Ex Parte Sapolsky et al

Patent Trial and Appeal Board

Oct 28, 2016

11713218 (P.T.A.B. Oct. 28, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
111713,218 02/28/2007 Robert M. Sapolsky
77974 7590 11/01/2016
Stanford University Office of Technology Licensing
Bozicevic, Field & Francis LLP
1900 University Avenue
Suite 200
East Palo Alto, CA 94303
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-462 (SOS-322) 3367
EXAMINER
MONTANARI, DAVID A
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
11/01/2016 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 ROBERT M. SAPOLSKY, NATHAN C. MANLEY,
SHEILA BROOKE, KLAUS M. DINKEL, CAROLINA D. MUNHOZ,
ANGELA L. RIEPEL, and ANDREA C. NICHOLAS 1
Appeal2014-001993
Application 11/713,218
Technology Center 1600
Before FRANCISCO C. PRATS, JOHN G. NEW, and TA WEN CHANG,
Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims to methods of
delivering therapeutic proteins to the central nervous systems of mammals.
The Examiner rejected the claims for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants state that the "real parties in interest are the Board of Trustees
of the Leland Stanford Junior University, by virtue of the assignments
recorded reel and frame 020412/0626." Br. 1.
Appeal2014-001993
Application 11/713,218
STATEMENT OF THE CASE
The sole rejection before us for review is the Examiner's rejection of
claims 13-15, 17, 20-24, and 26-33 under 35 U.S.C. § 103(a) as being
unpatentable over Fathman,2 Yebenes,3 Beerens,4 Falcone,5 and Sagar. 6
Non-Final Act. 3-7.7'8
Claims 13, 1 7, and 21, the independent claims on appeal, illustrate
the appealed subject matter and read as follows (Br. 12-13):
2 US 2003/0091548 Al (published May 15, 2003).
3 Justo Garcia de Yebenes and Maria Angeles Mena, Neurotrophic Factors
in Neurodegenerative Disorders: Model of Parkinson's Disease, 2
Neurotoxicity Res. 115-137 (2000) ("Yebenes").
4 A.M.J. Beerens et al., Protein Transduction Domains and their
Utility in Gene Therapy, 3 Current Gene Therapy 17-34 (2003) ("Beerens").
5 Marika Falcone et al., A Critical Role for IL-4 in Regulating Disease
Severity in Experimental Allergic Encephalomyelitis as Demonstrated in
JL-4-Deficient C57BL/6 ~Mice and BALB/c ~Mice, 160 J. Immunology 4822-
4830 (1998) ("Falcone").
6 Divya Sagar et al., Mechanisms of Dendritic Cell Trafficking Across the
Blood-brain Barrier, J. Neuroimmune. Pharmacol., pp. 1-21, published
online Aug. 6, 2011 ("Sagar"). The Sagar article does not include page
numbers; accordingly we cite to the first page as if it were page 1, and cite to
the remaining pages as if numbered consecutively.
7 Non-Final Rejection entered July 13, 2012.
8 The Examiner also entered an objection to claims 15, 22-24, 26-29, 32,
and 33, which Appellants contend is improper. Non-Final Act. 2-3; Br. 3--4.
We will not review that objection. See MPEP § 706.01 ("The practical
difference between a rejection and an objection is that a rejection, involving
the merits of the claim, is subject to review by the Patent Trial and Appeal
Board, while an objection, if persisted, may be reviewed only by way of
petition to the Director of the USPTO.").
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13. A method of delivering a neurotrophin to a central
nervous system (CNS) of a mammal, said method comprising:
administering into the bloodstream of said mammal
autologous or allogeneic dendritic cells, which dendritic cells
have been genetically engineered ex vivo by introduction of a
vector comprising a gene expression cassette that provides
genetic sequences required for expression of said neurotrophin;
wherein said dendritic cells localize to an inflammatory
lesion of said CNS, cross a blood brain barrier, and secrete said
neurotrophin within the CNS.
17. A method of delivering a therapeutic protein
comprising a protein translocation domain (PTD) to a central
nervous system (CNS) of a mammal, said method comprising:
administering into the bloodstream of said mammal
autologous or allogeneic dendritic cells, which dendritic cells
have been genetically engineered ex vivo by introduction of a
vector comprising a gene expression cassette that provides
genetic sequences required for expression of said therapeutic
protein comprising a protein translocation domain;
wherein said dendritic cells localize to an inflammatory
lesion of said CNS and secrete said therapeutic protein
comprising a translocation domain.
21. A method of delivering a CNS therapeutic protein
to a central nervous system (CNS) of a mammal, said method
compnsmg:
administering into the bloodstream of said mammal
autologous or allogeneic immature CD 11 c expressing dendritic
cells, which dendritic cells have been genetically engineered ex
vivo by introduction of a vector comprising a gene expression
cassette that provides genetic sequences required for expression
of a CNS therapeutic protein of interest;
wherein said immature CD 11 c expressing dendritic cells
localize to the region of an inflammatory lesion in the CNS,
cross a blood brain barrier, and thereupon secrete said CNS
therapeutic protein within the CNS.
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Application 11/713,218
OBVIOUSNESS
The Examiner's Position
The Examiner cited Fathman as teaching, as required by the rejected
claims, the use of dendritic cells as genetically engineered vehicles for
delivering therapeutic proteins, such as interleukin 4 (IL-4), to the nervous
system of a mammal. Non-Final Act. 3---6. The Examiner cited Falcone as
evidence that "the IL-4 administered by [Fathman] was known at the time of
filing to be a CNS therapeutic protein." Id. at 5. The Examiner cited Sagar
as evidence that "dendritic cells have the inherent capability of crossing the
BBB [blood brain barrier] of the CNS with ease and that genetically
modified dendritic cells localized to the CNS with respect to inflammation
(pg. 86 col. 1 parag. 2)." Id.
The Examiner conceded that Fathman differs from the rejected claims
in that Fathman "does not teach that the therapeutic proteins can be a
neurotrophin, BDNF [brain-derived neurotrophic factor,] or block neuronal
apoptosis and [also does not teach] modifying a therapeutic protein to have a
protein translocation domain (PTD)." Id.
To address the first asserted difference between Fathman and the
rejected claims, the Examiner cited Yebenes as evidence that it was known
in the art that a neurotrophin, such as BDNF, "would be an obvious
therapeutic protein involved in blocking neuronal apoptosis." Id. at 6.
To address the second asserted difference between Fathman and the
rejected claims, the Examiner cited Beerens as teaching that PTDs were
known to be useful "when wanting to ferry ... much larger molecules into
cells independent of classical endocytosis (pg. 18 lines 1-3)," and were
known also to be "powerful tools for gene therapy, since incorporating a
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PTD into a therapeutic gene can enable the spread of the therapeutic gene
into non-transfected cells and thus increase the therapeutic effect (pg. 18
parag. 3)." Id.
Based on the references' teachings, the Examiner concluded that an
ordinary artisan would have considered it obvious to modify Fathman's
teachings "regarding treatment of CNS inflammatory lesions with
genetically modified dendritic cells expressing a therapeutic protein such as
IL-4 [,] with the teachings of [Y ebenes] regarding the therapeutic uses of
neurotrophic proteins such as BDNF and GDNF to promote neuronal cell
survival and prevent neuronal cell apoptosis in a CNS lesion." Non-Final
Act. 6.
The Examiner reasoned that an ordinary artisan would have been
motivated to substitute Yebenes's neurotrophins for Fathman's IL-4 because
"it was known in the art that dendritic cells can serve as vehicles for
therapeutic trans genes that inherently home to sites of inflammation and
injury and that therapeutic proteins such as neurotrophins exhibit a
therapeutic effect on CNS inflammatory lesions." Id. The Examiner
reasoned that Beerens would have provided additional motivation to practice
the claimed invention "in teaching that PTDs are powerful tools to increase
the therapeutic effect of therapeutic proteins." Id.
The Examiner reasoned that an ordinary artisan would have had a
reasonable expectation of success that a PTD on a therapeutic protein, "such
as a neurotrophin, which functions intra-cellularly, as taught by [Fathman]
and [Y ebenes], would increase the therapeutic effect of the protein at the
CNS inflammatory lesion since it was known in the art that PTDs increase
therapeutic efficacy." Id. at 7. Further, the Examiner reasoned, an ordinary
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artisan would have had a reasonable expectation of success that "a
therapeutic protein such as a neurotrophin as taught by [Y ebenes] would
function as a therapeutic in the CNS since [Y ebenes] teaches that
neurotrophins enhance neuronal survival and reduce apoptosis in neuronal
cells." Id.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
primafacie case ofunpatentability ....
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
As to the presentation of separate arguments regarding individual
claims subject to a single ground of rejection, 37 C.F.R. § 41.37(c)(l)(iv)
explains as follows:
Under each heading identifying the ground of rejection being
contested, any claim(s) argued separately or as a subgroup shall
be argued under a separate subheading that identifies the
claim(s) by number. A statement which merely points out what
a claim recites will not be considered an argument for separate
patentability of the claim.
Appellants do not present their arguments under the separate
subheadings required by§ 41.37(c)(l)(iv). Appellants, nonetheless, present
argument as to four separate groups. Br. 3. We select claims 13, 17, 21, and
33 as representative of the groups identified by Appellants. 9 37 C.F.R.
9 Appellants identify claim 23 as part of Group IV. Br. 3. Claim 23 does
not, however, recite the step of freezing and storing the dendritic cells prior
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§ 41.37(c)(l)(iv).
Appellants' arguments do not persuade us that a preponderance of the
evidence fails to support the Examiner's prima facie case of obviousness as
to those representative claims.
We begin our analysis with claims 21and33. Claim 21 recites a
method of delivering a central nervous system (CNS) therapeutic protein to
the central nervous system (CNS) of a mammal. Br. 12.
The sole positive process step required by claim 21 is administering,
into the bloodstream of the mammal, autologous or allogeneic immature
CDl lc-expressing dendritic cells. Id. Claim 21 requires the administered
cells to have been genetically engineered ex vivo by introduction of a vector
comprising a gene expression cassette that provides genetic sequences for
expression of a CNS therapeutic protein of interest. Br. 12.
Claim 21 also requires the administered to cells localize to the region
of an inflammatory lesion in the CNS, cross a blood brain barrier (BBB),
and thereupon secrete said CNS therapeutic protein within the CNS. Id. at
13.
Claim 33 recites "[t ]he method according to Claim 21, further
comprising freezing and storing said dendritic cells prior to therapeutic use."
Id.
Turning to the cited references, Fathman discloses a method of
treating autoimmune disorders in patients by delivering "a suppressive agent
to the site of disease. Delivery is accomplished by introducing an expression
to therapeutic use, the limitation asserted as common to all claims of Group
IV. Rather, claim 33, which we designate as representative, includes that
feature. Br. 13.
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vector encoding the suppressive agent into cells targeted for such sites, and
administering the genetically modified cells to the patient." Fathman i-f 4.
Fathman discloses that autoimmune disorders treatable by its methods
include CNS-specific demyelinating diseases, such as multiple sclerosis
(MS) and experimental autoimmune encephalitis (EAE). Id. i-fi-111, 29, 42.
As the Examiner found, and as required by Appellants' claim 21,
Fathman discloses that genetically modified immature CD I le-expressing
dendritic cells may be used to deliver the suppressive agent to the disease
site. See id. i-fi-1 22-26.
As required by the sole method step positively recited in claim 21,
Fathman discloses that the "genetically modified cells may be used for the
treatment of disease in a recipient. Autologous cells or allogeneic cells may
be used. The cells may be administered in any physiologically acceptable
medium, normally intravascularly .... " Id. i-f 44.
As required by claim 21, the administered cells localize to the site of
the lesion in the CNS, and as required by claim 33, the administered cells
may be frozen and stored before use:
The cells may be frozen at liquid nitrogen temperatures and
stored for long periods of time, being capable of use on
thawing. . . . Once thawed, the cells may be expanded by use of
growth factors, and the like. The cells localize at the site of
lesions, where there is increased inflammation related to the
relevant autoantigen. . . . [F]or demyelinating diseases lesion
sites are primarily in the central nervous system.
F athman i-f 44.
As to claim 21 's requirement for the delivered protein to be a CNS
therapeutic protein, as the Examiner found, Fathman discloses that
autoimmune suppressive agents "of particular interest include IL-4
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[interleukin 4]." Id. if 4; see also id. if 14. Although Fathman does not
expressly state that IL-4 is a CNS therapeutic protein, as the Examiner
found, Falcone discloses that IL-4 plays a critical role in modulating the
severity of EAE, which is an animal model of MS. See Falcone 4822.
As to claim 21 's requirement for the cells to cross a blood brain
barrier (BBB), we acknowledge that Fathman does not state expressly that,
when its dendritic cells localize to the site of CNS inflammation, they also
cross the BBB. As the Examiner found, however, Sagar discloses that
dendritic cells, including immature dendritic cells, are inherently capable of
crossing the BBB:
Under inflammatory conditions of the CNS such as in
MS or HIVE [HIV encephalopathy], DCs [dendritic cells] along
with other circulating lymphocytes and
monocytes/macrophages readily gain access to the CNS,
resulting in edema, further inflammation, or demyelination ....
In steady-state conditions, DCs are found in low numbers in the
meninges, choroid plexus, and CSP ... , possibly because the
BBB limits penetration of immune cells into the brain
parenchyma.
Sagar 3.
In sum, based on the discussed teachings, we are persuaded that an
ordinary artisan would have had adequate reason to administer genetically
modified immature CD 11 c-expressing dendritic cells, including previously
frozen and stored cells, in order to deliver IL-4 to the CNS for the treatment
of EAE or MS. That is, Fathman, particularly when viewed in light of
Falcone, suggests performing processes having all of the steps and features
required by Appellants' claims 21 and 33, and provides a reasonable
expectation of therapeutic success when performing those processes. As
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evidenced by Sagar, the administered dendritic cells would inherently
localize to the lesion site, and cross the BBB, as claim 21 requires.
Accordingly, given the cited references' teachings, we agree with the
Examiner that the methods recited in claims 21 and 33 would have been
obvious to an ordinary artisan.
Appellants' arguments do not persuade us to the contrary. Appellants
contend that the claimed invention is "based on the unexpected finding by
Appellants that dendritic cells that have been cultured and genetically
modified ex vivo will localize to sites of injury and effectively cross the
BBB, so that a therapeutic protein can be delivered to the region of the CNS
injury." Br. 5. Appellants contend also that "the benefits of
cryopreservation [as recited in claim 33] on ex vivo generation of CNS
homing cells provides an unexpected benefit captured in the methods of the
invention." Id. Appellants direct us to Exhibit A (Manley)10 as evidence of
the efficacy of the claimed invention. Id.
Appellants do not, however, direct us to any specific persuasive
evidence, in the Specification or elsewhere in the record, in comparative
form or otherwise, supporting the assertions in the Appeal Brief that
dendritic cells' localizing to a CNS injury site and crossing the BBB were
unexpected, or that prior cryopreservation of the cells unexpectedly
influenced those properties in a positive fashion. It is well settled that
attorney argument is not an adequate substitute for that type of evidence.
See In re Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997).
10 Nathan C. Manley et al., Characterization of monocyte chemoattractant
protein-! expression following a kainate model of status epilepticus, 1182
Brain Res. 138-143 (2007) ("Manley").
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Contrary to Appellants' assertions of unexpectedness, moreover,
Fathman expressly discloses that its engineered cells localize to the site of
lesions, which, "for demyelinating diseases ... are primarily in the central
nervous system." Fathman i-f 44; see also id. i-f 53 ("Recent data suggest that
autologous dendritic cells (DCs) also can be transduced and home to sites of
inflammation."). Accordingly, as to the capacity of cultured dendritic cells
to localize to the site of a CNS lesion, Appellants do not persuade us that
they have advanced evidence of unexpectedness sufficient to overcome the
Examiner's prima facie case of obviousness.
As to the allegedly unexpected property of cultured dendritic cells
crossing the BBB, as noted above, and as the Examiner found, Sagar
discloses that property is inherent in both immature and mature dendritic
cells. Sagar 3-5. That Sagar, as Appellants argue (Br. 4, 6 n.1 ), is not prior
art to the claimed invention does not negate the fact that dendritic cells
inherently possess the BBB-crossing property.
As the Federal Circuit has explained, "[ m] ere recognition of latent
properties in the prior art does not render nonobvious an otherwise known
invention." In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir.
1991); see also In re Woodruff, 919 F.2d 1575, 1577-78 (Fed. Cir. 1990)
(obviousness rejection affirmed where using claimed elements in the manner
suggested by the prior art necessarily resulted in claim-recited effect). Thus,
because Fathman, particularly viewed alongside Falcone, suggests
performing processes that include all of the method steps required by claims
21 and 33, the claimed processes would have been prima facie obvious to an
ordinary artisan, even if it were true that dendritic cells' BBB-crossing
capacity was unknown at the time of Appellants' invention.
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Indeed, because the Examiner has advanced evidence sufficient to
suggest that the claimed functions of localizing to a CNS lesion and crossing
the BBB were inherent results of performing the process of administering
dendritic cells taught in Fathman, the Examiner has shifted to Appellants the
burden of showing that those results would not have occurred inherently
when practicing Fathman's process:
[W]here the Patent Office has reason to believe that a functional
limitation asserted to be critical for establishing novelty in the
claimed subject matter may, in fact, be an inherent
characteristic of the prior art, it possesses the authority to
require the applicant to prove that the subject matter shown to
be in the prior art does not possess the characteristic relied on.
In re Best, 562 F.2d 1252, 1254--55 (CCPA 1977) (quoting In re Swinehart,
439 F.2d 210, 212-13 (CCPA 1971)).
In the instant case, Appellants do not persuade us that they have met
that burden. Nor are we persuaded that Appellants have shown that an
ordinary artisan lacked motivation or a reasonable expectation of success in
administering dendritic cells as taught by Fathman.
To those ends, Appellants advance Exhibits B ( Creusot ), 11 C
(Tavare), 12 and D (Sallusto )13 to show that an ordinary artisan would have
11 Remi J. Creusot et al., Tissue-targeted therapy of autoimmune diabetes
using dendritic cells transduced to express IL-4 in NOD mice, 127 Clin.
Immunol. 17 6-187 (2008) ("Creusot").
12 Richard Tavare et al., Monitoring of In Vivo Function of
Superparamagnetic Iron Oxide Labelled Murine Dendritic Cells during
Anti-Tumour Vaccination, 6 PLoS ONE e19662 (2011) ("Tavare").
13 Federica Sallusto et al., Rapid and coordinated switch in chemokine
receptor expression during dendritic cell maturation, 28 Eur. J. Immunol.
2760-2769 (1998) ("Sallusto").
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expected dendritic cells to migrate to the lymph nodes, rather than a CNS
lesion, as taught in Fathman. Br. 7.
We first note that both Creusot (published in 2008) and Tavare
(published in 2011) were published after Appellants' February 28, 2007
filing date (see Br. 1 ). Neither reference, therefore, is prior art to the
claimed invention. Appellants, moreover, do not direct us to any specific
disclosures in either Creusot or Tavare that investigate or discuss the
behavior of dendritic cells in response to CNS inflammation or a CNS lesion
of the type exhibited in EAE or MS, the demyelinating disorders described
in Fathman. Accordingly, Appellants do not persuade us that, at the time of
Appellants' invention, either Creusot or Tavare would have undermined
Fathman's teachings, discussed above, that genetically modified dendritic
cells migrate to the site of a CNS lesion when administered to treat EAE or
MS.
Similarly, Appellants do not direct us to any disclosures in Sallusto
discussing specifically the behavior of dendritic cells in response to CNS
inflammation or a CNS lesion of the type exhibited by the disorders
described in Fathman. Indeed, while Sallusto does teach that dendritic cells
ultimately migrate to lymph nodes, Sallusto also discloses that, initially,
dendritic cells migrate to the site of inflammation. See Sallusto Abstract
("Dendritic cells (DC) migrate into inflamed peripheral tissues where they
capture antigens and, following maturation, to lymph nodes where they
stimulate T cells."). Sallusto, thus, actually supports Fathman's teaching
that genetically modified immature dendritic cells will migrate to a CNS
lesion under inflammatory conditions.
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We acknowledge, but are not persuaded by, Appellants' contentions
regarding the three cited clinical trials. Br. 7-8 (citing clinical trials
NCTOl 171469, NCT01235845, and NCT00639639). We first note that
Appellants do not direct us to the documents in the record supporting the
arguments made. See id. Thus, it is unclear on this record that any of the
cited disclosures is prior art to the rejected claims, such that the cited
disclosures may have undermined an ordinary artisan's view of the
discussed teachings in Fathman. The absence from the record of the
documents also prevents us, and the Examiner, from undertaking an
independent review. Moreover, Appellants do not explain specifically why
the expectation that dendritic cells would home to lymph nodes when
treating cancer tumors demonstrates that an ordinary artisan lacked an
expectation that, in different disorders (EAE and MS related inflammation),
an ordinary artisan would have doubted that dendritic cells would localize to
the site of inflammation as taught by Fathman, and supported by Sallusto
and Sagar, as discussed above.
We acknowledge, but are not persuaded by, Appellants' contentions
that "[ m ]ethods for ex vivo culture that were published in the art at the time
of filing produced a default state of mature activation of dendritic cells - a
state that is incompatible with migration to a CNS lesion." Br. 8; see also
id. at 9 ("[T]he prior art at the time of filing does not teach one of skill in the
art that dendritic cells, particularly immature dendritic cells, will localize to
an inflammatory lesion of the CNS.").
We first note that representative claim 21 does not expressly require
the dendritic cells to be cultured in any particular manner. Thus, to the
extent Appellants seeks to distinguish claim 21 from the cited prior art on
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the basis of culturing conditions, Appellants' arguments are not based on
limitations present in the claims. While claim 33 requires the cells to be
frozen and stored before use, Fathman discloses performing that step, as
discussed above.
Moreover, contrary to Appellants' assertion, Fathman discloses that
genetically modified dendritic cells, which as required by claim 21 may be
immature (see Fathman ,-r 25), are useful in its methods, and states expressly
that its modified cells will localize to a CNS lesion in a demyelinating
disorder such as EAE or MS. Id. ,-r 44. For the reasons discussed above, the
evidence advanced by Appellants does not persuade us that an ordinary
artisan lacked motivation for performing Fathman's process, or a reasonable
expectation that doing so would produce a useful therapeutic result.
In sum, Appellants' arguments, for the reasons discussed, do not
persuade us that the evidence of record fails to support the Examiner's prima
facie case of obviousness as to representative claims 21and33. Because,
for the reasons discussed, Appellants' evidence as to secondary
considerations of nonobviousness is insufficient to outweigh the evidence of
prima facie obviousness, we affirm the Examiner's rejection of claims 21
and 33 under§ 103(a). Because they were argued in the same groupings
(Br. 3), claims 20, 22-24, 27, and 29-32 fall with claims 21 and 33.
37 C.F.R. § 41.37(c)(l)(iv).
Turning to representative claim 13, the process recited in that claim is
similar to that recited in claim 21, discussed above, except that claim 13
does not limit the maturity of the dendritic cells, but does require the protein
delivered by the dendritic cells to be a neurotrophin. Br. 12. As noted
above, the Examiner cited Y ebenes as evidence that it would have been
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obvious to deliver a neurotrophin using Fathman's methods, because
neurotrophins would have been expected to enhance neuronal survival and
reduce apoptosis in neuronal cells. Non-Final Act. 6.
Appellants do not dispute the Examiner's characterization of Y ebenes,
nor do Appellants contend that an ordinary artisan would have lacked
motivation to make the modification of Fathman's process posited by the
Examiner. Rather, Appellants contend, "nothing in Y ebenes would lead one
of skill in the art to believe that an ex vivo genetically modified dendritic cell
would localize to an inflammatory lesion of the CNS, or to cross the blood
brain barrier, thereby enabling the delivery of therapeutic proteins to the
CNS." Br. 10.
For the reasons discussed above, we do not find these arguments
persuasive. Accordingly, we affirm the Examiner's obviousness rejection of
representative claim 13. Because they were argued in the same claim
grouping, claims 14 and 15 fall with claim 13. 37 C.F.R. § 41.37(c)(l)(iv).
Turning to representative claim 17, the process recited in that claim is
similar to that recited in claims 13 and 21, discussed above, except that
claim 1 7 does not limit the maturity of the dendritic cells, or require the cells
to cross the BBB. Br. 12. Claim 17 does, however, require the delivered
protein to include a protein translocation domain (PTD). Id. As noted
above, the Examiner cited Beerens as evidence that it would have been
obvious to include a PTD in the protein delivered by Fathman's methods,
because a PTD would have been expected to improve the therapeutic
efficacy of the delivered protein. Non-Final Act. 6.
Appellants "do not dispute that the use of protein transduction
domains (PTDs) to facilitate delivery of PTD-fused proteins across cell
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membranes into target cells was generally known in the art," nor do
Appellants contend that an ordinary artisan would have lacked motivation to
make the modification of Fathman's process posited by the Examiner. Br.
9-10. Rather, Appellants contend, an ordinary artisan lacked a reasonable
expectation of success because
PTDs, such as the HIV-derived Tat domain, can readily diffuse
across cell membranes and also typically contain a nuclear
localization sequence (NLS) to promote homing to the cell
nucleus. Both of these factors would be expected to interfere
with proper secretion of a PTD fusion protein following its
translation by a carrier cell, and this is why the vast majority of
existing PTD literature involves the use of purified PTD fusion
proteins from bacteria.
Id. at 10. Appellants do not, however, direct us to any specific persuasive
evidence supporting these factual assertions. We, therefore, do not find
these assertions persuasive. See In re Geisler, 116 F.3d at 1471 (argument
by counsel not an adequate substitute for evidence).
We acknowledge that the Beerens' s disclosure might be viewed as
somewhat prophetic:
PTDs, although at this moment mainly used for the
chemical or bacterial production of membrane permeable
proteins can become powerful tools for gene therapy. By
incorporating a PTD in the therapeutic gene product, the protein
produced in the transfected cell might be enabled to spread to
non-transfected cells, thereby creating an increased therapeutic
effect.
Beerens 18.
It is well settled, however, that"[ o ]bviousness does not require
absolute predictability of success .... For obviousness under § 103, all that
is required is a reasonable expectation of success." In re 0 'Farrell, 853
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F.2d 894, 903---04 (Fed. Cir. 1988); accord, Jn re Kubin, 561F.3d1351,
1359---61 (Fed. Cir. 2009). In the instant case, Appellants do not direct us to
specific persuasive evidence suggesting that an ordinary artisan lacked a
reasonable expectation that including a PTD in Fathman's delivered protein
would provide the increased therapeutic effect described in Beerens.
We acknowledge, but are not persuaded by, Appellants' contention
that, in contrast to the results seen in Exhibit A (Manley), Fathman's
methods were directed to delivery of proteins with an extracellular effect,
and, therefore, "one of skill in the art would not be motivated to utilize
sequences encoding a PTD fusion protein as there is no benefit to
intracellular activity in the prior art methods." Br. 10.
As noted above as to claim 13, and undisputed by Appellants, an
ordinary artisan would have been motivated to use a neurotrophin as the
delivered protein in Fathman's methods. As the Examiner found (Non-Final
Act. 7; Ans. 24), and Appellants do not dispute, neurotrophins were known
to act intracellularly as well as extracellularly. Accordingly, Appellants do
not persuade us that an ordinary artisan lacked a reason to include a PTD
domain when using neurotrophin as Fathman's delivered therapeutic protein.
To the contrary, as the Supreme Court explained in KSR Int 'l Co. v. Teleflex
Inc., 550 U.S. 398, 417 (2007), "if a technique has been used to improve one
device, and a person of ordinary skill in the art would recognize that it would
improve similar devices in the same way, using the technique is obvious
unless its actual application is beyond his or her skill."
In sum, for the reasons discussed, Appellants' arguments do not
persuade us that the evidence of record fails to support the Examiner's prima
facie case of obviousness as to representative claim 17. Because, for the
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Appeal2014-001993
Application 11/713,218
reasons discussed, Appellants' evidence as to secondary considerations of
nonobviousness is insufficient to outweigh the evidence of prima facie
obviousness, we affirm the Examiner's rejection of claim 17 under§ 103(a).
Because they were argued in the same grouping (Br. 3), claims 26 and 28
fall with claim 17. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
For the reasons discussed, we affirm the Examiner's rejection of
claims 13-15, 17, 20-24, and 26-33 under 35 U.S.C. § 103(a) for
obviousness over Fathman, Y ebenes, Beerens, Falcone, and Sagar.
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
19