Ex Parte Sampson et al

Patent Trial and Appeal Board

Sep 16, 2015

12092180 (P.T.A.B. Sep. 16, 2015)

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.
12/092,180 11/21/2008 John H. Sampson 000250.00067 9232
22907 7590 09/17/2015
BANNER & WITCOFF, LTD.
1100 13th STREET, N.W.
SUITE 1200
WASHINGTON, DC 20005-4051
EXAMINER
DUFFY, BRADLEY
ART UNIT PAPER NUMBER
1643
MAIL DATE DELIVERY MODE
09/17/2015 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 JOHN H. SAMPSON, DARELL D. BIGNER,
DUANE MITCHELL, and AMY HEIMBERGER
__________

Appeal 2013-001941
Application 12/092,180
Technology Center 1600
__________

Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and
ROBERT A. POLLOCK, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a method
of treating a tumor expressing EGFRvIII. The Examiner rejected the claims
as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.

1 Appellants identify the Real Party in Interest as Duke University,
which licensed the invention to Celldex Therapeutics (see App. Br.
2).
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Statement of the Case
Background
“[I]mmunotherapy trials suggest that despite the inherent
immunosuppression of malignant glioma patients, efficacious immune
responses can be generated. However, there is reluctance to not treat GBM
[glioblastoma] patients with some form of chemotherapy given the recently
established standard of care and the overall poor prognosis” (Spec. ¶ 4).
The Claims
Claims 1, 3, 4, 7–11, 13, 18, 19, 23, and 44–55 are on appeal.2
Independent claim 1 is representative and reads as follows:
1. A method of treating a tumor expressing EGFRvIII in
a subject, comprising the steps of:
administering to the subject an amount of an
EGFRvIII peptide effective to induce an IgG response to
EGFRvIII peptide or to induce EGFRvIII peptide-specific -
IFN producing CD8+ T cells, after administering an amount
of temozolomide or a pharmaceutically acceptable salt
thereof effective to induce lymphopenia of CD8+ T cells;
wherein the combined administration of the peptide and the
temozolomide or pharmaceutically acceptable salt thereof
increases immunotherapeutic efficacy.

The Issues
A. The Examiner rejected claims 1, 3, 4, 7, 10, 11, 13, 18, 19, 23, and
44–55 under 35 U.S.C. § 103(a) as obvious over Heimberger,3 Moscatello,4
Terando,5 and Su6 (Ans. 2–7).

2 The Examiner withdrew the rejection with regard to claims 5, 6,
12, 15–17, 20–22, and 24 (see App. Br. 2).
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B. The Examiner rejected claims 8 and 9 under 35 U.S.C. § 103(a) as
obvious over Heimberger, Moscatello, Terando, Su, Salceda,7 and Carter8
(Ans. 7–8).
A. 35 U.S.C. § 103(a) over Heimberger, Moscatello, Terando, and Su
The Examiner finds that Heimberger teaches “a method of treating a
subject having an intracerebral tumor, comprising administering an EGFR
peptide vaccine which is effective to produce an IgG response” (Ans. 3).
The Examiner acknowledges that Heimberger “does not teach that further
administration of a second chemotherapeutic agent which induces CD8+
lymphopenia such as temozolomide in combination with the EGFR peptide
vaccine” (Ans. 4).
The Examiner finds that Su teaches “a method of treating cancer in a
patient comprising administering TMZ, i.e., temozolomide[,] a DNA

3 Heimberger et al., Epidermal Growth Factor Receptor VIII
Peptide Vaccination Is Efficacious against Established
Intracerebral Tumors, 9 Clinical Cancer Research 4247–4254
(2003).
4 Moscatello et al., A Naturally Occurring Mutant Human
Epidermal Growth Factor Receptor as a Target for Peptide
Vaccine Immunotherapy of Tumors, 57 Cancer Research 1419–
1424 (1997).
5 Terando et al., On combining antineoplastic drugs with tumor
vaccines, 52 Cancer Immunol. Immunother. 680–685 (2003).
6 Su et al., Selective CD4+ Lymphopenia in Melanoma Patients
Treated With Temozolomide: A Toxicity With Therapeutic
Implications, 22 J. Clinical Oncology 610–616 (2004).
7 Salceda et al., US 2002/0155464 A1, published Oct. 24, 2002.
8 Carter, J., Conjugation of Peptide to Carrier Proteins via m-
Maleimidobenzoyl-N-Hydroxysuccinimide Ester (MBS) in The
Protein Protocols Handbook 689–692 (J.M. Walker Ed. 1996).
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alkylating agent[,] and that TMZ is FDA approved to treat brain tumors”
(Ans. 4). The Examiner finds that Su teaches that the “treatment regimen
can result in a reduction of CD8+ cells, i.e., CD8+ lymphopenia is observed”
but that Su also “makes the observation that TMZ reduces CD4+CD25+
regulatory T cells and suggest that TMZ might offer a pharmacologic
strategy that could actually lead to augmented immune results previously
observed in mouse models” (Ans. 4–5).
The Examiner finds that Terando teaches “how the effectiveness of
immunotherapeutic techniques, including adoptive T-cell transfer
immunotherapy and vaccine strategies, can be enhanced when used in
concert with lymphopenia-inducing chemotherapy” (Ans. 5).
The Examiner finds it obvious to combine because “Su et al establish
that TMZ is a DNA alkylating agent that induces lymphopenia, including
CD8+ cell lymphopenia and Terando provide motivation to combine
chemotherapy-induced lymphopenia with peptide vaccines and Heimberger
et al teach an EGFRvIII peptide that can induce an IgG response to treat
cancers expressing EGFRvIII” (Ans. 10–11).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Heimberger, Su, Moscatello, and
Terando render the claims obvious?
Findings of Fact
1. Heimberger teaches that the “EGFR gene is often amplified and
mutated in human neoplasms. The most common mutation, EGFRvIII,
enhances tumorigenicity and occurs in a large proportion of malignant brain
tumors and tumors that commonly metastasize to the brain, such as breast
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and non-small cell lung carcinomas” (Heimberger 4247, col. 2; references
omitted).
2. Heimberger teaches that the mutation “encodes a tumor-specific
protein sequence that is expressed on the surface of tumor cells but is not
present in normal tissues, making it an ideal target for antitumor
immunotherapy” (Heimberger 4247, col. 2).
3. Heimberger teaches that:
Tumors developed in all of the C57BL/6J mice vaccinated
with KLH in Freund’s adjuvant, and there were no long-
term survivors. In contrast, in two separate experiments,
tumors never developed in 70% of the PEP-3-KLH-
vaccinated mice (n = 10 mice/experiment). In addition, in
the PEP-3-KLH-vaccinated mice in which tumors did
develop, the volume was significantly less than that in the
KLH-vaccinated control mice.

(Heimberger 4249, col. 2).
4. Heimberger teaches that:
we performed in vivo depletion studies of granulocytes,
CD4+ T cells, CD8+ T cells, and NK cells in C57BLl6J
mice vaccinated with PEP-3-KLH 3 days before tumor
challenge to determine which cell subsets were involved in
the effector function. . . . Depletion of CD4+ T cells (n =
10) or granulocytes (n = 4) did not alter the efficacy of the
PEP-3-KLH vaccinations. However, depletion of CD8 + T
cells (n = 10) diminished the efficacy of the PEP-3-KLH
vaccination. Additionally, depletion of the NK cells led to a
significant decrease in the efficacy of the PEP-3-KLH
vaccinations, with 30% of the mice showing long-term
survival and no increase in the median survival time
compared with that in the KLH-vaccinated mice (P = 0.44).
Furthermore, the efficacy of the PEP-3-KLH vaccination in
suppressing tumor volume was abrogated when NK or
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CD8+ T cells were depleted . . . To determine whether
vaccination with PEP-3-KLH protected against the
formation of intracerebral tumors in this model, C57BL/6J
mice received three vaccinations.

(Heimberger 4250, col. 1–2).
5. Su teaches that “TMZ [temozolomide] has been approved by
the US Food and Drug Administration for treatment of anaplastic
astrocytoma at a dose of 150 to 200 mg/m2 orally (PO) daily for 5 days
every 4 weeks” (Su 610, col. 2).
6. Su teaches that in “patients receiving TMZ according to the
standard dose and schedule, lymphopenia seems to be uncommon. For
example, in the randomized phase III trial in which 156 patients were treated
with TMZ, lymphopenia was not reported” (Lu 615, col. 2).
7. Su teaches that, using their extended administration protocol, in
“all 11 patients, the absolute CD4+ T -cell counts were depressed (median
CD4+ lymphocyte nadir, 150/µl; range, 44 to 346); the absolute CD8+ T-cell
counts were also decreased in five of the patients” (Su 613, col. 1).
8. Su teaches that:
The CD4+ lymphopenia induced by TMZ may have
complex implications for experimental vaccine therapy.
CD4+ T-cell help is very important for immunity against
melanoma in mouse models. Vaccines meant to induce T -
cell responses might be compromised by CD4+ lymphopenia
induced by TMZ and patients who have been treated with
TMZ may be poor vaccine candidates. Alternatively, our
observation that TMZ depleted CD4+ CD25+ regulatory T
cells suggests that TMZ might offer a pharmacologic
strategy that could actually lead to an augmented immune
responses. For instance, selective depletion of CD4+ CD25+
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T cells enhances immunity induced by vaccine in mouse
models

(Su 616, cols. 1–2).
9. Terando teaches that:
With the advent of the increasing use of immunotherapy in
the clinical setting, investigators have sought to determine
ways in which to combine accepted chemotherapeutic
regimens with innovative immunotherapeutic techniques,
and have discovered that the lymphodepletion that results
from antineoplastic drug administration may be, in some
cases, advantageous in eliciting clinically relevant responses
to cancer immunotherapy. As well, several of these drugs
have been found, paradoxically, to actually augment
antitumor immunity.

(Terando 680, col. 1).
10. Terando teaches that “it may ultimately be found that
chemotherapy combined with vaccine therapy offers therapeutic advantages
over single-modality treatment” (Terando 680, co. 1).
11. Terando teaches that:
Nigam and colleagues vaccinated BALB-C mice with a
GM-CSF-secreting cancer cell vaccine followed 1 week
later by intraperitoneal administration of one of a variety of
anticancer drugs. . . . Of the 11 agents tested, doxorubicin
was the only drug that increased effector cell activity. While
nine of the remaining 10 drugs resulted in either no change
or a decrease in effector T-cell function, cyclophosphamide
appeared to be the only agent that reduced effector function
to the level of the unvaccinated controls. Based on previous
studies of the positive immunomodulatory effects of
cyclophosphamide, this was somewhat surprising.

(Terando 682, col. 2).
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12. Terando teachs that:
When neu-transgenic mice were given chemotherapy (with
cyclophosphamide, doxorubicin, or paclitaxel) prior to
vaccine administration, it was found that the animals
pretreated with cyclophosphamide and paclitaxel both
exhibited an increase in neu-specific T cells as determined
by ELISpot analysis . . . cyclophosphamide and paclitaxel
were found to augment tumor protection from neu- and
GMCSF- expressing whole tumor vaccines in neu-
transgenic animals when given prior to vaccination.

(Terando 683, col. 1).
13. Terando teaches that “two studies demonstrate that active
immunization strategies are significantly more successful when they are
employed in a lymphopenic host” (Terando 684, col. 1).
14. Terando teaches that:
Berd et al. in 1986 published the first trial of combined
cyclophosphamide and vaccine therapy to treat human
patients with melanoma. This study treated 19 patients with
metastatic melanoma with an autologous melanoma cell
vaccine either alone, or preceded by cyclophosphamide, and
demonstrated in vivo immunopotentiation by
cyclophosphamide as shown through increased DTH
responses from vaccine administration in the
cyclophosphamide pre-treatment group.

(Terando 683, col. 1; reference omitted).
15. Terando teaches that “[i]f a lymphopenic environment is
conducive to the proliferation of tumor-specific T cells, then it would follow
that active immunization strategies employed in a lymphopenic setting may
be more effective than those administered to an immunocompetent host”
(Terando 683, col. 2).
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16. Terando teaches that “[t]his is the first study in which
lymphodepletion has been used successfully to augment adoptive
immunotherapy in humans, and future studies are needed to test whether the
inclusion of vaccines in this setting provide additional therapeutic benefit”
(Terando 684, col. 2).
17. Moscatello teaches that the “fact that this mutant EGF receptor
is tumor specific and at least capable of eliciting a humoral response in
animals raises the possibility that a vaccine based on this alteration could be
used as a peptide vaccine against tumors” (Moscatello 1419, col. 2).
Principles of Law
“Obviousness does not require absolute predictability of success . . .
all that is required is a reasonable expectation of success.” In re O’Farrell,
853 F.2d 894, 903-04 (Fed. Cir. 1988).
Analysis
Claim 1
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 2–7; FF 1–17) and agree that claim 1
is obvious over Heimberger, Moscatello, Terando, and Su.
Terando suggests that cancer “chemotherapy combined with vaccine
therapy offers therapeutic advantages over single-modality treatment” (FF
10). Heimberger and Moscatello teach treatment of certain cancers
containing an EGFRvIII mutation with tumor vaccine therapies (FF 1–4,
17). Su teaches the use of temozolomide (TMZ) for cancer treatment (FF 5).
Su teaches that “TMZ depleted CD4+ CD25+ regulatory T cells suggests that
TMZ might offer a pharmacologic strategy that could actually lead to an
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augmented immune responses. For instance, selective depletion of CD4+
CD25+ T cells enhances immunity induced by vaccine in mouse models”
(FF 8).
We agree with the Examiner that the ordinary artisan, motivated by
Terando to combine chemotherapy with vaccine therapy (FF 10, 16), would
have reasonably lymphodepleted cancer patients with TMZ as taught by Su
(FF 7–8) prior to the EGFRvIII vaccine treatments of Heimberger and
Moscatello (FF 1–4, 17) because Terando teaches that “lymphodepletion has
been used successfully to augment adoptive immunotherapy” (FF 16) and Su
teaches that T cell depletion “enhances immunity induced by vaccine in
mouse models” (FF 8).
Appellants contend that “[t]aken together, the two references,
Heimberger and Su, would lead one of skill in the art to expect that TMZ
would diminish and/or abrogate the efficacy of EGFRvIII vaccination”
(App. Br. 5). Appellants contend that “Terando teaches that the
immunomodulation effects of non-TMZ drugs, cyclophosphamide,
adriamycin, and taxanes were varied and unpredictable” (App. Br. 5).
We do not find these arguments persuasive because they do not
recognize the significance placed by Terando and Su on timing of vaccine
treatment relative to chemotherapy. When Appellants note that only one out
of eleven drugs tested by Terando increased effector cell activity (see App.
Br. 5; FF 11), this result occurred when the tumor vaccine was administered
first and the drug was administered second (FF 11), an order that also differs
from that required by claim 1 of treating with TMZ first followed by
treatment with the EGFRvIII vaccine (see Claim 1).
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Terando cites a prior art example of efficacy when the claimed order
of administration is used, with chemotherapeutic followed by vaccine,
specifically teaching that “cyclophosphamide and paclitaxel were found to
augment tumor protection from neu- and GMCSF- expressing whole tumor
vaccines in neu-transgenic animals when given prior to vaccination” (FF
12).
Terando also cites a prior art human clinical example that
“demonstrated in vivo immunopotentiation by cyclophosphamide as shown
through increased DTH responses from vaccine administration” (FF 14).
That is, Terando teaches that treatment with the chemotherapeutic agent
cyclophosphamide enhanced the ability of a vaccine to treat melanoma (FF
14). Su also cites a prior art teaching that “selective depletion of CD4+
CD25+ T cells enhances immunity induced by vaccine in mouse models”
(FF 8).
Thus, while the evidence of record shows that administering a vaccine
first, followed by chemotherapeutic, may reduce vaccine efficacy (FF 11),
the evidence of record also demonstrates that administering a
chemotherapeutic agent first, followed by vaccine administration, frequently
enhances vaccine efficacy (FF 8, 12–16). This evidence therefore supports
the Examiner’s finding of a reasonable expectation in success in performing
the treatment required by claim 1 in the order required by claim 1 (Ans. 6–
7).
Appellants contend that “[i]t is improper according to Gore and
Grasseli to make the rejection because at least Heimberger, the primary
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reference, and Su teach away from the invention for treating tumors” (App.
Br. 7).
We do not find Appellants’ teaching away argument persuasive. A
teaching away requires a reference to actually criticize, discredit, or
otherwise discourage the claimed solution. See In re Fulton, 391 F.3d 1195,
1201 (Fed. Cir. 2004). Here, Heimberger teaches that immunodepletion
after vaccination reduced vaccine efficacy (FF 4), a finding that differs from
the order required by claim 1 and the order suggested by Terando, where
chemotherapeutic lymphodepletion occurs first, before vaccination (FF 16).
Similarly, Su also teaches that the order of administration may be important
and cites a prior art teaching that “selective depletion of CD4+ CD25+ T cells
enhances immunity induced by vaccine in mouse models” (FF 8).
Therefore, Heimberger and Su are consistent with Terando, that
administering a vaccine before lymphodepletion may reduce vaccine
efficacy (FF 11), and do not teach away from Terando’s teaching that
administering a chemotherapeutic causing lymphodepletion first followed by
vaccine enhances vaccine efficacy (FF 12–16).
Claims 44–49
Appellants contend that
none of the cited prior art teach or suggest the particular
timing or mode of the administration of the two agents as
recited in claims 44–49, namely, after the CD8+ T cells
begin to recover from nadir of the induced lymphopenia,
after TREG cells in the subject reach a peak and are declining
in response to the temozolomide, or repeatedly in a cycle.

(App. Br. 6).
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The Examiner finds that based on Terando “one of skill in the art
would have administered the EGFRvIII peptide after the CD8+ T cells begin
to recover from nadir, i.e., low point, of the induced lymphopenia because if
the chemotherapy was still reducing the number of T cells then homeostatic
proliferation would not be effective” (Ans. 11). The Examiner further finds
that Su and Heimberger “administer temozolomide or the peptide repeatedly,
so that when administering temozolomide or salt thereof and the peptide
after, one of skill in the art would continue cycling the treatments as needed
to achieve maximal treatment in the patient” (Ans. 11).
We find that Appellants have the better position regarding claims 44
and 45, but that the Examiner has the better position regarding claims 46–49.
Specifically, while Terando and Su teach the desirability of
lymphodepletion, the Examiner has not identified any specific teaching or
suggestion to administer the EGFRvIII peptide vaccine after the CD8+ cells
have begun to recover from their lowest level as required by claims 44 and
45. Instead, Terando teaches to administer the vaccine after performing
lymphodepletion but without identifying a specific level or degree of
lymphodepletion that should be achieved prior to vaccine administration.
Further, while the dosing schedule would be subject to optimization, the
evidence does not suggest a reason to wait until the CD8+ cells increase
from their lowest levels as required by the claims.
In contrast, claims 46 and 47 are simply drawn to a decline in TREG
cells in a subject, that is, to lymphodepletion (see Ans. 11–12). Because we
already agree with the Examiner that Terando and Su suggest
lymphodepletion prior to vaccine administration, we agree with the
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Examiner that Terando and Su are reasonably understood to suggest
administering vaccines after regulatory cells such as CD8+ cells begin
declining in number relative to their original starting peak due to the
chemotherapeutic agent (FF 8, 12–16).
We also agree with the Examiner that claims 48 and 49 are rendered
obvious by Heimberger and Su, where Heimberger teaches multiple vaccine
treatments (FF 4) and Su teaches cyclic dosing using TMZ (FF 5–6).
Therefore combining these two therapies into a cyclic dosing approach
reasonably represents routine optimization of the combination suggested by
Terando (FF 9).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
Heimberger, Su, Moscatello, and Terando render claims 1 and 46–49
obvious.
The evidence of record does not support the Examiner’s conclusion
that Heimberger, Su, Moscatello, and Terando render claims 44 and 45
obvious.
B. 35 U.S.C. § 103(a) over Heimberger, Moscatello, Terando,
Su, Salceda, and Carter
Appellants do not separately argue the claims in this obviousness
rejection. Having affirmed the obviousness rejection of claim 1 over
Heimberger, Su, Moscatello, and Terando, we also find that the further
combination with Salceda and Carter is sound and fact based and renders the
remaining claims obvious for the reasons given by the Examiner (see Ans.
7–8).
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SUMMARY
In summary, we affirm the rejection of claims 1 and 46–49 under 35
U.S.C. § 103(a) as obvious over Heimberger, Su, Moscatello, and Terando.
Pursuant to 37 C.F.R. § 41.37(c)(1), we also affirm the rejection of claims 3,
4, 7, 10, 11, 13, 18, 19, 23, and 50–55, as these claims were not argued
separately.
We reverse the rejection of claims 44 and 45 under 35 U.S.C. § 103(a)
as obvious over Heimberger, Su, Moscatello, and Terando.
We affirm the rejection of claims 8 and 9 under 35 U.S.C. § 103(a) as
obvious over Heimberger, Moscatello, Terando, Su, Salceda, and Carter.
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-IN-PART

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