & HIERL, LTD.
36th Floor
20 North Wacker Drive
Chicago, IL 60606
EXAMINER
PARAS JR, PETER
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
11/27/2013 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 RONG XIANG, HE ZHOU, and RALPH A. REISFELD

____________

Appeal 2012-0046931
Application 10/807,8972
Technology Center 1600
____________

Before TONI R. SCHEINER, JOHN A. EVANS, and ULRIKE W. JENKS,
Administrative Patent Judges.

EVANS, Administrative Patent Judge.

DECISION ON APPEAL

This is an appeal under 35 U.S.C. § 134(a) involving claims to an oral
DNA vaccine. The Examiner has rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We reverse.
Rather than reiterate the arguments of Appellants and the Examiner,

1 The record includes a transcript of the Oral Hearing held November 7,
2013.
2 The Real Party in Interest is Applied The Scripps Research Institute.
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Application 10/807,897
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we refer to the Appeal Brief (filed Aug. 18, 2011), the Answer (mailed Nov.
25, 2011), and the Reply Brief (filed Jan. 25, 2012).

STATEMENT OF THE CASE
The claims relate to a DNA vaccine suitable for eliciting an immune
response against cancer cells comprising a DNA construct operably
encoding a cancer-associated inhibitor of apoptosis-family protein, and an
immunoactive gene product, such as a cytokine or a ligand for a natural
killer cell surface receptor, in a pharmaceutically acceptable carrier. A
preferred cytokine is CCL21. Preferred ligands for a natural killer cell
surface receptor include human MICA, human MICB, human ULBP1,
human ULBP2, and human ULBP3. The cancer-associated inhibitor of
apoptosis (IAP)-family protein is preferably a survivin protein. (Spec. 8: 13-
25; 9: 13-21).
Claims 1, 26, 28, and 53 are on appeal; Claim 1 is independent;
Claims 2-25, 27, and 29-52 are canceled.3 The claims have not been argued
separately and, therefore, stand or fall together. 37 C.F.R. § 41.37(c)(1)(vii).
An understanding of the invention can be derived from a reading of
exemplary claim 1, which is reproduced below:
1. An oral DNA vaccine suitable for eliciting an immune
response against cancer cells in a patient comprising
a DNA construct operably encoding at least one survivin
protein and one CCL21 cytokine in a pharmaceutically

3 (App. Br. 11.)
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acceptable carrier;
wherein the DNA construct is incorporated in an
attenuated Salmonella typhimurium vector that targets Peyer’s
patches in the gut,
wherein the DNA vaccine induces a cytotoxic T-
lymphocyte immune response against tumor cells when orally
administered to the patient, and the attenuated Salmonella
typhimurium vector comprises an aroA-, dam- Salmonella
typhimurium strain.

The claims stand rejected as follows:
1. Claim 1 stands rejected under 35 U.S.C. § 103 as obvious over
Haupt4, Gordan5, Andersen6, Luther7, Lu8, Xiang9, and Dueger10.

4 Katharina Haupt, et al., The potential of DNA Vaccination against Tumor-
Associated Antigens for Antitumor Therapy, Exp Biol Med (Maywood).
227(4):227-37, 2002.
5 JD Gordan, et al., Universal tumor antigens as targets for immunotherapy,
Cytotherapy, 4(4):317-27, 2002.
6 Mads Hald Andersen, et al., Spontaneous Cytotoxic T-cell Responses
against Survivin-derived MHC Class I-restricted T-Cell Epitopes in Situ As
Well as ex Vivo in Cancer Patients, Cancer Res. 61(16):5964-8, 2001.
7 Sanjiv A. Luther, et al., Differing Activities of Homeostatic Chemokines
CCL19, CCL21, and CXCL12 in Lymphocyte and Dendritic Cell
Recruitment and Lymphoid Neogenesis, J. Immunol. 169(1):424-33, 2002.
8 Yichen Lu et al., US 5,733,760, issued Mar. 31, 1998.
9 Rong Xiang, et al., Protective Immunity Against Human
Carcinoembryonic Antigen (CEA) Induced by an Oral DNA Vaccine in
CEA-transgenic Mice, Clin Cancer Res. 7(3 Suppl):856s-864s, 2001.
10 E. L. Dueger, et al., Salmonella DNA Adenine Methylase Mutants Elicit
Protective Immune Responses to Homologous and Heterologous Serovars in
Chickens, Infect. Immun. 69(12):7950-4, 2001.
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(Ans. 4-15).
2. Claim 26 stands rejected under 35 U.S.C. § 103 as obvious over
Haupt, Gordan, Andersen, Luther, Lu, Xiang, Dueger, and Bennett11.
(Ans. 15-20).
3. Claim 28 stands rejected under 35 U.S.C. § 103 as obvious over
Haupt, Gordan, Andersen, Luther, Lu, Xiang, Dueger, and Tanabe12.
(Ans. 22-26).
4. Claim 53 stands rejected under 35 U.S.C. § 103 as obvious over
Haupt, Gordan, Andersen, Luther, Lu, Xiang, Dueger, Bennett, and
Tanabe. (Ans. 26-29).
INDEPENDENT CLAIM 1
ISSUES AND ANALYSIS
We agree with Appellants’ contentions that the person of skill in the
DNA vaccine arts would not have had a reasonable expectation of
successfully combining the teachings of the cited art to form the claimed
invention13. Appellants contend that Haupt, the primary reference relied
upon by the Examiner, fails to teach the claimed elements and limitations.
(App. Br. 6).

11 Bennett, US 6,335,194, issued Jan. 1, 2002.
12 Tanabe, et al., Direct submission, submitted to Genetics Institute, 87
Cambridge Park Drive, Cambridge, MA 02140, USA, on 03-JUN-1997,
direct submission of DNA sequences of CCL21.
13 Appellants’ arguments raise issues in addition to those specifically
discussed. We do not reach these additional issues, because we are
persuaded of error with regard to the identified, dispositive issues.
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Contention 1, Haupt teaches away from an oral DNA vaccine that
specifically targets intestinal Peyer’s Patches. Appellants contend that
Haupt does not teach oral DNA vaccines or the use of a DNA construct that
encodes a surviving protein and a CCL 21 cytokine. Appellants contend that
Haupt speculates that all tumor associated antigens (TAA) that are expressed
in tissue specifically could be possible targets for DNA vaccines if the
expressing tissue is not essential for health and survival. Appellants contend
that thus Haupt teaches away from the claimed invention because Peyer’s
patches play a vital role in the immune response against microorganisms and
are essential for health and survival. (App. Br. 6-7).
The Examiner cites Lu for teachings an “attenuated S. typh. vector
that targets Peyer’s patches in the gut” and that S. typh. has been proposed as
a means of providing effective delivery of desired antigens because
Salmonella, after oral injection, are concentrated within the Peyers’ patches
of the gut-associated lymphoid tissue (GALT) (Ans. 36). The Examiner
does not address Appellants’ arguments that Haupt teaches away from
administration to Peyers’ patches because they are essential for health and
survival.
Contention 2, Haupt is not combinable with Gordan with a
reasonable expectation of success. Appellants contend that Gordan
expressly states that there is no basis for predicting that survivin will be a
functional tumor rejection antigen. Appellants contend that Gordan teaches
that survivin may be expressed in normal tissues, but that expression in
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normal tissue militates against consideration of survivin as a desirable TAA.
(App. Br. 7).
The Examiner finds that Haupt does not teach survivin as a tumor
specific antigen. (Ans. 10). The Examiner finds that Gordan teaches that
survivin is one of four universal tumor specific antigens as targets of
immunotherapy. The Examiner finds that Andersen teaches that the human
inhibitor of apoptosis, survivin, is a prime candidate because it is expressed
in most human neoplasms but not in normal, differentiated tissues. Anderson
demonstrates spontaneous cytotoxic T-cell responses against surviving
derived MHC class I-restricted T-cell epitopes in breast cancer, leukemia,
and melanoma patients both in situ as well as ex vivo. (Ans. 35).
Appellants reply that Gordan disclose that survivin, among others, is a
potential candidate for a universal tumor-associated antigen (TAA). But, that
Gordan further states that survivin is expressed in some normal host tissues;
that survivin’s effectiveness as a tumor rejection antigen has not been
studied; and that survivin shows potential to be a target for specific
immunotherapy. Moreover, the teachings of Gordan do not pertain to a DNA
vaccine but describe peptide vaccination, dendritic cells pulsed with peptide
cocktails, and rely on the dendritic cells to initiate the immune response.
There is no mention of DNA vaccination, use of a S. typh. vector or oral
delivery of the vaccine. (Reply Br. 2-3). We agree with Appellants that
Gordan discloses that the use of surviving as a generalized, anti-cancer
vaccine is accompanied by a considerable amount of uncertainty.
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Contention 3, Haupt is not combinable with Luther with a
reasonable expectation of success. Appellants contend that neither Haupt
nor Luther provides a reason to make a DNA construct that encodes a
survivin and a CCL21 cytokine for an oral DNA vaccine. Appellants
contend that Haupt does not mention CCL21 and Luther merely reports that
CCL21 expression can induce infiltration of lymphocytes and dendritic cells
into secondary lymphoid organs. (App. Br. 8).
The Examiner finds that the T-cell specific enhancement of immune
response by CCL21 is the molecular mechanism that underlies DNA
vaccination taught by Haupt. (Ans. 35).
Appellants reply that Luther studied chemokines in vitro and
expressly states that the in vivo activity of chemokines remain unknown.
Moreover, Appellants contend that Luther teaches that infiltration by T cells,
B cells, and dendritic cells was only evaluated in the pancreatic islet cells
and lymphoid tissues, not throughout the body, and it is not known whether
the results were the direct action of CCL21 or due to induction of
downstream events. Moreover, Luther used transgenic mice to evaluate the
chemokines as opposed to introducing the chemokines via a vaccine. There
is no mention of survivin, a DNA vaccine, an oral vaccine, or introduction of
a DNA vaccine and a cytokine via an attenuated bacterial vector. (Reply
Br. 8).
We agree with Appellants that any combination of Haupt with Luther
is accompanied by a considerable amount of uncertainty.
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Contention 4, Haupt is not combinable with Lu with a reasonable
expectation of success. Appellants contend that although Lu teaches an
attenuated S. typh. vector for oral delivery of antigens, Haupt does not teach
an oral vaccine. Thus the person of skill would not have had a reason to
combine the teachings. (App. Br. 8).
The Examiner finds that Lu teaches that attenuated S. typh. after oral
injection are concentrated in Peyers’ patches. The Examiner does not
address Appellants’ arguments that Haupt teaches away from administration
to Peyers’ patches because they are essential for health and survival.
Appellants reply that Lu disclose an attenuated S. typh. vector.
However, the vector must have a wild type pag gene that has been replaced
by a gene encoding a truncated pag gene. The AroA mutation is a preferable
second mutation. In Lu the expression of the protein introduced via the
bacterial vector is directed by the pagC promoter. The present claims require
a doubly attenuated AroA- dam- vector and a tumor associated antigen, not a
viral antigen. No rationale has been advanced as to why a person of ordinary
skill in the art would have considered the teachings of Lu when considering
a single purpose cancer vaccine as described by Haupt. The teachings of Lu
even in combination with the other cited art, could not have led to the
limitations in the present claims in any event. (Reply Br. 4).
We agree with Appellants that any combination of Haupt with Luther
is accompanied by a considerable amount of uncertainty.
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Contention 5, Xiang does not teach the claimed vaccine.
Appellants contend that Xiang teaches an oral DNA vaccine comprising a
carcinoembyonic self-antigen (CEA) and a KS 1/4-IL2 fusion protein.
Appellants contend that Xiang teaches a vaccine with completely different
immunity-inducing components and, thus cannot provide any predictability
or reasonable expectation of success for the claimed vaccine. (App. Br. 8).
The Examiner finds that Xiang teaches that, in CEA-transgenic
C57BL/6J mice, an oral CEA-based DNA vaccine, delivered by a live,
attenuated AroA- strain of S. typh. induced tumor-protective immunity
mediated by a specific sub-population of T-cells. (Ans. 36).
We agree with Appellants that a vaccine comprising a CEA-KS 1/4-
IL2 fusion protein does not provide a reasonable expectation of success for
the claimed vaccine which comprises a survivin protein and a CCL21
cytokine.
CONCLUSIONS OF LAW
We find that Appellants have persuasively argued that the Examiner’s
prima facie case of obviousness fails to show that a person of ordinary skill
in the art at the time of the invention would have chosen and combined the
cited art and would have had a reasonable expectation of successfully
achieving the claimed invention.

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ORDER
The rejection of Claims 1, 26, 28, and 53 under 35 U.S.C. § 103 is
REVERSED.

REVERSED

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