Ex Parte Spies et al

Patent Trial and Appeal Board

Sep 27, 2013

11470500 (P.T.A.B. Sep. 27, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE PATENT TRIAL AND APPEAL BOARD
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Ex parte THOMAS SPIES and VERONIKA SPIES
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Appeal 2011-010586
Application 11/470,500
Technology Center 1600
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Before TONI R. SCHEINER, FRANCISCO C. PRATS, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 from the final rejection of
claims 26-31, directed to a method of treating cancer. The claims have been
rejected as lacking enablement and written descriptive support. We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 Appellants identify the Real Party-In-Interest as the Fred Hutchinson
Cancer Research Center, Seattle Washington (App. Br. 2).
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STATEMENT OF THE CASE
“The present invention relates generally to the field of immunology.
More particularly, it [involves] stimulation of immune functions through cell
surface molecules known as NKG2D, which may be targeted to treat cancer,
viral diseases, and other conditions.” (Spec. 1: 12-14.)
Claims 26-31 are pending and on appeal. Claims 1-25, 32, and 33
have been canceled (App. Br. 2). Claims 26-31 are reproduced below:
26. A method for treating cancer in a patient comprising obtaining T cells
from a cancer patient and administering to the T cells of the patient an
NKG2D ligand in an effective amount to stimulate the responsive T cell; and
administering the stimulated T cells to the patient.
27. The method of claim 26, wherein the NKG2D ligand is an anti-
NKG2D antibody or fragment thereof.
28. The method of claim 27, wherein the NKG2D ligand is a monoclonal
antibody, polyclonal antibody, humanized antibody, Fab, F(ab')2, or single
chain antibody that specifically binds the extracellular domain ofNKG2D.
29. The method of claim 28, wherein the NKG2D ligand is a monoclonal
antibody.
30. The method of claim 29, wherein the monoclonal antibody is 1D11
(ATCC deposit PTA-3056) or 5C6 (ATCC deposit PTA-3055).
31. The method of claim 26, wherein the cancer is breast cancer, lung
cancer, prostate cancer, cervical cancer, testicular cancer, brain cancer, renal
cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, head
& neck cancer, skin cancer and ovarian cancer.
Claims 26-31 stand rejected under 35 U.S.C. § 112, first paragraph, as
lacking enablement (Ans. 7-11).
In addition, claim 30 stands rejected under 35 U.S.C. § 112, first
paragraph, as lacking adequate written descriptive support for monoclonal
antibodies ID11 and 5C6 (Ans. 5-6).
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The Examiner relies on the following as evidence of lack of
enablement:
Veronika Groh et al., Tumour-derived soluble MIC ligands impair
expression of NKG2D and T-cell activation, 419 NATURE 734-737 (2002).
Amanda M. Jamieson et al., The Role of the NKG2D Immunoreceptor in
Immune Cell Activation and Natural Killing, 17 IMMUNITY 19-29 (2002).
Michael A. Morse et al., Current status of adoptive immunotherapy of
malignancies, 2 EXPERT OPIN. BIOL. THER. 237-247 (2002).
Bjorn Cochlovius et al., Therapeutic Antibodies, MODERN DRUG DISCOVERY
33-38 (2003).
Barbara Fazekas De St. Groth et al., T cell activation: in vivo veritas, 82
IMMUNOLOGY AND CELL BIOLOGY 260-268 (2004).
Lauren I. Richie Ehrlich et al., Engagement of NKG2D by Cognate Ligand
or Antibody Alone is Insufficient to Mediate Costimulation of Human and
Mouse CD8+ T Cells, 174 J. IMMUNOL. 1922-1931 (2005).
Kerima Maasho et al., Cutting Edge: NKG2D Is a Costimulatory Receptor
for Human Naïve CD8+ T Cells, 174 J. IMMUNOL. 4480-4484 (2005).
In addition, Appellants rely on the following evidence:
Andreas Diefenbach et al., Rae1 and H60 ligands of the NKG2D receptor
stimulate tumour immunity, 413 NATURE 165-171 (2001).
Ekaterina S. Doubrovina et al., Evasion from NK Cell Immunity by MHC
Class I Chain-Related Molecules Expressing Colon Adenocarcinoma, 171 J.
IMMUNOL. 6891-6899 (2003).
Daniel D. Billadeau et al., NKG2D-DAP10 triggers human NK cell-
mediated killing via a Syk-independent regulatory pathway, 4 NATURE
IMMUNOLOGY 557-564 (2003).

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ENABLEMENT
Issue
Following an analysis of the Wands factors,2 the Examiner found that
the Specification “has not provided sufficient guidance to enable one [of]
skill in the art to use claimed method for treating any cancer in any patient
by administering any NKG2D ligand in [a] manner reasonably correlated
with the scope of the claims” (Ans. 10), absent undue experimentation (id.at
11).
Appellants contend that the Specification, “taken in light of what was
known and accepted in the art teaches one of skill how to make and use the
present invention without having to conduct undue experimentation,” and
“one of skill would correlate the in vitro data presented with the in vivo
application claimed” (App. Br. 6).
The issue raised by this rejection is whether the evidence of record
supports the Examiner’s position that undue experimentation would have
been required to treat cancer patients using the claimed method.
Fact Findings
The following findings of fact (FF) are supported by a preponderance
of the evidence of record.

2 In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Factors to be weighed in
determining whether a disclosure is in compliance with the enablement
requirement include: (1) the quantity of experimentation necessary to
practice the invention, (2) the amount of direction or guidance presented, (3)
the presence or absence of working examples, (4) the nature of the
invention, (5) the state of the prior art, (6) the relative skill of those in the
art, (7) the predictability or unpredictability of the art, and (8) the breadth of
the claims.
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1. Independent claim 26 is directed to treating a cancer patient, by
obtaining T cells from the cancer patient and stimulating the T cells with an
NKG2D ligand, and administering the stimulated T cells to the patient.
2. The Specification “propose[s] the use of NKG2D ligands . . . to
stimulate NKG2D expressing T-cells. In particular, applicants envision the
use of such ligands to stimulate immune responses in a variety of clinical
situations” (Spec. 41: 19-21), for example, treatment of cancer or viral
infection (id. at 42: 4-25).
In accordance with one embodiment of the present
invention, there is provided a method for treating various
cancers, including breast cancer, lung cancer, prostate cancer,
cervical cancer, testicular cancer, brain cancer, renal cancer,
liver cancer, stomach cancer, colon cancer, pancreatic cancer,
head & neck cancer, skin cancer and ovarian cancer.
(Id. at 42: 5-8.)
3. Further according to the Specification, the method of treating
cancer comprises “(a) obtaining a population of antigen-specific T cells from
a subject having cancer, (b) contacting said population of antigen-specific T
cells with an anti-NKG2-D antibody, or an NKG2-D-binding fragment
thereof, and (c) administering said population to said subject” (Spec. 3: 22-
25).
4. There are no working examples, either ex vivo, or in vivo,
involving cell populations or tumors from cancer patients, although there are
in vitro examples involving cytomegalovirus-infected cells (see Examples 1
and 2 of the Specification).
5. Groh teaches that “[e]ctopic expression of NKG2D ligands
causes rejection of transfected tumour cells by natural killer (NK) cells and
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primed cytotoxic T cells in syngenic mice” (Groh 734). However, Groh also
teaches that:
“[T]umour shedding of MIC systemically impairs the responses
of CD8 αβ T cells and presumably NK cells, thus
compromising the immunological competence of individuals
with cancer. Although expression of MIC by nascent tumours
might, to some extent, be effective in mobilizing responses
from effector cells and NK cells, its shedding at progressive
stages of tumour growth probably promotes immune evasion.
Notably, the factors that determine the tumour-associated
expression of MIC and the shedding mechanism remain to be
defined. But monitoring the presence of sMICA in tissue or
peripheral blood samples might be applicable to the prognosis
or diagnosis of cancer, just as the MIC-NKG2D system might
offer possibilities for therapy.
(Groh 737.)
6. Doubrovina teaches that:
Evasion of host immune responses is well documented
for viruses and may also occur during tumor
immunosurveillance. The mechanisms involve alterations in
MHC class I expression, Ag processing and presentation,
chemokine and cytokine production, and lymphocyte receptor
expression. Epithelial tumors overexpress MHC class I chain-
related (MIC) molecules, which are ligands for the activating
receptor NKG2D on NK and T cells. . . . NK cells from patients
with colorectal cancer lack expression of activating NKG2D
and chemokine CXCRl receptors, both of which are
internalized. Serum levels of soluble MIC (sMIC) are elevated
and are responsible for down-modulation of NKG2D and
CXCRl. . . . In vitro, internalization of NKG2D and CXCRl
occurs within 4 and 24 h, respectively, of incubating normal
NK cells with sMIC-containing serum. Furthermore, natural
cytotoxicity receptor NKp44 and chemokine receptor CCR7 are
also down modulated in IL-2-activated NK cells cocultured in
MIC-containing serum - an effect secondary to the down-
modulation of NKG2D and not directly caused by physical
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association with sMIC. The patients’ NK cells up-regulate
expression of NKG2D, NKp44, CXCR1, and CCR7 when
cultured in normal serum or anti-MIC Ab-treated autologous
serum. NKG2D+ but not NKG2D- NK cells are tumoricidal in
vitro, and in vivo they selectively traffic to the xenografted
carcinoma, form immunological synapse with tumor cells, and
significantly retard tumor growth in the SCID mice. These
results suggest that circulating sMIC in the cancer patients
deactivates NK immunity by downmodulating important
activating and chemokine receptors.
(Doubrovina, Abstract.)
7. Richie Ehrlich teaches that:
The possibility that NKC2D may costimulate CD8+ T
cells has generated much excitement in the fields of tumor
biology, autoimmunity, and infectious disease . . . NKG2D may
be a potential candidate for therapeutic targeting to block
autoimmune T cells or enhance T cell responses to tumors or
pathogen-infected tissues. . . . However, in this report we
demonstrate that mAb- or ligand-mediated engagement of
NKG2D alone is not sufficient to costimulate proliferation or
effector functions of primary, resting, or activated human or
mouse CD8+ T cells. Thus, it will be important to identify the
subpopulations and cytokine conditions that render CD8+ T
cells permissive for NKG2D-mediated signaling.
(Richie Ehrlich 1930-1931.)
8. Morse teaches that
Adoptive immunotherapy involves the transfer of immune
effectors with antitumour activity into the tumour bearing host.
Early approaches such as lymphokine activator killer (LAK)
cells and tumour infiltrating lymphocytes (TlLs) have yielded
occasional clinical responses. More recently, attempts to
stimulate and/or select antigen-specific T-cells in vitro have
demonstrated that tumour-specific adoptive immunotherapy is
possible. These approaches require complicated and time
consuming in vitro stimulation procedures. Therefore, genetic
modification of bulk T-cell populations is an attempt to create a
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large population of T-cells with a single specificity. In addition
to work being done to develop the most potent effector, other
studies are working on improving T-cell trafficking to tumours
and interfering with the tumour-induced immunosuppression
that can impair in vivo T-cell activity.
(Morse, Abstract.)
Discussion
“[T]o be enabling, the specification of a patent must teach those
skilled in the art how to make and use the full scope of the claimed invention
without ‘undue experimentation.’” Genentech, Inc. v. Novo Nordisk, A/S,
108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557,
1561 (Fed. Cir. 1993)). In order to make a rejection, the Examiner has the
initial burden of establishing a reasonable basis to question the enablement
provided for the claimed invention. Wright, 999 F.2d at 1562.
As an initial matter, the Examiner finds that there are no in vivo
experiments described in the Specification, and the only in vitro experiments
involve activation of anti-cytomegalovirus-specific CD8 αβ T cells to
“enhance anti-CMV . . . cytotoxic CD8 αβ responses” (Ans. 7), i.e., to
stimulate and enhance T cell cytotoxicity against cytomegalovirus-infected
cells.
Appellants contend that the Specification “demonstrate[s], by using
cells displaying CMV antigens, that a cell presenting an antigen in
conjunction with an NKG2D ligand [e.g, anti-NKG2D antibody] enhances T
cell effector/target cell contacts and cytotoxicity” (App. Br. 12). Appellants
contend essentially that these results are predictive of the effects of
stimulating cancer antigen-specific T cells with NKG2D ligand because
“[c]ancer cells present a number of cancer antigens, much like a CMV
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infected cell presents CMV antigens. Thus, the results using CMV antigens
provide a model of T cell enhancement that can be used in modeling the
analogous situation in cancer cells” (id.). In other words, Appellants
contend that “lysis of a fibroblast expressing a CMV protein mimics lysis of
a tumor cell expressing a tumor antigen” (id. at 13-14).
Nevertheless, the Examiner finds that the state of the art at the time of
the invention, and even after the invention, shows that the correspondence
between tumor cells and virally-infected cells is neither as recognized nor as
predictable as Appellants contend (Ans. 7, 8). The Examiner further finds
that even if the in vitro experiments in the Specification had involved
activation of anti-tumor-specific CD8 αβ T cells “there is no correlation on
this record or art recognized correlation between the NKG2D activation by
NKG2D ligand” of tumor antigen-specific T cells in vitro and treating
cancer patients by adoptive immunotherapy using NKD2G-ligand stimulated
T cells (id. at 10).
Ultimately, the Examiner finds that the Specification “does not enable
one skilled in the art to practice the invention without an undue amount of
experimentation” (id. at 7), given “the unpredictability of the art, the lack of
sufficient guidance in the specification, the limited working examples, and
the limited amount of direction provided given the breadth of the claims”
(id. at 11).
Appellants, on the other hand, contend that “the art related to the
claimed invention was sufficiently developed [at the time of the invention]
to enable one of skill to implement the claimed invention given the
description and guidance provided in the application” (id. at 8); but “[t]he
Examiner has selectively . . . recognize[d] certain aspects of the art that
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allegedly support unpredictability of the claimed invention while ignoring
other aspects of the art (even within the same reference) that support the
enablement of the presently claimed invention” (id. at 7).
We agree with Appellants that the Examiner has, to some extent,
focused on specific aspects of the scientific literature that demonstrate
unpredictability in the art of adoptive immunotherapy; however, that does
not mean that treatment of cancer using adoptive immunotherapy was
straightforward or predictable at the time of the invention. Indeed, the
conflicting evidence at the time of the invention supports the Examiner’s
finding that there was no established, art recognized correlation between in
vitro stimulation of tumor-specific T cell with NKG2D ligand and treatment
of cancer patients.
For example, Appellants contend that the Examiner has focused on
Doubrovina’s statement that soluble NKG2D ligands (i.e., MICA and
MICB) in the sera of patients with colorectal cancer down-regulate both
activating and chemokine groups, resulting in NK cells that lack surface
expression of NKG2D, lack the ability to target the tumor, and are not
tumoricidal (App. Br. 8), rather than Doubrovina’s teaching that this lack of
expression can be reversed by culturing the NK cells in normal serum or
anti-MIC antibody-treated serum (id.). However, this aspect of activating
NK cells (or cytotoxic T cells for that matter) is not disclosed in the present
Specification, nor is there evidence of record that it was known in the art at
the time of the invention, since Doubrovina was published after the effective
filing date of the present application. Moreover, to the extent Appellants
contend “the tumors described in Doubrovina et al. express MIC at levels
that down regulate NKG2D and result in NKG2D- cells – these cells would
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not be responsive to an NKG2D ligand and would not be within the scope of
the currently claimed invention” (id. at 9), we note that the claims are not
limited to treating tumors that do not express MIC at levels that down-
regulate NKG2D.
Similarly, Appellants contend that the Examiner cites Groh as
“teaching downregulation of NKG2D expression in T cells from patients
with cancer without acknowledging the fact that only MIC expressing
cancers provide such downregulation” (id. at 10). Thus, Appellants contend,
“a number of cancers that do not express MIC or cancers that do not over-
express MIC are susceptible to the claimed treatment” (id.). Again,
however, the Specification says nothing about this distinction, and the
claims are not limited to treating tumors that do not express MIC at levels
that down-regulate NKG2D.
Moreover, Morse provides evidence that adoptive immunotherapy
normally requires complicated in vitro stimulation procedures, none of
which are addressed in Appellants’ Specification.
In any case, As explained in Genentech Inc. v. Novo Nordisk A/S, 108
F.3d 1361 (Fed. Cir. 1997) (citation omitted):
[A] specification need not disclose what is well known in the
art. However, that general, oft-repeated statement is merely a
rule of supplementation, not a substitute for a basic enabling
disclosure. It means that the omission of minor details does not
cause a specification to fail to meet the enablement
requirement. . . . It is the specification, not the knowledge of
one skilled in the art, that must supply the novel aspects of an
invention in order to constitute adequate enablement.
Id. at 1366.
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Finally, while we note Appellants’ contention that they “have
followed [the] teachings [of the Specification] and have in fact confirmed
the effectiveness of this approach as an anti-cancer treatment” (id. at 12),
Appellants have not provided evidence to that effect on this record.
As for Appellants’ contention that others, namely Diefenbach, and
Billadeau, have also “followed these teachings and . . . confirmed the
effectiveness of this approach as an anti-cancer treatment” (id. at 12-13),
Appellants have not established on this record that the protocols followed in
those references are consistent with the guidance provided in the
Specification.
The law is well settled that enablement must be commensurate in
scope with the claimed invention. E.g., Liebel-Flarsheim Co. v. Medrad,
Inc., 481 F.3d 1371, 1379 (Fed. Cir. 2007); Genentech, Inc. v. Novo Nordisk,
108 F.3d 1361, 1365 (Fed. Cir. 1997); In re Wright, 999 F.2d 1557, 1561
(Fed. Cir. 1993). A single embodiment may be sufficient, if that teaching
combined with the knowledge of the skilled artisan would enable the full
scope of the claim. See Johns Hopkins Univ. v. Cellpro Inc., 152 F.3d 1342,
1361 (Fed. Cir. 1998). However, in this case, despite the breadth of the
claims and the well-recognized challenges in treating cancer, no
embodiment involving tumor cells or tumors is disclosed. Nor have
Appellants established that there was an art recognized correlation between
virally-infected cells and tumor cells in this specific context, much less
treating cancer in patients. Without more, the skilled artisan would not have
had a reasonable expectation of success in doing so based on Appellants’
very limited disclosure.
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As explained in Rasmusson v. SmithKline Beecham Corp., 413 F.3d
1318 (Fed. Cir. 2005):
If mere plausibility were the test for enablement under section
112, applicants would obtain patent rights to ‘inventions’
consisting of little more than respectable guesses as to the
likelihood of their success. When one of the guesses later
proved true, the ‘inventor’ would be rewarded the spoils instead
of the party who demonstrated that the method actually worked.
That scenario is not consistent with the stautory requirement
that the inventor enable an invention rather than merely
proposing an unproved hypothesis.
Id. at 1325.
Having considered the respective positions of Appellants and the
Examiner, we find that the preponderance of the evidence of record supports
the Examiner’s position that Specification “does not enable one skilled in the
art to practice the invention without an undue amount of experimentation”
(Ans. 7).
WRITTEN DESCRIPTION
The Examiner finds that monoclonal antibodies ID 11 and 5C6 are
required to practice the invention of claim 30, and “[a]s a required element,
[they] must be known and readily available to the public or obtainable by a
repeatable method set forth in the specification” (Ans. 5). “If they are not so
obtainable or available, the enablement requirements of 35 U.S.C. 112, first
paragraph, may be satisfied by a deposit of the pertinent hybridomas which
produce these antibodies” (Ans. 5-6). The Examiner acknowledges that a
deposit was made, but finds that the conditions of the deposit have not been
made of record (id. at 6).
Appellants contend that monoclonal antibodies 1D11 and 5C6 were
deposited with the ATCC prior to the filing date of the application, and the
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Specification discloses the deposit date and ATCC accession numbers of the
antibodies (App. Br. 5; see also Spec. 15: 10-11). Appellants contend that
they must “submit a statement from a person in a position to corroborate the
fact, stating that the biological material which is deposited is a biological
material specifically identified in the application as filed” only “[w]hen the
original deposit is made after the effective filing date of an application for
patent” (id.).
This argument is not persuasive. The Examiner is not concerned with
establishing a so-called “chain-of-custody” affidavit for the antibodies (or
more accurately, for the hybridoma cell lines from which the antibodies are
produced), which is only required when the deposit is made after the filing
date. Rather, the Examiner is concerned with whether the conditions of the
deposit are sufficient to satisfy the written description requirement. Merely
stating that a pre-filing deposit has been made and providing the accession
numbers is not enough to satisfy the requirement. As the Examiner has
explained:
If the deposit [has] been made under the terms of the
Budapest treaty, an affidavit or declaration . . . stating that the
[biological material] has been deposited under the Budapest
Treaty and that the [biological material] will be irrevocably and
without restriction or condition released to the public upon the
issuance of a patent would satisfy the deposit requirement made
herein. See 37 CFR 1.808.
If the deposit has not been made under the Budapest treaty,
then an affidavit or declaration . . . stating that the deposit has
been made at an acceptable depository and that the criteria set
forth in 37 CFR 1.801-1.809, have been met.
(Final Rejection 3; Ans. 12.)
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Appellants direct us to no such affidavit or declaration as being of
record. Accordingly, the rejection of claim 30 as failing to satisfy the
written description requirement of 35 U.S.C. § 112, first paragraph, is
affirmed.
SUMMARY
The rejection of claims 26-31 as lacking enablement is affirmed.
The rejection of Claim 30 as lacking adequate written descriptive
support is affirmed.
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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