Ex Parte Ji et al

Patent Trial and Appeal Board

Oct 30, 2017

13114921 (P.T.A.B. Oct. 30, 2017)

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.
13/114,921 05/24/2011 Lin Ji UTSC.P1039US.C3 2458
108197 7590 11/01/2017
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, TX 78746
EXAMINER
GUSSOW, ANNE
ART UNIT PAPER NUMBER
1636
NOTIFICATION DATE DELIVERY MODE
11/01/2017 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):
docket @ phiplaw .com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LIN JI, JOHN DORRANCE MINNA, JACK ROTH, and
MICHAEL LERMAN1
Appeal 2015-002224
Application 13/114,921
Technology Center 1600
Before ULRIKE W. JENKS, BRIAN D. RANGE, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to methods of tumor suppression. The Examiner rejects the claims as not
enabled for the full scope as claimed and on the grounds of non-statutory
obviousness-type double patenting. We have jurisdiction under 35 U.S.C.
§ 6(b).
We AFFIRM.
1 According to Appellants, the Real Party in Interest is Board of Regents,
University of Texas System, Austin, Texas the licensee Genprex, Inc.
Austin, Texas. Appeal Br. 3.
Appeal 2015-002224
Application 13/114,921
STATEMENT OF THE CASE
The Specification discloses that “[tjumor suppressor genes (TSGs)
play a major role in the pathogenesis of human lung cancer and other
cancers. Lung cancer cells harbor mutations and deletions in multiple
known dominant and recessive oncogenes.” Spec. 2. Fusl is a tumor
suppressor gene located at chromosome 3, specifically 3p21.3. See id. at 4.
“[Cjytogenetic changes and allele loss on the short arm of chromosome 3
(3p) have been shown to be most frequently involved in about 90% of small
cell lung cancers (SCLCs) and >50% of non-small cell lung cancers
(NSCLCs).” Id. at 2. Tumor suppressor genes that are located in the 3p
region include: Gene 26 (CACNA2D2)340’ PL6, Beta* (BLU), LUCA-1
(HYAL1), LUCA-2 (HYAL2), 123F2 (RASSF1), Fusl, 101F6, Gene 21
(NPRL2), and SEM A3. Id. at 4.
Claims 63—73, 84—98, and 118—126 are on appeal, and can be found in
the Claims Appendix of the Appeal Brief. Claims 64, 69, and 72 are
representative of the claims on appeal, and read as follows:
63. A method for suppressing growth of a tumor cell
comprising contacting said cell with an expression cassette
comprising:
(a) an isolated polynucleotide encoding a human FUS1
polypeptide; and
(b) a heterologous promoter active in said tumor cell,
under conditions permitting the uptake of said polynucleotide
by said tumor cell.
69. A method of altering the phenotype of a lung tumor cell
comprising contacting said cell with an expression cassette
comprising:
(a) an isolated polynucleotide encoding a human FUS1
polypeptide; and
(b) a heterologous promoter active in said tumor cell,
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Application 13/114,921
under conditions permitting the uptake of said polynucleotide
by said tumor cell.
72. A method of inhibiting a cancer cell in a subject suffering
therefrom comprising administering to said subject an
expression cassette comprising:
(a) an isolated polynucleotide encoding a human FUS1
polypeptide; and
(b) a heterologous promoter active in tumor cells of said
subject, whereby expression of said FUS1 polypeptide inhibits
said cancer.
The Examiner rejects the claims as follows:
I. Claims 63—73, 84—98, and 118—126 under 35 U.S.C. § 112(a) or
35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with
the enablement requirement. See Ans. 2—8.
II. Claims 63—73, 84—98, and 118—126 on the ground of nonstatutory
obviousness-type double patenting over claims 1—35 of US Patent No.
7,902,441. See Ans. 9—10.
I. Enablement
The Examiner finds that Specification does not “teach the skilled
artisan how to practice the method such that therapeutic outcome is obtained
according to the method as broadly claimed.” Ans.3.
Does the preponderance of evidence of record support the Examiner’s
conclusion that the Specification is not enabled for the methods as claimed?
Findings of Fact
Breadth of Claims
FF1. The Examiner finds that the claims are broadly directed
a method for suppressing growth of a tumor cell, a
method of altering the phenotype of a tumor cell, and a
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Application 13/114,921
method of inhibiting cancer in a subject comprising
contacting the cell with an expression cassette
comprising a nucleic acid encoding FUS1 and a promoter
active in the tumor cell.
Ans. 3.
Amount of Direction and Guidance Presented— Working Examples
FF2. The Specification teaches testing the effect of overexpression of FUS1
in cell lines.
Human lung cancer cell lines (HI299, H358, H460, and
A549), with varied status of chromosome 3p or
individual 3p genes and a normal human bronchial
epithelial cell (HBEC) line were used to evaluate the
effects of 3p genes on cell growth arrest, proliferation,
apoptosis, and cell cycle kinetics in vitro and on growth
of the primary and metastatic tumors in animal models.
Spec. 87. The Specification teaches that Fusl overexpression of Ad-
Fusl in these tumor cells line reduced cell viability and increased
apoptosis. See id. at 90, 92, Figs. 6A—O & 8A—E. Fusl
overexpression inhibited tumor cell growth in vitro in H358, H460,
HI299, and A549 cells. See id. at 86—90 (Example 5), Figs. 6A—O.
FF3. The Specification teaches suppression of tumor growth in vivo.
The tumor suppressor function of 3p genes, 101F6, Fusl,
and Gene21 were evaluated in vivo by direct intratumoral
injection of these Ad-3p vectors into the A549
subcutaneous tumors in nude mice (FIG. 10). The
growth of tumors was recorded from first injection until
20 days after last injection. All of the tumors in the mice
treated with Ad-101F6, Ad-Fusl, and Ad-Gene21
showed significantly suppressed growth compared with
[untreated] tumors.
Id. at 93 (Examples 10, 11); see id. at Fig. 10.
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Application 13/114,921
FF4. The Specification teaches an “experimental lung metastasis models of
HI299 and A549 cells were used to study the effects of 3p genes on
tumor progression and metastasis by systematic treatment of lung
metastatic tumors through intravenous injection of either PAD3p or
LPD3p complexes.” Spec. 94 (Example 13). “The metastatic tumor
growth was significantly inhibited in PAd-101F6, PAd-Fusl, and PAd-
Gene21-treated mice, compared with those in control groups.” Spec.
94 (Example 12).
State of the Prior Art and Unpredictability of the Art
FF5. da Costa Prando2 teaches that “[ejpigenetic mechanisms are
frequently deregulated in cancer cells and can lead to the silencing of
genes with tumor suppressor activities.” da Costa Prando, Abstract.
Specifically, the reference shows that “the RASSFI gene was co­
regulated with TUSC2[/ FUS13], ZMYND10 andNPRL2 genes” and
mapped to same 3p21.3 gene region. Id. at 1422 (emphasis omitted).
FF6. Guidong4 teaches that FUS1 functions differently in different tissues.
For example:
previous observations showed a high level of FUS1
protein expression in healthy lung bronchial epithelia, but
2 Erika da Costa Prando et al., Evidence of epigenetic regulation of the tumor
suppressor gene cluster flanking RASSFI in breast cancer cell lines,
6 Epigenetics 1413-1424 (2011) (“da Costa Prando”).
3 “TUSC2 (tumor suppressor candidate 2, also named FUS1).” da Costa
Prando 1414 (emphasis omitted).
4 Guidong Li et al., Frequent Absence of Tumor Suppressor FUS1 Protein
Expression in Human Bone and Soft Tissue Sarcomas, 31 Anticancer
Research 11—22 (2011) (“Guidong”). Both the Examiner and Appellants
refer to this reference as “Guidong” throughout the Briefs and Answer for
consistency we will refer to this reference the same way in this opinion.
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a reduced or lost expression in preneoplastic respiratory
epithelia and malignant lung tumors, . . . [however, in]
immunohistochemical studies in bone and soft tissue
sarcomas], the expression of the FUS1 protein was
undetectable in both healthy and benign mesenchymal
tumor tissues. There are two possible explanations for
these results. Firstly, FUS1 may function differently as a
tumor suppressor in different tissues. Secondly, FUS1
may not be a major contributor to the tumorigenesis of
sarcomas.
Guidong 20.
FF7. Ivanova5 teaches that “[t]he role of TUSC2[/ FUS1 ] as a tumor
suppressor in lung cancer is widely accepted.” Ivanova 8. “TUSC2[/
FUS1] mRNA and protein levels in MPM [(Malignant
Mesothelioma)] as compared to normal peritoneum confirmed the
decrease in TUSC2[/FUS1] level in -84% of tumors irrespective of
stage and histological type.” Id. at 6. Ivanova concludes “that
restoration of TUSC2[/FUS1] activities in MPM patients may have
important therapeutic implications” in MPM. Id. at 12 (emphasis
added).
FF8. Edfelt6 teaches that there is evidence for genetic changes from
primary tumors to metastases, because most primary tumors displayed
a different gene expression profile compared to the associated lymph
node metastases. Edfelt 487. Novel genes such as Fusl “may be of
5 Alla V. Ivanova et al., Mechanisms of FUS 1 /TUSC2 deficiency in
mesothelioma and its tumorigenic transcriptional effects, 8 Molecular
Cancer 1-16 (2009)(“Ivanova”).
6 Katarina Edfelt et al., Different gene expression profiles in metastasizing
midgut carcinoid tumors, 18 Endocrine-Related Cancer 479—89 (2011)
(“Edfelt”).
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Application 13/114,921
importance for tumor progression” in midgut carcinoid tumorigenesis.
Id (emphasis added).
FF9. Gromeier7 teaches that “[t]he main advantage of replication-
competent oncolytic viruses over non-replicating viral gene therapy
vectors is their ability to propagate and spread from the site of
inoculation throughout the tumor mass and beyond.” Gromeier 503.
The main obstacle is the successful translation of “oncolysis produced
against tumor cells in vitro into cancer treatments with sufficient
antineoplastic activity in vivo without unacceptable side effects.” Id.
at 506.
FF10. Dermer8 teaches that “[w]hat is significant in culture . . . simply does
not have the same significance for cells in vivo.” Dermer 320.
FF11. Gura9 teaches that “[t]he fundamental problem in drug discovery for
cancer is that the model systems are not predictive at all.” Gura 1041.
“[DJrags tested in the xenografts appeared effective but worked
poorly in humans. . . . The xenograft models may also have missed
effective drugs.” Id. “Why gene knockouts in mice have effects so
different from those of the corresponding mutations in humans is
unclear.” Id. at 1042.
7 Gromeier & Wimmer, Viruses for the treatment of malignant glioma,
3 Current Opinion In Molecular Therapeutics 503-08 (2001)
(“Gromeier”).
8 Gerald B. Dermer, Another Anniversary for the War on Cancer, 12
Bio/Tech. 320-(1994) (“Dermer”).
9 Trisha Gura, Systems for identifying new drugs are often faulty, 278 Sci.
1041—42 (1997) (“Gura”).
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Principle of Law
When rejecting a claim under the enablement requirement of
section 112, the PTO bears an initial burden of setting forth a
reasonable explanation as to why it believes that the scope of
protection provided by that claim is not adequately enabled by
the description of the invention provided in the specification of
the application.
In re Wright, 999 F.2d 1557, 1561—62 (Fed. Cir. 1993). “[T]he question of
undue experimentation is a matter of degree. The fact that some
experimentation is necessary does not preclude enablement; what is required
is that the amount of experimentation ‘must not be unduly extensive.’” PPG
Indus., Inc. v. Guardian Indus. Corp., 75 F.3d 1558, 1564 (Fed. Cir. 1996).
Factors to be considered in determining whether a disclosure
would require undue experimentation... include (1) the quantity
of experimentation necessary, (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.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988) (footnote omitted) (citation
omitted).
Analysis
Claims 63—68, 72, 73, 8W-98, 118—121, and 123—126
Appellants contend that the Specification “presents considerable
evidence regarding the relevance of FUS-1 to lung cancers, with both in
vitro and in vivo inhibition by gene therapy having been established” and the
record shows that FUS-1 is involved in a wide range of cancers. Appeal. Br.
4 (citing da Costa Prando, Edfelt, Ivanova, Guidong). Appellants contend
that the Examiner’s reliance on the unpredictability of xenograft models is
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Application 13/114,921
“applying a standard for enablement that is not justified by the existing case
law.” Id. at 5.
We do not find Appellants’ arguments persuasive. The issue is not
whether the scientific principles of xenograft models observing the testing of
lung tumors disclosed in the Specification can reasonably be extrapolated to
all tumors regardless of their FUS1 expression status but rather whether the
very broad claim 63 is enabled by the Specification or whether undue
experimentation would have been required to enable the full scope of the
claims. The enablement requirement ensures that “the public knowledge is
enriched by the patent specification to a degree at least commensurate with
the scope of the claims.” Nat’l Recovery Techs., Inc. v. Magnetic Separation
Sys., Inc., 166 F.3d 1190, 1195—96 (Fed. Cir. 1999). The scope of the claims
must be “less than or equal to the scope of enablement.” Id. at 1196. There
are a number of dimensions of significant unpredictable experimentation that
would be required to enable even a minimal scope for claim 63, and the
evidence of record demonstrates that undue experimentation would have
been required to enable a reasonable subset of the embodiments
encompassed by claim 63.
The evidence in the Specification is such that the overexpression of
Fusl in lung cancer cell lines in vitro showed reduced tumor growth as
evidenced by reduced cell viability and increased apoptosis. FF2. The same
effect was observed using these lung cancer cells in a solid tumor model as
well as a metastasis model. FF3 & FF4. The art also recognizes the
association between Fusl expression (or lack thereof) and lung cancer. FF7.
The art however is not so clear with respect to other tumors
encompassed by claim 63. Indeed, the art shows that there is a lot of
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speculation whether Fusl, although an interesting target in many tumors,
would actually function to suppress other tumors. See FF5—FF8. The art
suggest that Fusl functions differently in different tissues, and by extension
in tumors. FF6. It is also not clear what role if any Fusl has in tumor
progression. FF6 & FF11. Thus, the involvement of Fusl in tumors, other
than lung tumors, is speculative. Additionally, the art recognizes that what
works in the test tube does not necessarily translate to actual therapies for
patients. FF9—FF11. Here, the Examiner has provides a reasonable
explanation why the Specification does not provide an enabling disclosure
for treating all tumors by overexpressing Fusl in a tumor as claimed. See
Ans. 2—8.
The evidence of record supports the Examiner’s conclusion that the
Specification does not enable claims 63—68, 72, 73, 84—98, 118—121, and
123-126.
Claims 69—71 and 12210
Claims 69-71 and 122 are directed at altering the phenotype of a lung
tumor cell by contacting the lung tumor cell with an expression cassette that
encodes human FUS1 polypeptide.
Appellants contend that the burden is on the Examiner to establish
lack of enablement. Appeal Br. 7. A rigorous or an invariable exact
10 Though not separately argued (see 37 C.F.R. 41.37(c)(l)(iv); see Appeal
Br. 3), in the interest of fairness and judicial economy, we treat claim 69 and
any dependents as separately argued because all the arguments presented in
the Appeal and Reply Briefs are made with an emphasis to lung tumors, the
subject matter of claim 69.
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correlation is not required. Id. (citing Cross v. Iizuka, 753 F.2d 1040, 1050
(Fed. Cir. 1985)).
We agree with Appellants that the Specification provides sufficient
support to enable the subject matter of claims 69—71 and 122. The
Specification discloses that “[rjecombinant Ad-3ps can efficiently deliver 3p
genes [that include Fusl] into and express them in various cell types in vitro
by directly infecting target cells and in vivo by intravenous or local injection
of vectors.” Spec. 85. The Specification tests various lung cancer cell lines
for their effect on overexpression of these 3p genes.
Human lung cancer cell lines (H1299, H358, H460, and A549),
with varied status of chromosome 3p or individual 3p genes and
a normal human bronchial epithelial cell (HBEC) line were used
to evaluate the effects of 3p genes on cell growth arrest,
proliferation, apoptosis, and cell cycle kinetics in vitro and on
growth of the primary and metastatic tumors in animal models.
FF2.
Lung cancer cell lines do not express detectable endogenous
levels of Fusl protein, and exogenous introduction of Fusl with
overexpression inhibited lung cancer cell growth in vitro. This
growth inhibition was seen in a lung cancer line suffering allele
loss for the region and in another carrying a homozygous
truncating mutation of FUSl.
Spec. 112. Fusl overexpression inhibited tumor cell growth in vitro in
H358, H460, H1299, and A549 cells. FF2. The tumor suppressor function
of 3p genes such as Fusl were evaluated in vivo by direct intratumoral
injection of Ad-3p vectors into the A549 [and HI299] subcutaneous tumors
in nude mice. FF3 & FF4. The same inhibition was also observed in a
metastasis model. Specifically, “[t]he development of A549 metastases was
significantly inhibited and the formation of metastatic tumor colonies on the
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surfaces of lungs from mice inoculated with A549 was reduced more than
80% in animals treated with . . . P-Ad-FUSl.” Spec. 109.
We recognize, but are not persuaded by, the Examiner’s position that
“few drugs tested in vivo are effective in treating cancer.” Final Act. 3;
Advisory Act.11 2; see FF9—FF11. Here, the Specification has shown that
the overexpression of Fusl in four different lung cancer cell lines in vitro
inhibited tumor cell growth, and the same effect was also shown in vivo in
two different tumor models in mice. We recognize that the ultimate goal
may be treating human tumors in human patients, however, the claims are
not so limited and they encompass the treatment methods described in the
Specification.
We are not persuaded that the Examiner has sufficiently shown that
the Specification is not enabled for the scope of the subject matter claimed.
Accordingly, we reverse the rejections of claims 69—71 and 122 as lacking
enablement.
II. Nonstatutory Obviousness-Type Double Patenting
The Examiner has also provisionally rejected the claims for
obviousness-type double patenting. Ans. 9-10; Final Act. 4—5. Appellants
have not argued the merits of the double-patenting rejection but request that
the provisional rejection be held in abeyance until the application is
otherwise in condition for allowance. See Appeal Br. 10 (“appellants are
prepared to submit a terminal disclaimer at the time that this is the only
remaining rejection”). We thus summarily affirm this rejection.
11 Advisory Action mailed March 18, 2014 (“Advisory Act.”).
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SUMMARY
We affirm the rejection of claims 63—68, 72, 73, 84—98, 118—121, and
123—126 as failing to comply with the enablement requirement.
We reverse the rejection of claims 69—71 and 122 as failing to comply
with the enablement requirement.
We summarily affirm the rejection of claims 63—73, 84—98, and 118—
126 on the ground of nonstatutory obviousness-type double patenting over
claims 1—35 of US Patent No. 7,902,441.
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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