Ex Parte Dudley et al

Board of Patent Appeals and Interferences

Jan 24, 2011

10526697 (B.P.A.I. Jan. 24, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MARK E. DUDLEY, STEVEN A. ROSENBERG,
and JOHN R. WUNDERLICH
__________

Appeal 2010-010858
Application 10/526,697
Technology Center 1600
__________

Before ERIC GRIMES, MELANIE L. McCOLLUM, and
STEPHEN WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of promoting cancer regression in a mammal by combining

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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chemotherapy and immunotherapy. The Patent Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.

STATEMENT OF THE CASE
The invention concerns “the combined use of immunotherapy and
chemotherapy to promote the regression of a cancer in a mammal.” (Spec.
[0001].)
Claims 23-40 are on appeal. Claim 23 is representative and reads as
follows:
23. A method of promoting the regression of a cancer in a mammal,
which method comprises:
(i) administering to the mammal nonmyeloablative lymphodepleting
chemotherapy, and
(ii) subsequently administering:
(a) autologous T-cells, which have been previously isolated and
selected for highly avid recognition of an antigen of the cancer, the
regression of which is to be promoted, by stimulation of the T-cells in vitro
with the antigen of the cancer, followed by one cycle of rapid expansion
using irradiated allogeneic feeder cells, OKT3 antibody, and IL-2, and,
either concomitantly with the autologous T-cells or subsequently to the
autologous T-cells, by the same route or a different route, a T-cell growth
factor that promotes the growth and activation of the autologous T-cells, or
(b) autologous T-cells, which have been previously isolated,
selected for highly avid recognition of an antigen of the cancer, the
regression of which is to be promoted, by stimulation of the T-cells in vitro
with the antigen of the cancer, and modified to express a T-cell growth
factor that promotes the growth and activation of the autologous T-cells,
followed by one cycle of rapid expansion using irradiated allogeneic feeder
cells, OKT3 antibody, and IL-2, whereupon the regression of the cancer in
the mammal is promoted.

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The Examiner rejected the claims as follows:
• claims 23-35, 37, and 38 under 35 U.S.C. § 103(a) as unpatentable
over Dudley2 or Gruenberg3 (WO 97/05239), each in view of Slavin,4
Riddell,5 and Rosenberg;6 and
• claims 36, 39, and 40 under 35 U.S.C. § 103(a) as unpatentable over
Dudley or Gruenberg (WO 97/05239), in view of Slavin, Riddell, and
Rosenberg, and further in view of Kawakami7 and Stevens.8

OBVIOUSNESS
The Issues
For both grounds of rejection, the Examiner relied upon a
combination of Dudley or Gruenberg, with Slavin, Riddell, and Rosenberg.
The Examiner’s position is that Dudley taught a method of promoting the
regression of melanoma which comprised administering an autologous T cell

2 Mark E. Dudley et al., Adoptive Transfer of Cloned Melanoma-Reactive T
Lymphocytes for the Treatment of Patients with Metastatic Melanoma, 24 J.
IMMUNOTHERAPY, no. 4, 363-373 (2001).
3 Int’l Publication No. WO 97/05239 by Micheal L. Gruenberg, published
Feb. 13, 1997.
4 US Patent No. 6,447,767 B1 issued to Shimon Slavin et al., Sep. 10, 2002.
5 Stanley R. Riddell et al., The use of anti-CD3 and anti-CD28 monoclonal
antibodies to clone and expand human antigen-specific T cells, 128 J.
IMMUNOLOGICAL METHODS, 189-201 (1990).
6 US Patent No. 5,126,132 issued to Steven A. Rosenberg, Jun. 30, 1992.
7 Kawakami et al., Identification of a human melanoma antigen recognized
by tumor-infiltrating lymphocytes associated with in vivo tumor rejection, 91
PROC. NATL. ACAD. SCI., 6458-6462 (1994).
8 Emily J. Stevens et al., Generation of Tumor-Specific CTLs from
Melanoma Patients by Using Peripheral Blood Stimulated with Allogeneic
Melanoma Tumor Cell Lines, 154 J. IMMUNOLOGY, 762-771 (1995).

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previously isolated, selected for highly avid recognition of melanoma
antigen, and expanded in vitro. (Ans. 3.) The Examiner found that Dudley
also disclosed subsequently administering IL-2 at various dosages (125,000
IU/kg and 720,000 IU/kg) to the same patient. (Id.) The Examiner found
that Dudley also disclosed that some patients additionally received the
MART-1 peptide. (Id.) According to the Examiner, Dudley taught that the
poor persistence of adoptive transfer of T cells could be overcome by
considering variations on the patient treatment protocol, including
lymphodepleting chemotherapy. (Id. at 3-4.) The Examiner found that
Dudley taught that such chemotherapy might improve lymphocyte survival
and treatment efficacy. (Id. at 4.)
The Examiner found that Gruenberg taught a method of promoting the
regression of cancer in a mammal comprising administering to a mammal
autologous T-cells which have been stimulated in vitro with antigen of the
cancer being treated, and administering IL-2 to the same patients at various
concentrations. (Id.)
According to the Examiner, the instantly claimed invention differs
from Dudley or Gruenberg in that these references did not explicitly teach
administering non-myeloablative lymphodepleting chemotherapy prior to
administering autologous T-cells which had been selected for highly avid
recognition of melanoma antigen, stimulated in vitro with the antigen of the
cancer, and subjected to one cycle of rapid expansion using irradiated
allogeneic feeder cells, OKT3 antibody and IL-2. (Id.)
The Examiner’s position is that Slavin taught a method of treating
melanoma patients, comprising administering to the patient non-
myeloablative treatment, including administering cyclophosphamide and
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fludarabine prior to administering hematopoietic cells. (Id.) The Examiner
found that Slavin disclosed using the non-myeloablative treatment to
overcome the poor persistence of adoptive transfer of T-cells. (Id.)
Additionally, the Examiner found that Slavin taught that the hematopoietic
cells administered may contain T-cells and that T-cell depletion of donor
stem cell preparations has been known to increase the risk of graft rejection.
(Id.) Thus, according to the Examiner, Slavin established that at the time of
the invention one of ordinary skill in the art would have known that
administering nonmyeloablative lymphodepleting chemotherapy to a
mammal was a routinely used method of inducing donor specific tolerance
in a method of treating cancer, including melanoma. (Id. at 5.)
The Examiner found that Rosenberg taught a method of treating
cancer, including melanoma, comprising administering to a patient an
effective amount of autologous tumor infiltrating lymphocytes. (Id.)
According to the Examiner Riddell taught a general methodology for
determining an effective amount of said cells and also taught that the
preferred amount is from about 5 x 109 to 5 x 1011 cells. (Id.)
The Examiner found that Riddell taught an in vitro method of growing
and expanding a large number of antigen specific T cells comprising rapid
expansion using irradiated allogeneic feeder cells, OKT3 antibody and IL-2.
(Id.) The Examiner found that Riddell disclosed an alternative culture
method to clone and propagate human T cells that permitted retention of
antigen specificity but did not require restimulation with antigen. (Id.) The
Examiner found that Riddell disclosed that the expanded antigen-specific T-
cells would be useful for adoptive immunotherapy. (Id.) According to the
Examiner, Riddell shows that at the time of the invention a skilled artisan
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would have known how to expand antigen specific T-cells using irradiated
allogeneic feeder cells, OKT3 antibody and IL-2. (Id.)
The Examiner found that all the claimed elements were disclosed in
the prior art and that a skilled artisan at the time of the invention would have
found it obvious to combine these known elements for their known functions
to yield predictable results. (Id.) Specifically, the Examiner found that a
skilled artisan at the time of the invention would have found it obvious to
combine the prior art teachings to obtain a method of promoting the
regression of cancer in a mammal comprising administering non-
myeloablative lymphodepleting chemotherapy comprising administration of
cyclophosphamide and fludarabine prior to administering autologous T-cells
which had been previously isolated, selected for highly avid recognition of
melanoma antigen and expanded in vitro. (Id. at 6.) The Examiner reasoned
that the artisan would have been motivated to do so to overcome the poor
persistence of adoptive transfer of T-cells. (Id.)
Appellants contend that “[t]he combination of cited references … fails
to teach or suggest a method of promoting the regression of a cancer in a
mammal comprising administering T cells which have undergone one cycle
of rapid expansion, as claimed in claim 23.” (App. Br. 4; Reply Br. 2.)
In particular, Appellants assert that “Riddell teaches away from using
one cycle of rapid expansion” by teaching that successful adoptive
immunotherapy requires large numbers of T-cells obtained through the use
of repetitive stimulation with anti-CD3. (App. Br. 4; Reply Br. 3.)
According to Appellants, Riddell’s teachings suggested that “a single rapid
expansion would not be expected to generate large enough numbers of T
cells for successful adoptive immunotherapy.” (App. Br. 5.)
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Appellants also assert that secondary considerations rebut any alleged
prima facie case of obviousness. (Id.) In particular, Appellants assert that
the Declaration of Dr. Mark E. Dudley, along with Example 1 in the instant
application, and studies published in peer-reviewed journals establish that
the presently claimed method provides unexpectedly superior clinical results
over prior art methods. (Id. at 5-6.) Appellants assert that these materials
disclosed that methods using multiple rounds of rapid expansion failed to
provide T-cells that persisted in the bloodstream of patients and provided
poor objective clinical results. (Id. at 6.) According to Appellants, in view
of these results, “one of ordinary skill in the art would logically attempt to
improve the persistence and effectiveness of the T-cells by increasing the
number of cycles of rapid expansion, not [by] decreasing the number of
cycles to one, as claimed.” (Id.) Additionally, Appellants assert that the
Dudley Declaration explains that the claimed method answered a long-felt
need in the art to treat patients by successfully producing positive objective
clinical results in patients using a treatment method wherein the T-cells
undergo one cycle of rapid expansion. (Id. at 7.) Based upon this same
evidence, Appellants assert that the Declaration established that the claimed
method succeeds where other methods have repeatedly failed. (Id. at 8.)
The issues with respect to these rejections are:
(a) whether the Examiner established that a skilled artisan at the time
of the invention would have found it obvious over the combined prior art to
administer autologous T-cells following one cycle of rapid expansion, as
recited in the claimed method, and if so,
(b) whether Appellants provided evidence of secondary considerations
such that the totality of evidence weighs in favor of nonobviousness.
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Finding of Fact
We agree with the Examiner’s explicit findings regarding the scope
and content of the prior art references (Ans. 3-7), with one exception that we
discuss in the Analysis below.

Principles of Law
In rejecting claims under 35 U.S.C. § 103, the Examiner bears the
initial burden of presenting a prima facie case of obviousness. See In re
Rijckaert, 9 F.3d 1531, 1532 (Fed. Cir. 1993).
It is well-established that a conclusion that the claimed subject matter
is prima facie obvious must be supported by evidence, as shown by some
objective teaching in the prior art or by knowledge generally available to one
of ordinary skill in the art that would have led that individual to combine the
relevant teachings of the references to arrive at the claimed invention. See
In re Fine, 837 F.2d 1071, 1074 (Fed. Cir. 1988).

Analysis
While we agree with the Examiner’s explicit findings of fact
regarding the disclosures of the prior art, we do not agree that “[a]ll the
claimed elements were known in the prior art….” (See Ans. 5.) As
Appellants have correctly asserted, the Examiner has not established, or
even alleged, that the prior art taught administering T cells which have been
subjected to one cycle of rapid expansion, as claimed. (See Reply Br. 2.)
The Examiner addresses this claim limitation in the Response by stating that
“one skilled in the art would expect that T cells that were subject to only one
cycle of rapid expansion of T cell would produce[] clinical response in
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patients” because the prior art taught that non-myeloablative treatment may
be used to overcome the poor persistence of adoptive transferred T cells.
(Ans. 11.) However, this reasoning was not provided as a basis for the
rejection, and does not appear to have an evidentiary foundation. The cited
prior art provided a suggestion to combine non-myeloablative chemotherapy
with adoptive immunotherapy in a method of promoting cancer regression.
What is missing is how these teachings, or the ordinary skill in the art,
would have additionally suggested to the skilled artisan the further step of
modifying the prior art methods by administering T-cells following only one
cycle of rapid expansion. Without this evidence, the Examiner has not
sufficiently supported a conclusion of prima facie obviousness. See
Rijckaert, 9 F.3d at 1532; Fine, 837 F.2d at 1074.
Because the Examiner has not established prima facie obviousness,
we do not need to discuss Appellants’ evidence of secondary considerations.
(See App. Br. 5-10.)

CONCLUSION OF LAW
The Examiner has not established that a skilled artisan at the time of
the invention would have found it obvious over the combined prior art to
administer autologous T-cells following one cycle of rapid expansion, as
recited in the claimed method.

SUMMARY
We reverse the rejection of claims 23-35, 37, and 38 under 35 U.S.C.
§ 103(a) as unpatentable over Dudley or Gruenberg, each in view of Slavin,
Riddell, and Rosenberg;
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we reverse the rejection of claims 36, 39, and 40 under 35 U.S.C.
§ 103(a) as unpatentable over Dudley or Gruenberg, in view of Slavin,
Riddell, and Rosenberg, and further in view of Kawakami and Stevens.

REVERSED

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