Ex Parte Rubiolo

Patent Trial and Appeal Board

Mar 16, 2017

12673695 (P.T.A.B. Mar. 16, 2017)

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.
12/673,695 01/13/2011 Cristina Rubiolo REDL:1000 1569
34725 7590 03/17/2017
CHALKER FLORES, LLP
14951 North Dallas Parkway, Suite 400
DALLAS, TX 75254
EXAMINER
JUEDES, AMY E
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
03/17/2017 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 CRISTINA RUBIOLO1
Appeal 2015-007475
Application 12/673,695
Technology Center 1600
Before ERIC B. GRIMES, RICHARD J. SMITH, and JOHN E.
SCHNEIDER, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to a
dendritic cell, which have been rejected as anticipated and obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
“Dendritic cells (DCs) are bone-marrow-derived antigen-presenting
cells (APCs) that play a pivotal role in both induction and regulation of the
immune response.” (Spec. 1.) The Specification discloses “a dendritic cell
1 Appellant identifies the Real Party in Interest as Cell Med Research
GmbH. (Appeal Br. 2.)
Appeal 2015-007475
Application 12/673,695
loaded with at least one nucleic acid molecule encoding a tumor associated
antigen protein or fragment thereof and at least one tumor associated antigen
protein or fragment thereof.” (Id. at 4.)
The Specification states that “[t]he antigen encoded by the at least one
nucleic acid molecule will be translated into an endogenous protein and
therefore processed by the DCs and exposed on their cell membrane
complexed to MHC-I. In this way, it triggers the cytotoxic response.” (Id.)
On the other hand, “the protein antigen loaded into DCs will be processed by
said DCs as foreign protein antigen and exposed on their cell membrane
complexed to MHC-II. In this way, it triggers the adaptive response.” (Id.)
The Specification states that
the double loading with at least a nucleic acid molecule and a
protein tumor antigen ensures: (a) a short-term response of the
immune system by activating the cytotoxicity through T-
cytotoxic, NK and NKT upon recognition of the antigen exposed
through MHC-I; (b) the stability of the cytotoxic response by
CD4+-dependent sustained CD8+ activation upon recognition of
the antigen exposed through MHC-II; (c) the activation of the
antibody mediated memory response.
(Id.) The Specification states that “this method can be applied to a
combined use of the two most common uTAAs [universal Tumor Associated
Antigens]: Survivin and TElomerase Reverse Transcriptase (TERT).” (Id.
at 5.)
Claims 1, 3, 5, 6, 11, and 12 are on appeal. Claim 1 is illustrative and
reads as follows:
1. A dendritic cell loaded with
at least one nucleic acid molecule encoding a tumor associated antigen
protein or fragment thereof, which is processed via MHC-I, and at least one
tumor associated antigen protein or fragment thereof which is processed via
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Application 12/673,695
MHC-II, and wherein the nucleic acid molecule encodes TElomerase
Reverse Transcriptase (TERT) and
the antigen protein is Survivin and wherein said fragments have at
least 10 contiguous amino acids residues of said tumor associated antigen
protein.
The claims stand rejected as follows:
Claims 1, 3, 5, 6, 11, and 12 under 35 U.S.C. § 102(b) as anticipated
by Zhao,2 with evidence provided by Kedinger3 and Nair4 (Ans. 2) and
Claims 1, 3, 5, 6, 11, and 12 under 35 U.S.C. § 103(a) as obvious
based on Hold,5 Decker,6 Fan,7 and Schmidt8 (Ans. 3).
2 Yangbing Zhao et al., “Inhibition of invariant chain expression in dentritic
cells presenting endogenous antigens stimulated CD4+ T-cell responses and
tumor immunity,” 102 Blood 4137-42 (2003).
3 Valerie Kedinger et al., “Sticky siRNAs targeting survivin and cyclin B1
exert an antitumoral effect on melanoma subcutaneous xenografts and lung
metastasesf 13 BMC Cancer 338 (2013). Our citation is to the copy of
record, which is paginated differently from the original.
4 Smita K. Nair et al., “Induction of cytotoxic T cell responses and tumor
immunity against unrelated tumors using telomerase reverse transcriptase
RNA transfected dendritic cells, ” 6 Nature Medicine 1011—17 (2000).
5 Lorenz Hold et al. “Immunotherapy of Metastatic Renal Cell Carcinoma
with Tumor Lysate-pulsed Autologous Dendritic Cells, ” 8 Clin. Cancer
Res. 3369-76 (2002).
6 William K. Decker et al., “Double loading of dendritic cell MHC class I
and MHC class II with an AML antigen repertoire enhances correlates of T-
cell immunity in vitro via amplification of T-cell help, ” 24 Vaccine 3203—
16(2006).
7 Yidong Fan et al., "'Differential Expression of Full-length Telomerase
Reverse Transcriptase mRNA and Telomerase Activity between Normal and
Malignant Renal Tissues, ”11 Clin. Cancer Res. 4331—37 (2005).
8 Susanne M. Schmidt et al., “Survivin is a shared tumor-associated antigen
expressed in a broad variety of malignancies and recognized by specific
cytotoxic T cells, ” 102 Blood 571—76 (2003).
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Application 12/673,695
I
The Examiner has rejected all of the claims on appeal as anticipated
by Zhao, as evidenced by Kedinger and Nair. The Examiner finds that Zhao
teaches “a dendritic cell that has been loaded with total mRNA from a
B16.F10 melonama [sic, melanoma] cell line,” and Kedinger and Nair
provide evidence that B16.F10 cells express TERT and survivin. (Ans. 2.)
The Examiner finds that Zhao also teaches “treating the dendritic cells
to inhibit the la [invariant] chain, which causes the dendritic cells to be
loaded with tumor peptides encoded by the mRNAs via the MHC class I and
MHC class II pathway.” (Id.) The Examiner concludes that Zhao
anticipates the claims because “the dendritic cells of Zhao et al. have
inherently been loaded with both survivin and TERT mRNA present in the
total mRNA from the B16.F10 cells, and the encoded TERT and survivin
proteins would be loaded onto the dendritic cells via both the MHC class I
and class II pathways after la chain inhibition.” (Id.)
We agree with the Examiner that the product disclosed by Zhao
appears to meet all of the limitations of claim 1, even though it is produced
by a different process. Specifically, claim 1 is directed to a dendritic cell in
which TERT has been processed via MHC-I and survivin has been
processed via MHC-II. Although claim 1 includes process limitations, the
claim is to a product, so if Zhao discloses a product having the same
properties, it anticipates claim 1.
Zhao discloses that “[e]ndogenously expressed antigens, such as
antigens expressed in DCs [dendritic cells] transfected with mRNA, will be
channeled preferentially into the class I processing pathway to activate the
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Application 12/673,695
CD8+ T-cell arm of the immune response.” (Zhao 4137, left col.) Zhao
“tested the hypothesis that. . . inhibition of invariant chain expression in
mRNA-transfected DCs will lead to enhanced presentation of class II-
restricted epitopes, [and] enhanced induction of CD4+ T-cell and CD8+ CTL
responses.” {Id. at 4138, left col.) Zhao reports that a “short incubation of
mRNA-transfected dendritic cells with antisense oligonucleotides directed
against the invariant chain enhances the presentation of mRNA-encoded
class II epitopes and activation of CD4+ T-cell responses in vitro and in
vivo.” {Id. at 4137, abstract.)
Zhao states that “mice were immunized with . . . total B16/F10.9
tumor RNA” and “the antitumor effect seen in tumor-bearing mice
immunized with . . . B16/F10.9 tumor RNA transfected DCs . . . was
enhanced when the DCs were treated with Ii [invariant chain] AS
[antisense], but not control, ODNs [oligodeoxynucleotides].” {Id. at 4140,
right col.) Nair states that B16/F10.9 tumors express TERT. (Nair 1013,
left col.) Kedinger discloses that B16/F10 expresses survivin. (Kedinger 2,
left col.)
Thus, Zhao discloses dendritic cells that process endogenous antigens,
such as those expressed from transfected mRNAs, via both MHC-I and
MHC-II because expression of the invariant chain has been inhibited, and
that have been transfected with total mRNA from B16/F 10.9 tumor cells.
Nair and Kedinger provide evidence that B16/F10.9 tumor cells express
TERT and survivin. Therefore, the dendritic cells disclosed by Zhao would
reasonably appear to process TERT (and survivin) via MHC-I and to process
survivin (and TERT) via MHC-II. The evidence of record is sufficient to
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Application 12/673,695
shift the burden to Appellant to show that the prior art product does not meet
the limitations of claim 1. See In re Marosi, 710 F.2d 799, 803 (Fed. Cir.
1983) (“Where a product-by-process claim is rejected over a prior art
product that appears to be identical, although produced by a different
process, the burden is upon the applicants to come forward with evidence
establishing an unobvious difference between the claimed product and the
prior art product.”).
Appellant argues that “Zhao did nothing more than total mRNA
loading of the cells. Zhao does not teach the loading of a specific and
unique gene.” (Appeal Br. 14.) However, claim 1 uses the transition term
“comprising” and therefore encompasses dendritic cells that express
additional antigens that have been processed via either the MHC-I or
MHC-II pathway. Appellant’s argument is therefore not persuasive.
Appellant also argues that “that inhibition of the la chain would
inhibit MHC Class-II cell surface expression, which is the opposite of the
present invention. . . . The total mRNA of Zhao would only be expected to
result in the loading of antigenic peptides via the MHC Class-I pathway.”
(Appeal Br. 14.)
Zhao expressly states, however, that “incubation of mRNA-
transfected dendritic cells with antisense oligonucleotides directed against
the invariant chain enhances the presentation of mRNA-encoded class II
epitopes and activation of CD4+ T-cell responses in vitro and in vivo.”
(Zhao 4137, abstract (emphasis added).) Appellant cites no evidence to
show that Zhao’s disclosure is inaccurate, and the unsupported argument is
not persuasive.
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Application 12/673,695
Finally, Appellant argues that “there is no teaching of the second
element of the claimed invention, viz., that a separate polypeptide is also
provided to the dendritic cell for presentation via the MHC class-II
pathway. . . . The present invention claims two specific tumor associated
antigens that are loaded, in parallel, to DIRECTLY target both MHC Class-I
and MHC Class-II.” (Appeal Br. 14.)
We agree with the Examiner, however, that
the claims are directed to a product, and the patentability of a
product does not depend on its method of production in the
absence of a structural difference in the claimed product. Thus,
arguments relating to differences in the process steps for how the
dendritic cells are produced (i.e. via external protein loading, vs.
loading via protein encoded from mRNA after la chain
inhibition) does not carry patentable weight in the absence of a
structural difference in the claimed product.
(Ans. 5.) For the reasons discussed above, the evidence supports a
reasonable conclusion that the product disclosed by Zhao meets all of the
structural limitations of claim 1, and Appellant has provided no evidence to
the contrary.
We affirm the rejection of claim 1 under 35 U.S.C. § 102(b) based on
Zhao, with evidence provided by Nair and Kedinger. Claims 3, 5, 6, 11, and
12 fall with claim 1 because they have not been argued separately. 37
C.F.R. §41.37(c)(l)(iv).
II
The Examiner has rejected claims 1, 3, 5, 6, 11, and 12 as obvious
based on Holtl, Decker, Fan, and Schmidt. The Examiner finds that Holtl
teaches dendritic cells loaded with the proteins from a cell lysate of renal
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Application 12/673,695
cell carcinoma (RCC) cell line A-498, and that Fan and Schmidt provide
evidence that A-498 expresses both TERT and survivin. (Ans. 3.)
The Examiner finds that Decker teaches that “double loading of
dendritic cells with both total tumor cell lysate and total tumor derived
mRNA can mediate superior effector T cell responses compared to either
alone, since it results in loading via both the MHC class I and class II
pathways.” {Id. at 3 4.) The Examiner concludes that it would have been
obvious “to further load the dendritic cells of Hold et al., with RCC tumor
cell derived mRNA (which would also comprise mRNA encoding hTERT
and survivin, as evidenced above), as taught by Decker” because Decker
teaches that “double loading of dendritic cells with both tumor cell lysate
and tumor derived mRNA can mediate superior effector T cell responses
compared to either alone since it results in loading via both the MHC class I
and class II pathways.” {Id. at 4.)
We agree with the Examiner that claim 1 would have been obvious
based on the teachings of the cited references. Hold discloses “dendritic
cell-based immunotherapy in patients with metastatic renal cell carcinoma
(RCC).” (Hold 3369, abstract.) Hold states that patients with metastatic
RCC were vaccinated with “autologous monocyte-derived dendritic cells . .
loaded with lysate of cultured autologous or allogeneic permanent tumor
cells (A-498).” {Id.) Hold reports that “[i]n 2 of 27 evaluable patients, any
evidence of disease disappeared (complete response). . . . One patient had
an objective partial response. Seven patients had stable disease, the
remaining 17 patients had progressive disease.” {Id.)
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Fan provides evidence that telomerase reverse transcriptase (hTERT;
Fan 4331, right col.) is expressed in A-498 cells (id. at 4335, Fig. 4). Schmidt
states that “expression of survivin could be detected in all tested human tumor
cell lines,” including A-498. (Schmidt 573, left col. and Fig. 1).
Decker states that “[tjherapeutic vaccination with dendritic cells
presenting tumor-specific antigens is now recognized as an important
investigational therapy for the treatment of neoplastic disease.” (Decker
3203, abstract.) Decker “doubly-loaded human dendritic cells with both
AML[acute myelogenous leukemia]-specific tumor lysate and AML-specific
tumor mRNA” and found that “these doubly-loaded dendritic cells can
mediate superior primary, recall, and effector lytic responses in vitro in
comparison to those of dendritic cells loaded with either tumor lysate or
tumor mRNA alone.” (Id.) Decker concludes that “the double loading of
dendritic cell MHC class I and MHC class II with tumor mRNA and tumor
lysate, respectively, may be a more effective immunotherapeutic strategy
than the loading of dendritic cells with either antigen source by itself.” (Id.
at 3214, left col.)
We agree with the Examiner that it would have been obvious, based
on Decker, to double-load the dendritic cells disclosed by Holtl with both
tumor lysate and tumor mRNA from A-498 cells, because Decker discloses
that doing so provides more effective cancer immunotherapy than dendritic
cells loaded with tumor lysate alone. As shown by Fan and Schmidt, A-498
cells express both TERT and survivin and thus the double-loaded dendritic
cells would include both proteins among those loaded via the tumor lysate
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and via the mRNA. Therefore, both proteins would be processed by both
MHC-I and MHC-II.
Appellant argues that “[t]he present invention discloses the loading of
two specific tumor associated antigens in parallel via two different pathways
to DIRECTLY target MHC Class-I and MHC Class-II antigen presentation,”
while Hold and Decker teach loading dendritic cells with all of the proteins
and mRNA from tumor cells. (Appeal Br. 16.)
This argument is unpersuasive because, as discussed above with
regard to the anticipation rejection, claim 1 uses the transition term
“comprising” and therefore encompasses dendritic cells that express
additional antigens that have been processed via either the MHC-I or
MHC-II pathway. Since Fan and Schmidt provide evidence that A-498 cells
express TERT and survivin, the dendritic cells made obvious by the cited
references meet the limitations of claim 1.
Appellant also argues that there would be no reasonable expectation
of “obtaining] an equivalent antigen loaded dendritic cell that would present
the two specific claimed antigens to target-specific T cells for killing
specific cancer cell targets in a highly efficiency, well-defined manner
providing immediate and long term immunity.” (Appeal Br. 17.)
Claim 1, however, defines a product; specifically, a dendritic cell that
expresses at least TERT processed via MHC-I and expresses at least survivin
processed via MHC-II. Claim 1 is not directed to a process of killing cancer
cell targets, let alone in a highly efficient, well-defined manner providing
immediate and long term immunity. The dendritic cells made obvious by
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Application 12/673,695
the cited references meet the structural limitations of claim 1 and therefore
render it unpatentable under 35 U.S.C. § 103(a).
Claims 3, 5, 6, 11, and 12 have not been argued separately and
therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm both of the rejections on appeal.
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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