Ex Parte Hsueh et al

Patent Trial and Appeal Board

Jul 27, 2016

12657679 (P.T.A.B. Jul. 27, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/657,679 01125/2010
77974 7590 07/29/2016
Stanford University Office of Technology Licensing
Bozicevic, Field & Francis LLP
1900 University Avenue
Suite 200
East Palo Alto, CA 94303
Aaron J.W. Hsueh
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
STAN-616US2 2199
EXAMINER
COX, THADDEUS B
ART UNIT PAPER NUMBER
3735
NOTIFICATION DATE DELIVERY MODE
07/29/2016 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@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte AARON J.W. HSUEH and JING LI 1
Appeal2014-005844
Application 12/657,679
Technology Center 3700
Before DONALD E. ADAMS, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants state the real parties-in-interest is the Board of Trustees of the
Leland Stanford Junior University. App. Br. 2.
Appeal2014-005844
Application 12/657,679
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 1, 2, 4, 6-10, and 11-13.
Specifically, claims 1, 2, 4, 8-10, and 13 stand rejected as unpatentable
under 35 U.S.C. § 103(a) as being obvious over the combination of Liu (US
2011/0015169 Al, January 20, 2011) ("Liu") and Heng-Yu Fan et al.,
Targeted Disruption of PTEN in Ovarian Granulosa Cells Enhances
Ovulation and Extends the Life Span of Luteal Cells, 22(9) MOLECULAR
ENDOCRINOLOGY 2128--40 (2008) ("Fan").
Claims 6-7 stand rejected as unpatentable under 35 U.S.C. § 103(a) as
being obvious over the combination of Liu, Fan, and Olorunseun 0.
Ogunwobi and Ian L.P. Beales, Glycine-Extended Gastrin Stimulates
Proliferation via JAK2- and Akt-Dependent NF-KB Activation in Barrett's
Oesophageal Adenocarcinoma Cells, 296 MOLECULAR AND CELLULAR
ENDOCRINOLOGY 94-102 (2008) ("Ogunwobi").
Claim 11 stands rejected as unpatentable under 35 U.S.C. § 103(a) as
being unpatentable over Liu, Fan, and DeFrees et al. (US 2008/0015142 Al,
January 17, 2008) ("DeFrees").
Claim 12 stands rejected under 35 U.S.C. § 103(a) as unpatentable
over Liu, Fan, DeFrees, and Dolmans-Van Der Vorst et al. (US
2010/0215713 Al, August 26, 2010) ("Dolmans").
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
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Application 12/657,679
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to methods for activating dormant
ovarian primordial follicles in a mammal to promote development in
preovulatory follicles. Abstract.
REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A method of activating dormant mammalian
ovarian primordial follicles, the method comprising:
transiently contacting at least one dormant mammalian
ovarian follicle with an inhibitor of PTEN and an activator of
PI3K, in a dose effective to activate the at least one dormant
mammalian ovarian follicle for a period of from one hour to three
days.
App. Br. 9.
ISSUES AND ANALYSES
We agree with, and adopt, the Examiner's findings and conclusion
that the appealed claims are prima facie obvious over the cited prior art
references. We address the arguments raised by Appellants on appeal
below.
A. Claims 1, 2, 4, 8-10, and 13
Issue 1
Did the Examiner err in finding the combination of Liu and Fan
teaches or suggests a PI3K activator? App. Br. 3.
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Analysis
Appellants argue that there is a difference between an activator of
Pl3K signaling and a PI3K activator (as claimed). App. Br. 3. According to
Appellants, PI3K is an enzyme that is part of a complex PI3K/AKT
signaling pathway, and increased activity of PI3K leads to increased
phosphorylation of AKT, which is generally considered to be the "read-out"
of activated Pl3K signaling pathway activity. Id. Therefore, Appellants
argue, a compound that increases AKT phosphorylation (without activating
the PI3K enzyme) can be considered to be activators of PI3K signaling (i.e.,
compounds that increase activity of the PI3K signaling pathway). Id. at 3--4.
Appellants disagree with the Examiner's finding that Fan teaches a
PI3K activator because Fan teaches follicle stimulating hormone ("FSH")
that, according to Appellants, activates the PI3K pathway increasing AKT
phosphorylation (among other functions) and enhancing granulosa cell
differentiation, not activating the PI3K enzyme. Appellants point out that
their Specification discloses that the term "PI3K activator," as recited in the
claims, refers to an activator of the PI3K enzyme-a compound that
"interact[s] directly with PI3K", and not simply as an activator of the PI3K
pathway. Id. (citing Spec. ,-i 49); Reply Br. 4-5. Appellants therefore assert
that, although FSH increases AKT phosphorylation, FSH is not a PI3K
activator that "targets" the PI3K enzyme, "interact[ing] directly with PI3K,"
and thereby functioning "specifically" to activate PI3K. Appeal Br. 4-5;
Reply Br. 5.
We are not persuaded. Appellants contend that activation of PI3K-
AKT pathway can be achieved by some means other than direct activation of
PI3K itself, i.e., that the PI3K-AKT pathway can be activated, producing
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phosphorylated AKT, without direct activation of Pl3K. See App. Br. 3--4.
However, Appellants adduce no evidence in support of this contention. As
such, it constitutes little more than attorney argument, to which we accord
little probative value. See In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir.
1984) (Arguments and conclusions unsupported by factual evidence carry no
evidentiary weight).
Fan, however, explicitly teaches: "FSH and LH activate RAS and the
downstream targets RAFI, MEK, and ERKl/2 as well as PI3K and the
downstream targets AKT and the transcription factor FOXOl." Fan 2137
(emphasis added and internal citations omitted). We agree with the
Examiner that a person of ordinary skill would understand this teaching of
Fan as meaning FSH activates PI3K which activates the downstream AKT
via the PI3K-AKT pathway. We are not persuaded by Appellants' argument
that the disclosures of Appellants' Specification demand that we construe
the claim term "an activator of PI3K" as requiring that the activator directly
activate PI3K. See, e.g., Reply Br. 5. Appellants' Specification discloses:
"Activators of Pl3K increase the activity of the enzyme" and does not
require that the activation be only direct, i.e., via binding at a receptor site,
and not indirect, e.g., mediated by a receptor-G-protein complex. See Spec.
,-i 49. We therefore find that both modes of activation of the PI3K enzyme,
direct and indirect, are within the scope of the claim language.
Additionally, the fact that FSH has complex activity (App. Br. 5), is
immaterial, since the claims do not require the PI3K activator to have a
singular activity. We are therefore not persuaded by Appellants' arguments
in regard to this issue.
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Issue 2
Did the Examiner err in finding the combined cited prior art teaches or
suggests the transient application of both a PI3K activator and a phosphatase
tensin homolog (PTEN)? App. Br. 5.
Analysis
Appellants contend there is an additive effect exposing follicular cells
to both a PTEN inhibitor and a Pl3K activator. App. Br. 5-6 (citing Spec.
Fig. l lB. According to Appellants, if the feedback regulation from PTEN
deletion was sufficient to activate Pl3K, then there would be no expected
benefit to including a second agent that activates Pl3K. Id. at 6. However,
Appellants argue, the data provided in Appellants' Specification demonstrate
the benefit from both agents being present. Id.
Appellants also argue that because Fan is directed to a "granulosa
cell" ("GC") PTEN knockout mouse strain in which PTEN is specifically
depleted in GCs of antral follicles and in luteal cells, it does not demonstrate
an effect in primordial dormant follicles as recited in claim 1. App. Br. 6
(citing Fan 2128-29). Appellants further contend that Fan neither teaches
nor suggests transient contact of the primary follicles with an inhibitor of
PTEN. Id.
The Examiner responds that the combination of Liu and Fan teaches
both a PTEN inhibitor and a Pl3K activator. Ans. 4. The Examiner also
finds Liu teaches that activation of the PI3K pathway is essential in
determining whether the primordial follicle remains dormant or becomes
activated. Id. (see Liu iJ 163). The Examiner therefore finds, Liu provides
motivation for a person of ordinary skill to combine references, because
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activation of the Pl3K pathway is essential to activation of the follicles,
regardless of the type. Id. Moreover, Fan teaches it is well-known in the art
that FSH has an effect in developing follicles; and the Examiner finds Fan
thus provides further motivation for combining the references, as such a
combination could both activate dormant primordial follicles and also assist
in follicular development. Id.
Finally, the Examiner finds that although Fan teaches using a PTEN-
knockout mouse strain, Liu teaches transient contact with the follicles. Ans.
4-5.
We agree with the Examiner. As an initial matter, Fan teaches FSH is
an activator ofthePI3K-AKT pathway, whereas PTEN is known to be an
inhibitor of that pathway. See Fan Abstr.; 2137. Appellants' point to no
evidence supporting their contention that because disinhibition of the PI3K-
AKT pathway is sufficient to activate follicular cells, one would not expect
to see additional effects by also exposing the cells to an activator of that
pathway-.
Furthermore, with regard to Appellants' argument that Fan does not
teach transient contact with a PTEN inhibitor, "one cannot show non-
obviousness by attacking references individually where ... the rejections are
based on combinations of references." In re Keller, 642 F.2d 413, 426
(C.C.P.A. 1981). Fan teaches use of a PTEN-knockout mouse strain as a
means of inhibiting PTEN-mediated inhibition (i.e., disinhibition) of the
PI3K-ATK pathway, as well as FSH activation of PI3K. See Fan Abstr;
2137. We agree with Appellants that a knockout of the gene encoding
PTEN to inhibit PTEN-mediated inhibition (i.e., disinhibition) of the PI3K-
ATK pathway as is taught by Fan (Fan Abstr; 2137) is likely not a "transient
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contact with an inhibitor of PTEN"; however, Liu teaches the use of
transient exposure to PTEN inhibitors. In particular, Liu states:
The method can comprise incubating the follicles and/or
oocytes in a physiologically acceptable medium comprising one
or more inhibitors of PTEN. The medium can further comprise a
gonadotropin such as FSH and/or CG.
The duration of the incubation can be any time that is
sufficient to obtain activation and/or maturation of the ovarian
follicles and/or oocytes.
The PTEN inhibitor can be present in any concentration
providing activation and/or maturation of the ovarian follicles
and/ or oocytes, such as a concentration in the interval from 1 nM
to 1.0 mM, especially from 1.0 to 100 µM.
Liu ,-i,-i 7-9 (paragraph numbers omitted). Liu thus teaches exposing follicles
to PTEN inhibitors for durations sufficient to activate the follicular cells.
Claim 1 recites, in relevant part: "transiently contacting ... with an inhibitor
of PTEN and an activator of PI3K, in a dose effective to activate the ...
dormant mammalian ovarian follicle." We agree with the Examiner that Liu
thus teaches a "transient" exposure to a PTEN inhibitor in that the follicular
cells are exposed to the PTEN inhibitor, at a sufficient dosage, until such
time as the desired effect (i.e., activation of the follicular cells) is obtained.
Furthermore, we agree with the Examiner that Liu also teaches
activation of "dormant mammalian ovarian primordial follicles" via
application of PTEN inhibitors. Liu teaches:
Accordingly, the present invention provides methods for the in
vitro activation and maturation of ovarian follicles and oocytes
comprising the use of one or more inhibitors of PTEN. The
methods can be applied to activate follicles during in vitro
maturation of follicles and oocytes for in vitro fertilization. The
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follicles can be non-growing follicles, such as primordial,
intermediate and primary follicles.
Liu iJ 6 (emphasis added). Liu thus teaches activation of "dormant
mammalian ovarian primordial follicles" via application of PTEN inhibitors
and we agree with the Examiner that a person of ordinary skill would be
motivated to combine the teachings of Fan and Liu to promote follicle
activation via the additive effect achieved by treating the follicle with a
PTEN inhibitor (thus disinhibiting PI3K) and a PI3K activator, such as
FSH.2 We consequently affirm the Examiner's rejection of claims 1, 2, 4, 8-
10, and 13.
B. Claims 6 and 7
Appellants argue these claims separately, but rely upon the same
arguments presented in support of claims 1, 2, 4, 8-10, and 13, supra. App.
Br. 6. Appellants argue the teachings of Ogunwobi do not overcome the
deficiencies of Liu and Fan. Id.
2 Appellants argue further, in their Reply Brief, that: "there is no FSH
receptor in oocytes or surrounding granulosa cells in the primordial follicles.
Thus, FSH treatment cannot activate the dormant primordial follicles."
Reply Br. 6. This argument is untimely and should have been made in the
Appeal Brief. See 37 C.F.R. § 41.37(c)(l)(vii); see also Ex parte Borden, 93
USPQ2d 1473, 1474 (BPAI 2010) (Informative) ("[T]he reply brief [is not]
an opportunity to make arguments that could have been made in the
principal brief on appeal to rebut the Examiner's rejections, but were not").
Additionally, Appellants adduce no evidence to support this contention, and
we therefore accord it little probative value. See De Blauwe, 736 F.2d at
705.
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Application 12/657,679
We have related supra why we are not persuaded by Appellants'
arguments, and we incorporate by reference that reasoning here. We
therefore affirm the Examiner's rejection of claims 6 and 7.
C. Claim 11
Appellants argue claim 11 separately, but rely upon the same
arguments presented in support of claims 1, 2, 4, 8-10, and 13, supra. App.
Br. 7. Appellants argue the teachings of DeFrees do not overcome the
deficiencies of Liu and Fan. Id.
Appellants argue further that although DeFrees teaches certain
pegylated modifications of FSH, it does not teach or suggest their use in the
specific methods of the invention. App. Br. 7. Appellants contend their
invention demonstrates that a combination of agents will activate dormant
follicles, and that sequential exposure to FSH accelerates the development of
primary and secondary follicles to the early antral and preovulatory stages.
Id. Appellants assert the use of FSH in this method is not taught or
suggested by the cited reference. Id.
The Examiner responds that Liu teaches exposing the activated
follicle with FSH or an analog thereof in vitro. Ans. 5. The Examiner finds
that a person of ordinary skill in the art would have known that FSH is
important to the growth and maturation of ovarian follicles, as explicitly
taught by DeFrees. Id. at 5-6 (citing, e.g., DeFrees, ,-i 2). The Examiner
therefore concludes it would have been obvious to one of ordinary skill in
the art to modify the combination of Liu and Fan by administering FSH or
an analog thereof to said recipient following implantation in order to help
stimulate the growth and maturation of the follicle. Id. at 6.
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We have related supra why we are not persuaded by Appellants'
arguments, and we incorporate by reference that reasoning here. We
therefore affirm the Examiner's rejection of claims 6 and 7. Moreover, we
agree with the Examiner that it was well-known in the contemporary art that
FSH is important to the growth and maturation of follicles. See DeFrees ,-i 2.
We therefore find Appellants' arguments do not overcome the Examiner's
primafacie conclusion of obviousness and we affirm the rejection of claim
11.
D. Claim 12
Appellants argue claim 12 separately, but rely upon the same
arguments presented in support of claims 1, 2, 4, 8-10, and 13, supra. App.
Br. 7. Appellants argue the teachings of Dolmans do not overcome the
deficiencies of Liu and Fan. Id.
Appellants argue further Dolmans does not teach a method in which a
dormant follicle is matured in vitro for subsequent implantation. App. Br. 7.
Rather, Appellants argue, Dolmans teaches methods of avoiding in vitro
maturation. App. Br. 7. Appellants point to Dolmans' recitation of:
[I]n vitro development of human primordial follicles has
certainly proved challenging. Since the time required for follicles
to grow is so long in humans (up to 120 days) and the precise
mechanism involved in this process is unknown, this possibly
discourages researchers from conducting studies in this area and
so far this alternative did not offer any successful results.
Id. (quoting Dolmans ,-i 4). Appellants assert Dolmans provides an
alternative to in vitro maturation, in which a scaffold is provided for grafting
isolated follicles, and thus teaches away from the present invention. Id.
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The Examiner points out that Dolmans was not used as a reference for
teaching specific methods, but rather to demonstrate the knowledge of the
prior art and to provide a motivation to combine the remaining references.
Ans. 6. The Examiner finds Dolmans teaches that in vitro development of
human primordial follicles was challenging, but that it would avoid a
significant number of drawbacks and would be a promising avenue to
explore. Id. The Examiner finds that although Dolmans does not teach a
method for in vitro maturation of follicles, that method is taught by the
combination of Liu, Fan, and DeFrees, as explained supra. Id.
We agree with the Examiner. Claim 12 recites: "The method of
Claim 11, where the recipient is autologous to the ovarian follicle." App.
Br. 9. We concur with the Examiner's reasoning that Dolmans teaches that
it would be advantageous to explore in vitro activation of follicular cells.
After teaching the difficulties of implanting cryopreserved tissues (see
Dolmans ,-i 3), Dolmans teaches:
To avoid such drawbacks, these primordial follicles could be in
vitro cultured. They would have also their oocyte matured and
fertilized in vitro, and the resulted embryo could be transferred
to the mother. However, in vitro development of human
primordial follicles has certainly proved challenging. Since the
time required for follicles to grow is so long in humans (up to
120 days) and the precise mechanism involved in this process is
unknown, this possibly discourages researchers from conducting
studies in this area and so far this alternative did not offer any
successful results.
Dolmans ,-i 4. Dolmans thus teaches it would be desirable to activate
follicles in vitro, and we agree with the Examiner's finding that this would
provide further motivation to a person of ordinary skill to combine the
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references to arrive at Appellants' claimed invention. We consequently
affirm the Examiner's rejection of claim 12.
DECISION
The Examiner's rejection of claims 1, 2, 4, 6-10, and 11-13 as
unpatentable under 35 U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § l.136(a)(l). See 37 C.F.R.
§ l.136(a)(l )(iv).
AFFIRMED
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