Ex Parte Bzik et al

Patent Trial and Appeal Board

Mar 3, 2017

13276577 (P.T.A.B. Mar. 3, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
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Alexandria, Virginia 22313-1450
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/276,577 10/19/2011 David J. Bzik DC0369US.P3 3320
26259 7590 03/07/2017
LICATA & TYRRELL P.C.
66 E. MAIN STREET
MARLTON, NJ 08053
EXAMINER
LEONARD, ARTHUR S
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
03/07/2017 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
following e-mail address(es):
PTOactions@licataandtyrrell.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID J. BZIK, BARBARA A. FOX, STEVEN N. FIERING,
JOSE R. CONEJO-GARCIA, and JASON BAIRD
Appeal 2016-005291
Application 13/276,577
Technology Center 1600
Before DONALD E. ADAMS, DEMETRA J. MILLS, and
FRANCISCO C. PRATS, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL1
This appeal under 35 U.S.C. § 134(a) involves claims 9 and 10 (App.
Br. 3). Examiner entered rejections under 35 U.S.C. § 103(a). We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
1 Appellants identify the real party in interest as “the Trustees of Dartmouth
College” (App. Br. 1).
Appeal 2016-005291
Application 13/276,577
STATEMENT OF THE CASE
The claims are directed to “a method for preventing or treating cancer
by administering to a subject in need of treatment an effective amount of an
attenuated mutant of Toxoplasma gondii” (Spec. ^ 6). Claims 9 and 10 are
representative and reproduced below:
9. A method for preventing or treating ovarian cancer
comprising administering to a subject in need of treatment an
effective amount of an attenuated mutant of Toxoplasma gondii
that stimulates maturation of immature immunosuppressive
dendritic cells and anti-tumor immunity to prevent or treat the
subject’s ovarian cancer.
10. A method for preventing or treating melanoma comprising
administering to a subject in need of treatment an effective
amount of an attenuated mutant of Toxoplasma gondii that
comprises in its genome recombinant nucleic acid molecules
encoding one or more melanoma antigens thereby preventing or
treating the subject’s melanoma.
(App. Br. 15.)
The claims stand rejected as follows:
Claim 9 stands rejected under 35 U.S.C. § 103(a) as unpatentable over
the combination of Kim,2 Subauste,3 and Hobohm.4
2 Ju-Ock Kim et al., Inhibition of Lewis Lung Carcinoma Growth by
Toxoplasma gondii through Induction ofTHl Immune Responses and
Inhibition of Angiogenesis, 22 J. Korean Med. Sci. Suppl. S38-46 (2007).
3 Carlos S. Subauste and Matthew Wessendarp, Human Dendritic Cells
Discriminate Between Viable and Killed Toxoplasma gondii Tachyzoites:
Dendritic Cell Activation After Infection with Viable Parasites Results in
CD28 and CD40 Ligand Signaling That Controls IL-12-Dependent and -
Independent T Cell Production ofIFN-y, 165 J. of Immunology 1498-05
(2000).
4Uwe Hobohm, Fever and cancer in perspective, 50 Cancer Immunol.
Immunother 391-96 (2001).
2
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Application 13/276,577
Claim 10 stands rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Hunter,5 Donald,6 Ren,7 Pardoll,8 and Dubensky.9
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
The rejection over the combination of Kim, Subauste, and Hobohm:
FACTUAL FINDINGS (FF)
FF 1. Appellants disclose that:
Ovarian cancer is most frequently found as a disease
compartmentalized in the peritoneal cavity, which facilitates the
adoptive transfer of immune cells or the application of adjuvants
directly in the tumor microenvironment. Unfortunately, multiple
immunosuppressive mechanisms converge at ovarian cancer
locations to eventually abrogate both ongoing anti-tumor
immunity and the effect of adoptively transferred tumor-reactive
lymphocytes. . . . While these immature [dendritic cells (DC)]
are immune-suppressed by the ovarian tumor, they possess the
ability to phagocytose antigen in their tumor environment, and
acquire the capacity to effectively present processed antigens in
the right milieu. . . . However, rather than boosting adaptive
immune responses, ovarian cancer-associated DCs are not
activated to mature, are strongly immunosuppressive, and
5 Christopher A. Hunter et al., Cutting Edge: Systemic Inhibition of
Angiogenesis Underlies Resistance to Tumors During Acute Toxoplasmosis,
J. of Immunology 5878-81 (2001).
6 Robert G. K. Donald, Toxoplasma gondii Cyclic GMP-Dependent Kinase:
Chemotherapeutic Targeting of an Essential Parasite Protein Kinase, 1
Eukaryotic Cell 317-28 (2002).
7 Ren et al., US 6,214,888 Bl, issued Apr. 10, 2001.
8 Drew M. Pardoll, Spinning Molecular Immunology Into Successful
Immunotherapy, 2 Nature Reviews Immunology 227-38 (2002).
9 Dubensky et al., WO 2005/009463 A2, published Feb. 3, 2005.
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support blood vessel formation, which promotes tumor
development. . . . Adjuvant therapy that could mediate the
maturation of these immature dendritic cells would reverse the
immunosuppression and foster immunostimulation for
therapeutic purposes. Such an approach could be used as a
primary immunotherapy, as a conditioning therapy for adoptive
T cell therapy, or as a therapy to boost T-cell antitumor
responses.
(Spec. H 4.)
FF 2. Appellants disclose that “[i]n the context of [their] invention, a
mutation includes a substitution, deletion, or insertion at the desired locus
which decreases or abolishes the activity of the protein encoded by said
locus” {id. U 15).
FF 3. Appellants disclose that “[wjhile the instant mutant T. gondii may be
used as is in the prevention or treatment of cancer, the [T. gondii] mutant can
also be further modified to deliver one or more tumor antigens,” wherein
“[t]he T. gondii-Qxpressed tumor antigen subsequently enters the mammalian
antigen presenting cell’s (APC) antigen processing and presenting pathway
as a substrate for generation of class I and class II peptides which generate
CD8 and CD4 T cell responses” {id. ^ 20). According to the Specification,
the mutant T. gondii is a “T. gondii attenuated mutant strain of T. gondii
(i.e., CPS) that cannot replicate in vivo, but can elicit a strong Thl immune
response characterized by high local levels of IL-12 and IFN-y and high
systemic levels of IL-12p70” (Spec. 5 and 7).
FF 4. Kim discloses that T. gondii “is an obligate intracellular protozoan
parasite that induces anti-tumor activity against certain types of cancers”
(Kim, Abstract).
FF 5. Kim discloses that “in order to determine the antitumor and anti-
angiogenic activities of T. gondii infection in [Lewis lung carcinoma,] LLC-
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bearing mice, C57BL/6 mice were injected with LLC cells alone or in
combination with T. gondii” (Kim, S38-S39; see also id. at S39: col. 1, first
full paragraph (“mice were orally infected with the ME49 strain to evaluate
antitumor activity”); Ans. 4).
FF 6. Examiner finds that the ME49 strain of T. gondii is an avirulent
strain of T. gondii (Ans. 4).
FF 7. Kim discloses that:
Lung cancer immunotherapy may represent one new approach
that has low toxicity and high specificity, but implementation
has been a challenge due to poor antigenic characterization
and the ability of lung cancers to escape immune responses [].
Several different immunotherapeutic treatment strategies and
mouse models have been developed. In this study, we utilized
LLC cells, which remain highly tumorigenic in C57BL/6 mice
and produce primary tumors and lung metastases histologically
indistinguishable from the original tumor line. . . . After T.
gondii infection, tumor volumes were significantly decreased in
the TG/FFC- and TG/FFC/QA-injected mice as compared with
the EEC- and FFC/QA[10]-injected mice.
(Kim S44: col. 2, first full paragraph (emphasis added; endnotes removed);
see generally Ans. 12.)
FF 8. Subauste discloses that “dendritic cells (DC). . . infected with viable
[T. gondii] parasites up-regulated the expression of CD40, CD80, CD86, and
HFA-DR and down-regulated expression of CD115. These changes are
indicative of DC activation induced by T. gondii” (Subauste, Abstract; Ans.
4).
FF 9. Examiner finds that “Kim and Subauste are silent with respect to [a]
method using attenuated T. gondii to treat ovarian cancer” (Ans. 4).
10 Kim defines “QA” as the Quil-A adjuvant (see Kim, Abstract and S39:
col. 1, third full paragraph).
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FF 10. Examiner relies on Hobohm to disclose that “it was known that DCs
generated an antitumor immune response in vivo to a variety of cancer types
including melanoma, ovarian cancer, and lung cancer in response to
bacterial infections/toxins” {id. at 5 (citing Hobohm 393-394: Tables 1 and
2); see also Hobohm 394: col. 2, last full paragraph).
ANALYSIS
Based on the combination of Kim, Subauste, and Hobohm, Examiner
concludes that, at the time Appellants’ invention was made, it would have
been prima facie obvious to activate DCs with T. gondii and use the T.
gondii activated DCs to treat, inter alia, melanoma and ovarian cancer in
vivo (Ans. 5). In this regard, Examiner finds that a person of ordinary skill
in this art would have considered the use of T. gondii activated DCs to treat
cancer types that share a biological nexus with respect to in vivo
immunotherapy predictable and nothing more than the expected properties
of the immune response to microorganisms, such that “the successful
treatment of one cancer type (i.e., lung cancer) provides a reasonable
expectation of success in treating the others (to wit, ovarian cancer)” {id.).
We are not persuaded.
We recognize Examiner’s characterization of “the avirulent ME49
strain” of T. gondii as “an attenuated mutant of Toxoplasma gondii” (Ans.
4). Examiner, however, failed to establish an evidentiary basis on this
record to support a conclusion that the avirulent ME49 strain of T. gondii is
a mutant, rather than a wild-type strain of T. gondii {see App. Br. 7; see id. at
10; FF 6; cf. Ans. 4). In addition, there is no dispute on this record that
Subauste discloses “the effect of unattenuated wild-type Toxoplasma gondii
{i.e., the virulent RH strain) on maturation of dendritic cells” (App. Br. 7;
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see id. at 10; see generally FF 8). In this regard, we recognize Examiner’s
assertion that “the only limitation that Subauste teaches in regard to [wild-
type] T. gondii" s ability to mature DCs is that it must be viable, and not
killed” (Ans. 9). As Appellants explain, however, Examiner failed to
establish an evidentiary basis on this record to support a conclusion that the
combination of Kim and Subauste suggests “an attenuated mutant
Toxoplasma gondii,” as is required by Appellants’ claim 9 (App. Br. 7-8 and
10; Reply Br. 2-3; see FF 2). In addition, Appellants explain that “Hobohm
highlights the use of infectious bacteria that cause illness. In contrast, the
present invention is directed to the use of an attenuated mutant of
Toxoplasma sondii, i.e., a protozoan” (App. Br. 8; see FF 10; cf. FF 4).
Thus, as Appellants explain “the teachings of Hobohm are of little relevance
to [Appellants’] invention” (id.).
Further, we note that Kim discloses that T. gondii “is an obligate
intracellular protozoan parasite that induces anti-tumor activity against
certain types of cancers” (FF 4 (emphasis added)). In this regard, Examiner
recognizes that “Kim and Subauste are silent with respect to [a] method
using attenuated T. gondii to treat ovarian cancer” (FF 9). Thus, while
Hobohm may suggest that “it was known that DCs generated an antitumor
immune response in vivo to a variety of cancer types including melanoma,
ovarian cancer, and lung cancer in response to bacterial infections/toxins,”
Examiner failed to establish that the combination of Kim, Subauste, and
Hobohm make obvious a method of preventing or treating ovarian cancer,
which comprises the administration of an effective amount of an attenuated
mutant of the Toxoplasma gondii protozoan (FF 10 (emphasis added); cf.
App. Br. 15 (Appellants’ claim 1); see generally App. Br. 8 and 10). In re
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Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) (“rejections on obviousness
grounds cannot be sustained by mere conclusory statements; instead, there
must be some articulated reasoning with some rational underpinning to
support the legal conclusion of obviousness”).
The rejection over the combination of Hunter, Donald, Ren, Pardoll, and
Dubensky:
FACTUAL FINDINGS (FF)
FF 11. Hunter “found that infection with toxoplasma gondii effectively
blocked neoplastic growth of a nonimmunogenic B16.F10 melanoma” and
that “this effect was independent of cytotoxic T or NK cells, production of
NO by macrophages, or the function of the cytokines IL-12 and TNF-a,”
suggesting “that antitumor cytotoxicity was not the primary mechanism of
resistance,” but instead was the result of “severe hypoxia and avascular
necrosis that are incompatible with progressive neoplastic growth.” Thus,
Hunter’s “results identify the suppression of tumor neovascularization as a
novel mechanism critical for infection-induced resistance to tumors”
(Hunter, Abstract; see Ans. 6).11
FF 12. Examiner finds that “Hunter is silent with respect to [a] method
using attenuated T. gondii that is a genetically modified strain comprising
melanoma antigens” (Ans. 6).
FF 13. Examiner finds that Donald discloses “that T. gondii can be
genetically modified to stably (i.e., genomic incorporation of exogenouse
11 We recognize Examiner’s characterization of Hunter’s “avirulent ME49
strain” of T. gondii as “an attenuated mutant of Toxoplasma gondii” (Ans.
6). Examiner, however, failed to identify a disclosure in Hunter, or any
other document of record, that supports Examiner’s characterization of
Hunter’s ME49 strain of T. gondii.
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DNA) express the heterologous protein PKG” (id. (citing Donald, Abstract
and 318: col. 1, first full paragraph)).
FF 14. Donald discloses that “[a] genetic disruption of T. gondii PKG can
only be achieved if a complementing copy of PKG is provided in trans,
arguing that PKG is an essential protein” and that “[sjtrains of T. gondii,
disrupted at the genomic PKG locus and dependent upon the T. gondii
T761 [Q or M]-substituted PKGs, are as virulent as wild type in mice,” but
“unlike mice infected with wild-type T. gondii that are cured by
[trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-( 1 -methylpiperidine-4-yl)-
lH-pyrrol-3-yl]pyridine (compound 1)], mice infected with the laboratory­
generated strains of T. gondii do not respond to treatment,” leading Donald
to “conclude that PKG represents the primary molecular target responsible
for the antiparasitic efficacy of compound 1” (Donald, Abstract; see
generally Ans. 6).
FF 15. Ren discloses “that monoterpene diols result in induction of
melanogenesis in S91 mouse melanoma cells by stimulating the nitric
oxide/cyclic GMP/protein kinase G signal transduction pathway” (Ren 13:
6-10; see Ans. 6 (Examiner finds that Ren discloses “that increased PKG
signaling has been correlated with melanoma . . . and therefore would be
considered a melanoma antigen to one of ordinary skill in the art”).
FF 16. Pardoll discloses that:
Antigen-based immunotherapy of cancer is crucially dependent
on the identification of tumour-rejection antigens. The largest
number of immunologically defined tumour antigens has been
discovered by the serological screening of phage-display
libraries from tumours using the serum of cancer patients[].
Although this approach identifies hundreds of antigens
recognized by antibodies circulating in cancer patients, it does
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not provide insights into which of these antigens could generate
effective antitumour immunity.
(Pardoll 228: Box 1 (endnotes omitted); see generally Ans. 6-7.)
FF 17. Pardoll discloses that “[t]he most commonly identified melanoma
antigens are not tumour-specific but rather, melanocyte specific. Examples
include tyrosinase, tyrosinase-related protein 1 (TRP1), TRP2, gplOO and
MARTl/melan-A[]” (Pardoll 228: Box 1 (endnotes omitted); see Ans. 6-7).
FF 18. Pardoll discloses that there is a “growing armamentarium of
vaccine vectors,” wherein “[o]f the three main classes of microbes—virus,
bacterium and fungus—viruses and bacteria have been investigated most
intensively” (Pardoll 234: col. 1, first full paragraph; see Ans. 6-7).
FF 19. Dubensky discloses that “[a] variety of strategies are presently being
developed to isolate and generate autologous dendritic cells (DC), and
subsequently load them with antigen or peptides ex vivo prior to patient
vaccination,” however, “[djespite the development of a variety of methods
to load and to stimulate the activation and maturation of dendritic cells that
has led to encouraging clinical data, there still are not standard efficient and
cost effective methods for combining antigen loading with dendritic cell
activation and maturation” (Dubensky 5; see generally Ans. 7).
FF 20. Dubensky discloses that:
Cultured dendritic cells infected ex vivo with antigen delivery
vectors can, in response to infection, undergo activation,
maturation, and MHC-restricted presentation of epitopes.
Dendritic cells, however, are sometimes poorly infected by the
selected antigen delivery vector. Also, the selected antigen
delivery vector can sometimes interfere with dendritic cell
function or development.
(Dubensky 6; see generally Ans. 7.)
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FF 21. Dubensky “provides novel uses of modified microbes such as
bacteria, and attenuated Listeria, in particular, to load and to induce the
activation and maturation of antigen-presenting cells, such as dendritic cells,
in vitro or ex vivo. The resulting antigen-presenting cells are useful in
vaccines and immunotherapy” (Dubensky 7; see Ans. 7).
FF 22. Dubensky discloses the “[tjherapeutic vaccination of mice using
Listeria strains with and without S-59 treatment,” wherein “a C57B1/6
mouse melanoma tumor model was used” (Dubensky 281-282; see also
id. 8 (“4’-(4-amino-2-oxa)butyl-4,5’,8-trimethylpsoralen, also referred to
[by Dubensky] as ‘S-59’”); see Ans. 7).
FF 23. Dubensky discloses that “microbes of [Dubensky’s] invention may
be altered to contain a heterologous nucleic acid sequence encoding a
specific tumor antigen” (Dubensky 174; see Ans. 7 (citing Dubensky ^ 174
(Examiner finds that Dubensky “contemplates the use of melanoma specific
antigens gplOO, TRP and MART”)).
ANALYSIS
Based on the combination of Hunter, Donald, Ren, Pardoll, and
Dubensky, Examiner concludes that, at the time Appellants’ invention was
made, it would have been prima facie obvious to “combine the presence of a
tumor antigen as taught by Donald and Ren” with Hunter’s method of using
T. gondii to suppress tumor neovascularization (see Ans. 6; see generally FF
11-15). In this regard, Examiner finds that Pardoll and Dubensky provide a
reasonable expectation of success to the combination of Hunter, Donald, and
Ren by disclosing the use of “attenuated microbes as platforms for
delivering tumor antigens to dendritic cells as a means of cancer
immunotherapy” (Ans. 7). We are not persuaded.
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As Appellants explain, although “Hunter teaches that infection with
attenuated wild-type Toxoplasma gondii. . . blocks neoplastic growth of
nonimmunogenic B16.F10 melanoma,” Hunter “does not teach or suggest
the use of an attenuated mutant Toxoplasma gondii that comprises in its
genome recombinant nucleic acid molecules encoding one or more
melanoma antigens” (App. Br. 11). Therefore, Appellants contend, “given
that the effect of the Toxoplasma gondii was attributed to the suppression of
angiogenesis, this reference would not have suggested the use of
Toxoplasma gondii to express a tumor antigen” (App. Br. 11-12; see FF 11-
12). We agree with Appellants’ contention that Examiner failed to establish
a nexus between the use of Tgondii to suppress angiogenesis and the use of
T. gondii encoding one or more melanoma antigens to elicit an immune
response in a subject (see App. Br. 11-13; Reply Br. 5-6).
In this regard, we note that the evidence relied upon by Examiner
supports a conclusion that “[ajntigen-based immunotherapy of cancer is
crucially dependent on the identification of tumour-rejection antigens” and,
as Appellants explain, Examiner failed to establish that PKG is such an
antigen (see FF 16; see also App. Br. 12 (“there is no suggestion anywhere
in the teachings of Donald that the parasitic PKG proteins therein are tumor
antigens” and “nowhere does Ren suggest that PKG protein is a tumor
antigen”); cf. FF 17 and 23). Further, while Pardoll and Dubensky do
suggest melanoma antigens, they neither disclose the use of PKG protein as
a melanoma antigen nor disclose the use of T. gondii as a vehicle for the
delivery of such an antigen in vivo (see FF 16-23; see also App. Br. 13
(“neither of [Pardoll and Dubensky] teaches or suggests an attenuated
mutant of Toxoplasma gondii that comprises in its genome recombinant
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nucleic acid molecules encoding one or more melanoma antigens”); cf. Ans.
14-15).
In sum, Examiner failed to establish that the combination of Hunter,
Donald, Ren, Pardoll, and Dubensky make obvious the subject matter of
Appellants’ claim 10. Kahn, 441 F.3d at 988.
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness.
The rejection of claim 9 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Kim, Subauste, and Hobohm is reversed.
The rejection of claim 10 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Hunter, Donald, Ren, Pardoll, and Dubensky is
reversed.
REVERSED
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