Ex Parte Valadkhan et al

Patent Trial and Appeal Board

Aug 25, 2016

13395984 (P.T.A.B. Aug. 25, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/395,984 03/14/2012 Saba Valadkhan
68705 7590 08/29/2016
TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP
1300 EAST NINTH STREET
SUITE 1700
CLEVELAND, OH 44114
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.
CWR-019146US PCT 7386
EXAMINER
BERTOGLIO, VALARIE E
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
08/29/2016 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):
rkline@tarolli.com
docketing@tarolli.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SABA V ALADKHAN and FERESHTEH JAHANIANI KENARI
Appeal2015-003788
Application 13/395,9841
Technology Center 1600
Before JEFFREYN. FREDMAN, RYAN H. FLAX, and DAVID COTTA,
Administrative Patent Judges.
COTT A, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of transdifferentiating a non-neuronal non-terminally differentiated
mammalian cell into a neuronal cell. The Examiner rejected the claims on
appeal under 35 U.S.C. § 112 (a) as failing to comply with the enablement
requirement.
We affirm.
1 According to Appellants, the real party in interest is Case W estem Reserve
University (Appeal Br. 2).
Appeal2015-003788
Application 13/395,984
STATEMENT OF THE CASE
Claims 1-2 and 6-8 are on appeal. Claim 1, the only independent
claim, is illustrative and reads as follows:
1. A method of transdifferentiating a non-neuronal
non-terminally differentiated mammalian cell into a neuronal
cell comprising:
transfecting the non-neuronal non-terminally
differentiated mammalian cell with a nucleic acid encoding
functioning long non-coding BORG RNA specific to the
species of the mammalian cell, such that functioning long non-
coding BORG RNA is overexpressed in the cell; and
culturing the transfected cell in a growth medium,
whereby the cell is transdifferentiated into a cell having one or
more morphological, physiological and/or immunological
feature( s) of a neuronal cell.
The Examiner rejected claims 1-2 and 6-8 under 35 U.S.C. § 112(a)
for failure to comply with the enablement requirement. The Examiner found
that the claims encompassed transdifforentiating any non-terminally
differentiated cell type of any mammalian species. Final Act. 3. The
Examiner found that the Specification exemplified only transdifferentiation
of mouse fibroblast and myoblast cells. Id. at 3--4. With respect to enabling
transdifferentiation for all species of mammals, the Examiner concluded:
"one of skill in the art cannot extrapolate the findings relating to the effect of
mouse BORG overexpression in mouse cells to expression of any other
species of BORG in any other [mammalian] species of cells." Id. at 4. With
respect to enabling transdifferentiation for all cell types, the Examiner
concluded that it would be difficult for the person of ordinary skill to
"extrapolate the limited teachings in the specification to other cell types."
Id.
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FINDINGS OF FACT
Breadth of Claims
1. Claim 1 encompasses transdifferentiating any non-terminally
differentiated cell type from any mammalian species into a neuronal cell.
Presence of Working Examples
2. The Specification provides two working examples of
transdifferentiated cells. The two examples are of mouse C2C12 myoblasts
and mouse C3H10Tl/2 embryonic fibroblasts transfected with mouse
BORG RNA. Spec. iTiT 89-94.
3. The Specification states that the transfected C2C12 and
C3H10Tl/2 cells underwent morphological changes. The Specification
states: "[r]ather than fusing together and forming myotubes, they [C2C12
cells] remained separated as individual cells and formed round cell bodies
with elongated, sometimes branched processes, usually at opposite poles of
the cell (Fig. 2B)." Id. iT 90. The Specification further states: "the BORG
overexpressing C3H10Tl/2 cells, and not the control or vector transfected
cells, showed morphological changes similar to those observed with C2C12
cells overexpressing BORG." Id. iT 94.
4. The Specification states that the transfected C2C12 cells
showed an increase in "protein expression level of mature neuronal markers
MAP2, TUJ-1, NF200, tau, NeuN and synapsin." Id. iT 92.
5. The Specification states that analysis of the "gene expression
pattern [in transfected C3H10Tl/2 cells] indicated the upregulation of the
neuronal differentiation marker MAP2, similar to what had been observed
with the C2Cl2 cells." Id. iT 94.
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Amount of Direction of Guidance Provided
6. The Specification states: "It is to be understood that certain
genetic material encoding BORG RNA contemplated herein, is unique to the
mammalian species from which the cells are derived." Id. if 48.
7. The Specification states: "The BORG gene is found in all
sequenced mammalian genomes and shows moderate sequence
conservation, as is the case with other long non-coding RNAs." Id. if 85.
8. The Specification states: "MAP2, TUJ-1, tau, NeuN and
synapsin are highly specific to neuronal tissues and their expression is
considered indicative of neuronal differentiation." Id. if 92.
9. The Specification states: "BORG RNA can reprogram at least
two different mesodermal cell types into a neuronal fate. Taken together
with the cell type[-]specific expression of BORG in primary neurons and
neural tissues, these data indicate that the BORG RNA is a non-coding RNA
regulator of neuronal differentiation pathways.'' Id. ,-r 94.
State of the Art and Unpredictability of the Art
10. The Examiner found that the "state of the art at the time of
filing held that transdifferentiation of cells is highly unpredictable and not
well understood with numerous obstacles to be overcome." Ans. 4.
11. The Specification states: "generation of neurons from other cell
types has proven to be extremely difficult and remains a major limiting
factor in both research and therapeutic efforts in the field of neuroscience."
Spec. ii 3.
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Application 13/395,984
12. Poumasr2 teaches:
Most currently available iTD [induced transdifferentiation]
strategies have been developed using mouse cells. However, it is
still unclear whether the known reprogramming factors in mice
are appropriate or sufficient for the lineage reprogramming of
human cells. Recently, it has been demonstrated that human
fibroblasts transdifferentiate into functionally immature neuronal
cells [33] when infected with three TFs, Asel 1, Brn2, andMytl 1,
that were reported to achieve transdifferentiation of mouse
fibroblasts into neurons [32]. However, the addition of NeuroDJ
improved the efficiency and maturation of generating neuronal
cells [33]. Additionally, maturation and synapsis of
transdiff erentiated neuronal cells in human take longer time in
comparison with mouse neurons [33]. Therefore, to achieve the
full potential of transdifferentiation for research and therapy, the
current protocols developed in mouse cells should be translated
into the human ones. In this context, the strategy of an 'initial
epigenetic activation phase' seems to be much more broadly
applicable in human cells due to the possibility for the induction
of these factors without permanent genetic modification, thus
defining a more general platform for transdifferentiation and
cell-based therapies.
Poumasr 1937-38.
13. Poumasr teaches "[fJunctional tests must be used to
determine whether the obtained cells exhibit similar physiological
behaviors to their in vivo counterparts." Id. at 1937.
14. Poumasr teaches:
The potential of a somatic cell for transdifferentiation into a
specific cell lineage may create a bias in its basal
transdifferentiation tendencies toward a given cell lineage. For
example, transdifferentiated cardiomyocytes derived from
2 Poumasr et al., Concise Review: Alchemy of Biology: Generating Desired
Cell Types from Abundant and Accessible Cells, 29 STEM CELLS 1933-1941
(2011).
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Application 13/395,984
cardiac and dermal fibroblasts exhibit a different level of
similarity to neonatal cardiomyocytes when compared at the
transcriptional and functional levels [29]. It has also been shown
that iPS cells derived from different adult tissues vary
substantially in their teratoma-forming propensity, which
correlated with the persistence of undifferentiated cells [ 66].
Id. 1938.
Level of Skill in the Art
15. The Appellants contend that the person of ordinary skill in the
art would have a "high level of skill." Reply Br. 4.
ANALYSIS
"[T]o be enabling, the specification of a patent must teach those
skilled in the art how to make and use the full scope of the claimed invention
without 'undue experimentation."' In re Wright, 999 F.2d 1557, 1561 (Fed.
Cir. 1993).
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. The scope of the
claims must be less than or equal to the scope of the enablement.
The scope of enablement, in tum, is that which is disclosed in the
specification plus the scope of what would be known to one of
ordinary skill in the art without undue experimentation.
National Recovery Techs. Inc. v. Magnetic Separation Sys., Inc., 166 F.3d
1190, 1195-96 (Fed Cir. 1999).
Some experimentation, even a considerable amount, is not "undue" if,
e.g., it is merely routine, or if the Specification provides a reasonable
amount of guidance as to the direction in which the experimentation should
proceed. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
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Id.
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.
Claim 1 is broad, encompassing a method of transdifferentiating any
non-terminally differentiated type of mammalian cell. See FFI. The
Specification, however, only exemplifies differentiation (with respect to
morphology and the presence of neuronal cell markers) of two cell types,
fibroblasts and myoblasts. FF2-5. The Examiner concluded that a person of
ordinary skill in the art would have been unable to practice the invention
with respect to cell types beyond the two disclosed in the Specification. The
Examiner explained:
Different cell types differ in their plasticity. As well, without an
understanding of how BORG RNA functions, one cannot
reasonably predict that it will function the same way in all cell
types. The art holds that transdifferentiation of cells is highly
unpredictable. In general, transdifferentiation of cells is induced
by transcription factors (see Poumasr, Stem Cells, 2011,
29:1933-1941). It is again noted, that BORG is an untranslated
RNA whose mechanism of function is not known, rendering it
difficult to extrapolate the limited teachings in the specification
to other cell types.
As set forth above, the specification teaches only use of myoblast
and fibroblast in the claimed method. In light of the
unpredictability of transdiff erentiation and the lack of
characterization of the role of BORG RNA in cells, it would be
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Application 13/395,984
highly unpredictable, without additional experimentation, to
determine what cell types can be transdifferentiated into neuronal
cells using the functionally uncharacterized BORG RNA.
Final Act. 4, 5.
The Examiner's explanation of why the claims do not support
transdifferentiation of cells other than fibroblasts and myoblasts is
reasonable and well supported by the record. The only Wands factor that
weighs in favor of enablement is Appellants' contention that the person of
ordinary skill in the art would have a "high level of skill." The remaining
Wands factors weigh strongly against enablement. The record shows that
the art is unpredictable, the scope of the claims is broad, and the
Specification provides little guidance on the applicability of its method to
cell types other than the two provided in the working examples, fibroblasts
and myoblasts. FFl-14. Moreover, Appellants do not direct us to any
evidence or offer any argument as to how or why a person of ordinary skill
in the art could apply the teachings of the Specification with respect to
myoblast and fibroblast cell lines to other types of cells. Accordingly, we
find that the preponderance of evidence of record supports the determination
that the Specification does not enable the full scope of the claims with
respect to all of the types of cells encompassed by the claims. 3
3 In the last substantive paragraph of their Reply Brief, Appellants argue for
the first time that claim 7, which is limited to cells of mesodermic origin, is
enabled. Reply Br. 6-7. We find that this argument was waived because it
was not included in the principal brief, which deprives us of the Examiner's
response. See Exparte 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").
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Application 13/395,984
We also find that the evidence of record supports that the
Specification does not enable the full scope of the claims with respect to all
of the species of mammals encompassed by the claims. The Examiner
explained:
[T]he specification only teaches mouse BORG and mouse cells.
The art is essentially void of teachings relating to BORG, its
conservation across species and its role in neuronal
differentiation. Furthermore, the specification and the art are
silent with regard to mechanism of BORG function. Thus, one
of skill in the art cannot extrapolate the findings relating to the
effect of mouse BORG overexpression in mouse cells to
expression of any other species of BORG in any other species of
cells.
Transdifferentiation is a highly complex process (see above) and
there is absolutely no evidence that BORG RNA will
transdifferentiate non-mouse cells in the same manner that is
taught for mouse cells in the instant specification. Absent any
evidence that BORG is conserved between mouse and another
mammalian species, one cannot reasonably predict that BORG
will have the same effect on non-mouse cells that it has on mouse
cells.
Final Act. 3--4, 6.
Appellants argue that, in finding that the claims were not enabled for
all species of mammals, the Examiner "is undervaluing the high level of skill
that an ordinary skilled artist in the relevant art would have .... " Reply
Br. 2. Appellants point to the teaching of the Specification that the Borg
gene is "found in all sequenced mammalian genomes and shows moderate
sequence conservation," and contend that a person of ordinary skill could
"determine the appropriate BORG functional nucleic acids for a given
species through nothing more than routine experimentation." Id. at 2-3.
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We are not persuaded. Poumasr expressly teaches that it is "unclear
whether the known reprogramming factors in mice are appropriate or
sufficient for the lineage reprogramming of human cells" and provides
examples showing differences between mouse and human
transdifferentiation. FF12. The teachings of the specification with respect
to non-mouse mammalian species are limited to generalized statements
regarding sequence conservation. Spec. i-f 85 (teaching that BORG RNA
shows "moderate sequence conservation," and is found in "all sequenced
mammalian genomes"). The teachings of the Specification with respect to
how BORG RNA functions are drawn only from experiments conducted on
mouse cells and reach conclusions only as to "part of the cellular function of
BORG." Spec. i-f 88 (describing experiments conducted in mouse
neuroblastoma cells, the results of which "suggest that BORG RNA is
required for the conversion of the pre-differentiation N2A cells to fully-
differentiated neurons'' and "indicate[] that at least part of the cellular
function of BORG was mediated by the transcript itself ... ").
Given the uncertainty reflected in Poumasr, the limited guidance
provided by the Specification is not sufficient to allow the person of
ordinary skill to practice the claimed invention on non-mouse cells without
undue experimentation. Looking at the Wands factors, the record shows that
the art is unpredictable, the scope of the claims is broad, the Specification
provides working examples of only one species, and the guidance offered by
the Specification is limited. FF2-14.
Appellants argue that "the Examiner fails to provide evidence in fact
that a corresponding human or other mammal BORG RNA sequence is not
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Application 13/395,984
functionally equivalent to a mouse sequence." Appeal Br. 6. Appellants
overstate the burden upon the examiner. As the Federal Circuit explained:
\Vhen 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; this includes; of course; providing sufficient
reasons for doubting any assertions in the specification as to the
scope of enablement. If the PTO meets this burden, the burden
then shifts to the applicant to provide suitable proofs indicating
that the specification is indeed enabling.
In re Wright, 999 F.2d. 1557, 1561---62 (Fed. Cir. 1993). Here, the Examiner
provided a reasonable and well-supported explanation of why the claims
were not enabled. No more was required of the initial burden and
Appellants have not presented persuasive evidence to the contrary.
Accordingly, we find that the Specification does not enable the full scope of
the claims with respect to all of the species of mammals encompassed by the
claims.
The Examiner also concluded that the Specification did not enable the
person of ordinary skill to use cells produced by the claimed method because
it was unclear that the cells produced were, in fact, neuronal cells. Final
Act. 4--5. Our finding that the preponderance of the evidence supports that
the claims are not enabled with respect to the full scope of species and types
of cells encompassed by the claims makes it unnecessary to address this
basis of the Examiner's enablement rejection.
In sum, for the reasons discussed, Appellants' arguments do not
persuade us that a preponderance of the evidence fails to support the
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Examiner's rejection of claim 1 under 35 U.S.C. § 112 (a) as failing to
comply with the enablement requirement. Because they were not argued
separately, claims 2 and 6-8 fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
For these reasons and those set forth in the Examiner's Answer, the
Examiner's final decision to reject claims 1-2 and 6-8 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).
AFFIRMED
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