Ex Parte Kirkin et al

Patent Trial and Appeal Board

Feb 23, 2017

12522048 (P.T.A.B. Feb. 23, 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.
12/522,048 12/03/2009 Alexei Kirkin 218042-0002 5407
24267 7590 02/27/2017
CESARI AND MCKENNA, LLP
88 BLACK FALCON AVENUE
BOSTON, MA 02210
EXAMINER
JUEDES, AMY E
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
02/27/2017 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ALEXEI KIRKIN and KARINE DZHANDZHUGAZYAN
Appeal 2016-005277
Application 12/522,048
Technology Center 1600
Before DONALD E. ADAMS, RYAN H. FLAX, and DAVID COTTA,
Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL1
This appeal under 35 U.S.C. § 134(a) involves claims 1—3 and 22
(App. Br. 2).2 Examiner entered rejection under 35 U.S.C. § 103(a). We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellants identify the real party in interest as “Cytovac A/S” (App. Br. 2).
2 Pending “claims 4—21 have been withdrawn [from consideration as
directed to] non-elected subject matter” (App. Br. 2).
Appeal 2016-005277
Application 12/522,048
STATEMENT OF THE CASE
Appellants’ disclosure “relates primarily to compositions suitable for
inducing immune responses against malignancies; therefore the
compositions can be used as a vaccine or for generating cytotoxic cells for
adoptive immunotherapy” (Spec. 1: 4—6). Claim 1 is representative and
reproduced below:
1. A method of preparing an antigen-presenting composition
enriched in CD4+ cells as compared to CD8+ cells, comprising
the steps of obtaining autologous mature dendritic cells from
blood monocytes by culturing the blood monocytes with GM-
CSF and IL-4 and incubating the cultured blood monocytes
with a maturation mixture that includes IL-l[-]beta, TNF-alpha,
IL-6, and PGE2, stimulating proliferation of autologous normal
non-activated lymphoid cells by coculturing the autologous
normal non-activated lymphoid cells with the autologous
mature dendritic cells to obtain proliferating cells, and
chemically treating the proliferating cells with an agent that
induces DNA demethylation or an agent that induces histone
acetylation to induce expression of cancer/testis antigens,
wherein the agent that induces DNA demethylation is
5-aza-2’-deoxycytidine, 5-azacytidine, 5-fluoro-2’-
deoxycytidine, or zebularine, the agent that induces histone
acetylation is trichostatin A, and the autologous mature
dendritic cells are not loaded with the cancer/testis antigens.
(App. Br. 8.)
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Application 12/522,048
The claims stand rejected as follows:
Claims 1—3 and 22 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of De Santis,3 Protocols,4 Scandella,5 and
Scheinecker.6
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Scheinecker discloses:
The in vitro proliferation of T cells in response to
stimulation by autologous non-T cells has been termed the
autologous mixed lymphocyte reaction (AMLR)[j. The AMLR
has been shown to bear specificity and memory [], and, as a
genuine immunologic response, proliferation of T cells in the
AMLR is triggered by MHC class I and II products via the T
cell Ag receptor and seems to be regulated by the same
mechanisms that control Ag-specific T cell activation []....
Whereas the predominant cell proliferating in the AMLR
was found to be CD4+ [] and to belong to the CD45RA+
memory Th cell subset [], several cell types, including
monocyte/macrophages (Mos) [], dendritic cells (DCs) [], null
cells [], NK cells [], and B cells [], as well as Ag- and mitogen-
3 De Santis, WO 03/012086 Al, published Feb. 13, 2003.
4 Current Protocols in Immunology 7.10.1—7.10.9 (John Wiley & Sons, Inc.
1994).
5 Elke Scandella, et al., Prostaglandin E2 is a Key Factor for CCR7 Surface
Expression and Migration of Monocyte-Derived Dendritic Cells, 100 Blood
1354—61 (2002).
6 Clemens Scheinecker et al., Initiation of the Autologous Mixed Lymphocyte
Reaction Requires the Expression of Costimulatory Molecules B7-1 and B7-
2 on Human Peripheral Blood Dendritic Cells, 161 J. Immunol. 3966—73
(1998).
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Application 12/522,048
activated T cells [], have been considered to act as stimulator
cells in the AMLR.
Nevertheless, comparative analyses have led to the
suggestion that DCs bear the unique ability to stimulate
autologous T cells in the AMLR []. However, DCs constitute
only a minor fraction (0.1—1.0%) of PBMCs [peripheral blood
mononuclear cells], and the isolation procedure used until
recently depended on physical separation with prolonged
culture in serum. . . .
[Scheinecker] demonstrate[s] that under serum-free conditions
only matured peripheral blood DCs are able to induce
considerable proliferation of autologous T cells and that this
proliferation depends on up-regulation of costimulation
associated molecules[, B7-1 and B7-2,] on DCs.
(Scheinecker 3966 (footnotes and endnotes omitted) and 3972; see Ans. 3.)
FF 2. Protocols discloses that “[ajntigen-presenting cells must generally be
present to obtain activation of lymphocytes by mitogens and antigens in
culture” and
[w]hen the concentration of antigen-presenting cells in the
population to be tested is inadequate for the response to be
measured, 5% to 10% autologous adherent cells should be
added to the culture. As with all other variables in the
proliferation assay, preliminary titrations of the number of
antigen-presenting cells required for an optimal response should
be carried out.
(Protocols 7.10.7; Ans. 3 (Protocols discloses “that antigen presenting cells
must generally be present to obtain activation of the lymphocytes by
mitogens and that autologous antigen presenting cells can be added to the
cultures to improve proliferative responses”).)
FF 3. Protocols discloses that “[a] wide array of lymphocyte-activation
agents may be used depending on the experimental question,” wherein
“[sjources of commonly used activation agents and useful concentration
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ranges are shown in Table 7.10.2,” which lists the mitogen, PHA as a
“Human Lymphocyte Activator[]” (Protocols 7.10.7; id. at Table 7.10.2;
Ans. 3).
FF 4. Scandella discloses that “monocyte-derived DCs (MoDCs) can be
obtained through in vitro differentiation of monocytes in the presence of
granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4” and
then introduced to “a cocktail of proinflammatory mediators, such as
TNF-a, IL-ip, IL-6, and prostaglandin E2 (PGE2), to mature [the] MoDCs
for application” (Scandella 1354—1355; see Ans. 3).
FF 5. De Santis discloses:
[A] method of generation of antigen presenting cells,
comprising:
a) collecting said cells from a subject[;]
b) activating said collected cells;
c) culturing and optionally expanding ex vivo said
activated cells;
d) treating said cultured and optionally expanded cells
with DNA hypomethylating agents so that said cells
concomitantly express multiple tumor associated antigens.
The cells obtainable according to the method of [De
Santis’] invention, as well as the cellular components thereof
whether alone or in combination with said cells, are useful for
prevention and treatment, in particular in a mammal, human
beings included, of malignancies of different histotype that
constitutively express one or more of the multiple tumor
associated antigens that are expressed in said cells.
(De Santis 11:19 — 12:12; see also id. at 49: 2—11 (De Santis’ claim 1); 51:
6—7 (De Santis’ claim 18); 51: 16—17 (De Santis’ claim 22 (“Use according
to claim 18, wherein said cancer antigens [produced by De Santis’ method]
are Cancer Testis Antigens”)); see Ans. 2—3.)
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FF 6. De Santis discloses that “cells suitable for [De Santis’] method
[include] . . . [(a)] [p]hytohemagglutinin (PHA) + recombinant human
interleukin-2 (rhIL-2)-activated, DNA hypomethylating agent-treated
PBMC, generated from purified PBMC of cancer patients in advanced stage
of disease or healthy subjects” (De Santis 14: 7—8; id. at 15: 3—7; Ans. 2—3).
FF 7. De Santis discloses that “[h]ypomethylating agents, also known in
the art as demethylating agents, useful for the purposes of [De Santis’
method] are well known in the art,” wherein “[a] preferred DNA
demethylating agent is 5-aza-cytidine or, more preferred, 5-aza-2’-
deoxycytidine” (De Santis 18: 1—6; Ans. 2—3).
FF 8. De Santis discloses that “[t]he activation step [of its] method ... is
carried out following the general common knowledge, in any case reference
can be made to [Protocols]” (De Santis 17: 16—19; Ans. 3).
FF 9. Examiner finds that De Santis “differs [from Appellants’ claim 1] by
not activating the PBMC with mature dendritic cells obtained by culturing
blood monocytes with GM-CSF and IL-4 and incubating with a maturation
mix[ture] [that includes IL-1 beta, TNA-alpha, IL-6, and PGE2]” and relies
on the combination of Protocols, Scandella, and Scheinecker to make up for
this deficiency in De Santis (Ans. 3).
FF 10. Examiner finds:
It is well established that the percentage of CD4 T cells in
peripheral blood is greater than the percentage of CD8 T cells
(see Fig 2 of [Appellants’] [Specification, for example) and the
ordinary artisan could expect to obtain a composition enriched
in CD4 T cells are compared to CD8 T cells.
(Ans. 4; see Spec. 9: 8—11 (Appellants’ “mixed antigen-unloaded mature
dendritic cells with a non-adherent fraction of lymphocytes and found that
after 7—8 days of incubation, there was an intensive proliferation of
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Application 12/522,048
lymphocytes. The proliferating cultures were mainly T lymphocytes
enriched in CD4+ lymphocytes” (emphasis removed)).)
ANALYSIS
Based on the combination of De Santis, Protocols, Scandella, and
Scheinecker, Examiner concludes that, at the time Appellants’ invention was
made, it would have been prima facie obvious to prepare an antigen-
presenting composition enriched in CD4+ cells as compared to CD8+ cells by
culturing blood monocytes with GM-CSF and IL-4 to obtain MoDCs that
are not loaded with cancer/testis antigens, maturing the MoDCs with
TNA-a, IL-ip, IL-6, and PGE2, using the mature MoDCs to stimulate the
proliferation of autologous normal non-activated lymphoid cells by
coculturing the autologous normal non-activated lymphoid cells with the
autologous MoDCs, and then treating the proliferating cells with an agent
that induces DNA demethylation, such as 5-aza-cytidine or 5-aza-2’-
deoxycytidine to induce expression of cancer/testis antigens (FF 1—9; see
generally Ans. 3^4; see also Ans. 6 (“the obviousness rejection does not
need to rely on replacing PHA with mature dendritic cells . . ., [because
Appellants’] claims do not exclude the presence of a mitogen such as
PHA”). In this regard, Examiner reasons that because peripheral blood
naturally contains a higher percentage of CD4+ T cells than CD8+ T cells,
the stimulation of proliferation of both sets of T cells will necessarily result
in T cell population that is enriched with CD4+ cells compared to CD8+ T
cells (see FF 10).
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Appellants’ claim 1 is open to include, inter alia,
“phytohemagglutinin (PHA) or pokeweed mitogen (PWM) to co-stimulate
blood monocytes,” therefore, we are not persuaded by Appellants’
contention to the contrary (App. Br. 3; see Ans. 6).
We are not persuaded by Appellants’ contention that Protocols
“conflicts with the teaching of De Santis,” because “De Santis . . .
[discloses] that PBMC can be stimulated to proliferate with mitogen alone,
e.g., PHA (App. Br. 5). While, the prior art may suggest various ways to
stimulate the proliferation of PBMC, Appellants failed to provide persuasive
evidence or argument to support a conclusion that a person of ordinary skill
in this art would not have found it prima facie obvious to combine two
known methods to achieve the expected result of stimulating the
proliferation of PBMC (e.g., a mitogen in addition to antigen-presenting
cells, such as mature dendritic cells) (see FF 1—9). To the contrary,
Protocols suggests the use of antigen-presenting cells in combination with
other lymphocyte-activation agents (FF 2—3). Therefore, for the foregoing
reasons, we are not persuaded by Appellants’ contention that Protocols “runs
against the teaching of DeSantis” (App. Br. 5—6). “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).
For the foregoing reasons, we are not persuaded by Appellants’
contention relating to an “[alternate protocol” set forth in Protocols,
wherein Appellants contend that Protocols “is clearly not meant to be a
protocol for preparative activation of lymphocytes for in-vivo use,” because
Protocols relates to a method “for assessing proliferative responses of human
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lymphocytes,” “would not have led a skilled artisan to use autologous
mature dendritic cells that have been obtained by culturing blood monocytes
with GM-CSF and LI-4 and incubation with a maturation mix to activate
autologous normal non-activated lymphoid cells,” “a person having ordinary
skill in the art would not have considered the teachings of Protocols at all
relevant when setting out to modify the method set forth in DeSantis,” “is
completely silent regarding using dendritic cells as the autologous non-T
cells for activating PBMC, much less using autologous mature dendritic
cells not loaded with CTA,” and “teaches methods where a radioactive
isotope is incorporated into PBMC in an attempt to develop an activation
technology for cells that would be subsequently used as a vaccine,” all of
which fail to account for Protocols contribution to the combination of
De Santis, Protocols, Scandella, and Scheinecker (Reply Br. 3—4). In this
regard, we note that Protocols discloses that the combination of a mitogen
and antigen presenting cells results in the stimulation of T cell proliferation
in vitro (FF 2—3). In sum, Appellants’ provide no persuasive evidence or
argument to support a conclusion that the combination of De Santis,
Protocols, Scandella, and Scheinecker fails to make obvious Appellants’
claimed invention (see FF 1—9; cf. Reply Br. 3—4).
Examiner relied upon Scheinecker to disclose that in an autologous
mixed lymphocyte reaction (AMLR), such as that suggested by the
combination of De Santis, Protocols, Scandella, and Scheinecker, “the
predominant cell proliferating in the AMLR was found to be CD4+” T cells
(see FF 1). Therefore, for the foregoing reasons, we are not persuaded by
Appellants’ contention regarding Scheinecker alone or in combination with
De Santis, Protocols, and Scandella (see generally App. Br. 6).
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Examiner relies on Scandella to disclose a method of obtaining
monocyte-derived dentritic cells in vitro, therefore, we are not persuaded by
Appellants’ contention that Scandella “would not have served to motivate a
skilled person in the field to use dendritic cells in vitro as an activator in the
De Santis method,” which fails to account for all of Scandella’s disclosure as
relied upon by Examiner or Scandella’s contribution to the combination of
De Santis, Protocols, and Scheinecker (FF 4, see also FF 1—3 and 5—9; cf.
App. Br. 6).
Appellants fail to identify a disclosure in their Specification to support
their contention that “enrichment in the context of claim 1 means that the
ratio between concentrations of CD4+ and CD8+ cells is higher in the end
product, i.e., the antigen presenting composition, than in the starting co­
culture of mature dendritic cells and non-activated lymphoid cells.” Nor do
Appellants provide persuasive evidence to rebut the Examiner’s contention
that the predominant population of T cells in PBMC are CD4+, relative to,
inter alia, CD8+ cells and, thus, the method suggested by the combination of
De Santis, Protocols, Scandella, and Scheinecker will necessarily result in an
antigen-presenting composition enriched in CD4+ cells as compared to CD8+
cells, as is required by Appellants’ claim 1 (see Reply Br. 4—5; cf. FF 1—9;
Ans. 6). In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s
argument in a brief cannot take the place of evidence.”).
For the foregoing reasons, we are not persuaded by Appellants’
reliance on Jonuleit’s disclosure that “dendritic cells obtained from [the]
type of maturation process [suggested by the combination of De Santis,
Protocols, Scandella, and Scheinecker] stimulates CD4+ and CD8+ cells to
the same degree as they exhibit an almost identical proliferation” (Reply Br.
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6 (emphasis removed)). Instead, we find no error in Examiner’s reasoning
that because peripheral blood contains a higher percentage of CD4+ T cells
than CD8+ T cells, stimulating the proliferation of both sets of T cells will
necessarily result in T cell population that is enriched with, i.e., contains a
higher percentage of, CD4+ cells compared to CD8+ T cells (see FF 10).
We are not persuaded by Appellants’ contention that “Scheinecker
disparages the use of GM-CSF” and “would have led a skilled person away
from the claimed invention,” because Scheinecker speculates that “at sites of
inflammation[, in vivo,] where GM-CSF is produced in highly increased
amounts and causes an enhanced DCs activation [], a locally deranged
AMFR response may lead to loss of self-tolerance as observed in certain
autoimmune diseases” (Scheinecker 3972 (emphasis added, endnotes
omitted); Reply Br. 5—6). Appellants fail to explain how Scheinecker’s
speculation regarding what might happen in a very specific in vivo situation,
relates to Appellants’ claimed in vitro method of preparing an antigen-
presenting composition enriched in CD4+ cells as compared to CD8+ cells as
is made obvious by the combination of De Santis, Protocols, Scandella, and
Scheinecker.
Further, Appellants fail to provide persuasive evidence or argument to
support a conclusion that Scheinecker teaches away from Appellants’
claimed method or combination with De Santis, Protocols, and Scandella. In
re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) (A reference is said to “teach
away” from a claimed invention when it “suggests that the line of
development flowing from the reference’s disclosure is unlikely to be
productive of the result sought by the applicant”). In this regard, we are not
persuaded by Appellants’ contention that Scheinecker’ speculation
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“disparages the use of GM-CSF” for any purpose, or more specifically, for
the purposes it is used for in Appellants’ claimed invention or in the
combination of De Santis, Protocols, Scandella, and Scheinecker (Reply Br.
6).
Appellants fail to establish that the dendritic cells suggested by the
combination of De Santis, Protocols, Scandella, and Scheinecker are “loaded
with cancer antigens,” therefore, we are not persuaded by Appellants’
contention to the contrary or reliance on Thumer to disclose dendritic cells
that are loaded with cancer antigen (Reply Br. 6).
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness. The rejection of claim 1 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of De Santis, Protocols,
Scandella, and Scheinecker is affirmed. Claims 2, 3, and 22 are not
separately argued and fall with claim 1.
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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