Ex Parte Falo et al

Board of Patent Appeals and Interferences

Feb 26, 2009

10608424 (B.P.A.I. Feb. 26, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte LOUIS D. FALO, JR. and CHRISTINA M. CELLUZZI
__________

Appeal 2008-45491
Application 10/608,424
Technology Center 1600
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Decided:2 February 26, 2009
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Before TONI R. SCHEINER, DONALD E. ADAMS, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL

1 The real party in interest is the University of Pittsburgh.
2 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).

Appeal 2008-4549
Application 10/608,424

This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1, 2, and 4-12, all the claims pending in the application. We have
jurisdiction under 35 U.S.C. § 6(b).
STATEMENT OF THE CASE
Tumor cells and virally infected cells express antigens
which can be targeted by CTLs [cytotoxic T lymphocytes], but
the tumor cells and virally infected cells themselves do not
stimulate CTL immunity. This is presumably because the tumor
cells and viral cells are incapable of providing the antigen or
antigens in the appropriate context of co-stimulation. Antigen
presenting cells (APC), however, express a variety of co-
stimulatory molecules and cytokines. The present invention
provides formulations in which APCs are fused to or are in a co-
culture with either tumor cells or virally infected cells. The
fused cells and/or co-cultured cells are then used to provide a
complete array of tumor antigens or viral antigens that can be
delivered to the endogenous pathway of APCs from MHC Class
I specific presentation and CTL stimulation. Fusion or co-
culture of the APCs with the tumor cells or virally infected cells
causes the tumor antigens to become more immunogenic by
association with the professional APCs. The fusion products and
the co-culture products express properties of both the APC and
the tumor; these products are capable of priming a CTL
response.

(Spec. 4: 5-19.)
The present invention is directed to “a formulation comprising
hybridomas of antigen presenting cells fused to . . . virally infected cells”
(Spec. 1: 5-7).
Claims 1, 4, and 8 are representative of the subject matter on appeal:
1. A formulation comprising at least one hybridoma having at least one
first cell fused to at least one second cell;
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wherein said first cell is an antigen presenting cell selected from the
group consisting of a macrophage and a dendritic cell, and said second cell
is a virally infected cell.

4. The formulation of claim 1, wherein said virally infected cells are
selected from the group consisting of cells infected with influenza virus,
human immunodeficiency virus, cytomegalovirus, human papilloma virus
and herpes simplex virus.

8. A pharmaceutical composition comprising: at least one hybridoma;
and a suitable pharmaceutical carrier;
wherein each hybridoma is comprised of at least one first cell fused to
at least one second cell;
wherein said first cell is an antigen presenting cell selected from the
group consisting of a macrophage and a dendritic cell, and said second cell
is a virally infected cell.

The Examiner relies on the following evidence:
BASIC & CLINICAL IMMUNOLOGY 697 (Daniel P. Stites et al. eds., Appleton
& Lange 6th ed. 1987).

GENES 736 (Benjamin Lewin ed., John Wiley & Sons 3rd ed. 1987).

CHARLES A. JANEWAY, JR. & PAUL TRAVERS, IMMUNOBIOLOGY 2.20-21
(Garland Publishing 1994).

I. Frank & M. Pope, The Enigma of Dendritic-Cell Immunodeficiency Virus
Interplay, 2 CURRENT MOLECULAR MEDICINE 229-248 (2002).

Josh P. Roberts, Are HIV Vaccines Fighting Fire with Gasoline?, 18 THE
SCIENTIST 26 (2004).

Appellants rely on the following additional evidence:
Concepción Marañón et al., Dendritic Cells Cross-Present HIV Antigens
from Live as Well as Apoptotic Infected CD4+ T Lymphocytes, 101 PNAS
6092-6097 (2004).

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The Examiner rejected claims 1, 2, and 4-12 under 35 U.S.C. § 112, first
paragraph for lack of enablement.
We reverse.
PRINCIPLES OF LAW
“[A] specification disclosure which contains a teaching of the manner
and process of making and using the invention in terms which correspond in
scope to those used in describing and defining the subject matter sought to
be patented must be taken as in compliance with the enabling requirement of
the first paragraph of § 112 unless there is reason to doubt the objective truth
of the statements contained therein which must be relied on for enabling
support.” In re Marzocchi, 439 F.2d 220, 223 (CCPA 1971) (emphasis in
original). “[It] is incumbent upon the Patent Office, whenever a rejection on
this basis is made, to explain why it doubts the truth or accuracy of any
statement in a supporting disclosure and to back up assertions of its own
with acceptable evidence or reasoning which is inconsistent with the
contested statement.” Id. at 224. In other words, “the PTO bears an initial
burden of setting forth a reasonable explanation as to why it believes that the
scope of protection provided by [the] claim[s] is not adequately enabled by
the description of the invention provided in the specification of the
application; this includes, of course, providing sufficient reasons for
doubting any assertions in the specification as to the scope of enablement.”
In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993).
Moreover, the enablement analysis must be focused on the product or
method defined by the claims. “Title 35 does not require that a patent
disclosure enable one of ordinary skill in the art to make and use a perfected,
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commercially viable embodiment absent a claim limitation to that effect.”
CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333, 1338 (Fed. Cir. 2003).
See also In re Cortright, 165 F.3d 1353, 1359 (Fed. Cir. 1999) (claims to
method of “restoring hair growth” encompassed achieving full head of hair
but did not require it). “Usefulness in patent law, and in particular in the
context of pharmaceutical inventions, necessarily includes the expectation of
further research and development. The stage at which an invention in this
field becomes useful is well before it is ready to be administered to
humans.” In re Brana, 51 F.3d 1560, 1568 (Fed. Cir. 1995).
Finally, it is well settled that a post-filing publication cannot be used
to supplement an insufficient disclose, but can be offered as evidence that a
disclosed device would have been operative. Gould v. Quigg, 822 F.2d
1074, 1078 (Fed. Cir. 1987).
THE ISSUE
The issue raised by this appeal is whether the Examiner has met his
initial burden of setting forth a reasonable explanation as to why it would
have required undue experimentation for one skilled in the art to make and
use a hybridoma comprising an antigen presenting cell fused to a virally-
infected cell.
FINDINGS OF FACT
FF1 Appellants claim a formulation comprising a hybridoma having
at least one virally infected cell fused to at least one antigen presenting cell
(APC) selected from the group consisting of a macrophage and a dendritic
cell.
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FF2 According to the Specification, “a hybridoma is a physical
combination of at least two different kinds of cells” (Spec. 6: 14-15), and the
Specification describes “two different hybridomas . . . namely a hybridoma
between at least one APC and one tumor cell; and a hybridoma between at
least one APC and at least one virally infected cell” (id. at 6: 15-18).
FF3 “In a preferred embodiment, the APC-tumor cell or APC-virally
infected cell hybridoma is formed by fusing the two types of cells together
with polyethylene glycol (PEG)” (Spec. 8: 4-6).
FF4 The Specification teaches that
Tumor cells and virally infected cells express antigens
which can be targeted by CTLs [cytotoxic T lymphocytes], but
the tumor cells and virally infected cells themselves do not
stimulate CTL immunity . . . presumably because the tumor
cells and viral cells are incapable of providing the antigen or
antigens in the appropriate context of co-stimulation. Antigen
presenting cells (APC), however, express a variety of co-
stimulatory molecules and cytokines.

(Spec. 4: 5-10.)
FF5 According to the Specification,
[F]ormulations in which APCs are fused to or are in a co-
culture with either tumor cells or virally infected cells . . .
provide a complete array of tumor antigens or viral antigens
that can be delivered to the endogenous pathway of APCs from
MHC Class I specific presentation and CTL stimulation.
Fusion or co-culture of the APCs with the tumor cells or virally
infected cells causes the tumor antigens to become more
immunogenic by association with the professional APCs. The
fusion products and the co-culture products express properties
of both the APC and the tumor; these products are capable of
priming a CTL response. This results in the destruction of
tumor cells that express similar antigens. Similar results are
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seen when the formulations comprise products using virally-
infected cells . . . destruction of the virus.

(Spec. 4: 10-22.)
FF6 The Specification teaches that “the present invention obviates
the need to identify specific antigens that elicit a CTL response by providing
a mechanism that delivers . . . viral antigens into the MHC [C]lass I
restricted antigen processing pathway of professional APCs. By delivering
the entire array of antigens produced by . . . a virally infected cell to the
APCs, a mechanism is provided for broad, polyvalent immunization” (Spec.
4: 23-28).
FF7 There are no working examples involving fusions or co-cultures
of APCs and virally-infected cells in the Specification. However, Examples
1-4 of the present Specification demonstrate that “splenocytes from mice
immunized with co-cultures or fusion products of DCs [dendritic cells] and
B16 [melanoma cells] lysed B16 targets while splenocytes from mice
immunized with co-cultures or fusion products of DCs and 3LL [lung
carcinoma cells] lysed 3LL targets” in vitro (Spec. 14: 29-31). That is, lysis
was tumor specific (id. at 14: 28). “Furthermore, lysis was CD8-T cell
mediated as splenocytes depleted for CD8 or Thy 1.2 did not lyse tumor-
specific targets” (id. at 14: 32-33).
FF8 Example 5 of the present Specification “demonstrate[s] that
immunization with products of DC-tumor cell fusions or co-cultures can
induce tumor-specific CTLs and potent protective anti-tumor immunity
against two distinct, poorly immunogenic tumors” in vivo (Spec. 17: 3-6).
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Example 6 demonstrates that the products of DC-3LL fusions or co-cultures
induced tumor regression in mice with established tumors (id. at 17: 8-23).
FF9 According to Frank,
A dendritic cell (DC) encountering an immunodeficiency
virus should pose a threat to the virus, by efficiently processing
and presenting viral antigenic determinants to activate specific
anti-viral T and B cell immunity. While this may occur in vivo,
it is apparent that DC-entrapped viruses can freely spread
between cells, move to distal tissues, and proliferate rapidly
particularly upon meeting CD4+T cells. In fact, the latter is
further augmented when the T cells are activated. Thus, it
seems that immunodeficiency viruses exploit the unique ability
of DCs to survey the periphery and capture incoming
pathogens, traffic around the body often targeting the lymphoid
tissues, and efficiently communicate with naïve and memory T
cells. Combined with the fact that DCs are likely the first
leukocytes interacting with virions crossing the mucosae, these
features provide the basis on which the virus maximizes its
chance to establish infection even in the face of immune
activation.

(Frank, Abstract.)
FF10 On the other hand, Frank also teaches
While the virus expertly exploits the DC to forge its survival
and dissemination, DCs probably also process viral
determinants in vivo, presenting them to activate (at least low-
level) virus-specific immunity . . . Such immune activation
likely occurs throughout infection until the immune system
ultimately collapses due to the overwhelming virus production
and depletion of CD4+ T cells. The extensive capacity of DCs
to capture and process antigens via a number of different
mechanisms for the activation of CD4+ and CD8+ T cells
underscores the potential usefulness of these cells in ensuring
activation of broad immune responses . . . However, it is vital
that approaches to properly target these pathways be developed
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to capitalize on the DC for vaccine and therapeutic
interventions.

(Frank 241, col. 1.)
FF11 Marañón, cited by Appellants as evidence that the “invention
works as claimed” (Reply Br. 4), teaches that dendritic cells co-cultured with
live, HIV infected CD4+ T cells process and present antigen efficiently
(Marañón 6095, col. 2). Marañón suggests that “this HIV antigen
presentation pathway could be exploited to eradicate latently infected
reservoirs, which are poorly recognized by patients’ immune systems” (id.,
Abstract).
ANALYSIS
The Examiner concluded that the Specification “does not reasonably
provide enablement for [making or using] a formulation comprising a
hybridoma, said hybridoma comprising a DC [dendritic cell] and a tumor
cell” (Ans. 4).
In particular, the Examiner asserts that the Specification is not
enabling for making the claimed hybridoma because a hybridoma comprises
“‘a transformed cell line grown in vitro that is a somatic hybrid of 2 parent
cell lines’” (Ans. 63), in “‘a state of unrestrained growth in culture,
resembling or identical with the tumorigenic condition’” (id.4). The
Examiner concludes that the Specification “fails to teach how to make the
[dendritic cell - virally infected cell] ‘hybridoma’ of the instant claims” (id.)

3 Citing BASIC & CLINICAL IMMUNOLOGY 697.
4 Citing GENES 736.
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because “neither the mortal DC nor the mortal virally-infected cell is capable
of contributing transformation/immortality to the claimed formulation” (id.).
We do not agree that the term “hybridoma” requires immortalization
in the context of the present claims and Specification. Appellants’ use of
“hybridoma” rather than “hybrid” may be unconventional, but it is clear
from the plain language of claim 1 that the claimed hybridoma is simply a
virally infected cell fused to a dendritic cell or a macrophage. This
interpretation is consistent with the Specification, which differentiates
between a possibly immortalized hybridoma “between at least one APC and
one tumor cell,” and a hybridoma “between at least one APC and at least one
virally infected cell” (FF2).
The Examiner does not dispute that an antigen presenting cell and a
virally infected cell can be physically combined “by fusing the two types of
cells together with polyethylene glycol” as taught by the Specification
(FF3).
We conclude that the Examiner has not met his initial burden of
establishing that the Specification would not have enabled one of skill in the
art to make the claimed “hybridoma.”
The Examiner also asserts that the Specification is not enabling for
using the claimed formulations because the “the formulations . . . are
pharmaceutical compositions and require enablement as such” (Ans. 4), but
the Specification “provides no teachings sufficient to enable claims drawn to
a DC hybridoma which induces effective anti-virally-infected cell
immunity” (id.), especially “in the case of HIV infection” (id.).
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According to the Examiner, Frank provides evidence “that the
formulations of the instant claims would be more likely to exacerbate viral
infections than to treat or prevent them” (Ans. 5), at least in part because
dendritic cell-entrapped immunodeficiency viruses can be spread to other
cells, and can also be transported intact to distal tissues (id.).
Nevertheless, despite the ability of immunodeficiency viruses to
withstand dendritic cell-entrapment to some degree, Frank teaches that
dendritic cells also process and present immunoviral determinants in vivo
just as they would other viral determinants, activating low level virus-
specific immunity in the process. Thus, Frank suggests that the extensive
capacity of dendritic cells to capture and process viral antigens via a number
of different mechanisms for the activation of CD4+ and CD8+ T cells could
be useful in ensuring activation of broad immune responses (FF10).
Appellants cite Marañón in support of the enablement of the claims.
The Examiner essentially dismisses Marañón on two grounds: that the
reference “comes some seven years after the priority date of the instant
application, thus, it cannot be used to establish the enablement of the instant
application as of its priority date” (Ans. 7), and “the reference employs live
antigen-loaded dendritic cells and not the fusion products of the instant
claims” (id).
Nevertheless, Marañón must considered to the extent it is offered as
evidence that the “invention works as claimed” (Reply Br. 4). See Gould
822 F.2d at 1078. Moreover, while it is true that the reference discloses
dendritic cells co-cultured, rather than fused with HIV-infected cells, we
agree with Appellants that its disclosure is relevant to the claimed invention.
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Specifically, Appellants contend that Marañón “demonstrates that an
APC, a dendritic cell, that expresses viral antigen could be used to eradicate
virus” (id.). As discussed above, Marañón demonstrates that dendritic cells
co-cultured with live, HIV infected CD4+ T cells process and present HIV
antigens efficiently, and suggests that “this HIV antigen presentation
pathway could be exploited to eradicate latently infected reservoirs” (FF11).
Also discussed above, the present Specification demonstrates that dendritic
cell-tumor cell fusions and dendritic cells co-cultured with tumor cells are
comparable in their ability to induce tumor-specific CTLs and protective
anti-tumor immunity (FF7, 8). The Examiner has not provided a reasonable
explanation for doubting that dendritic cells fused with virally-infected cells
would not similarly process and present HIV antigens in a manner
comparable to Marañón’s co-cultured dendritic cells.
Finally, to the extent the Examiner asserts that the Specification must
demonstrate “effective anti-virally-infected cell immunity” in vivo (Ans. 4),
we note that “[u]sefulness in patent law, and in particular in the context of
pharmaceutical inventions, necessarily includes the expectation of further
research and development. The stage at which an invention in this field
becomes useful is well before it is ready to be administered to humans.”
Brana, 51 F.3d at 1568. The evidence offered by the Examiner does not
support his conclusion that the claimed invention had not reached “the stage
at which an invention in this field becomes useful” (id.) at the time of filing.
We conclude that the Examiner has not met his initial burden of establishing
that the Specification would not have enabled one of skill in the art to use
the claimed hybridoma.
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CONCLUSIONS OF LAW
The Examiner has not met his initial burden of setting forth a
reasonable explanation as to why it would have required undue
experimentation for one skilled in the art to make and use a hybridoma
comprising an antigen presenting cell fused to a virally-infected cell.
The rejection of claims 1, 2, and 4-12 under 35 U.S.C. § 112, first
paragraph for lack of enablement is reversed.

REVERSED

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