Ex Parte Martin

Board of Patent Appeals and Interferences

Sep 28, 2010

11101287 (B.P.A.I. Sep. 28, 2010)

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.
11/101,287 04/07/2005 J. Tyler Martin 8325-0040 5737
20855 7590 09/28/2010
ROBINS & PASTERNAK
1731 EMBARCADERO ROAD
SUITE 230
PALO ALTO, CA 94303
EXAMINER
HAMA, JOANNE
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
09/28/2010 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte J. TYLER MARTIN
__________

Appeal 2010-004652
Application 11/101,287
Technology Center 1600
__________

Before DEMETRA J. MILLS, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL1
This appeal under 35 U.S.C. § 134 involves claims to methods of
treating diabetic neuropathy. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
Appeal 2010-004652
Application 11/101,287

2
STATEMENT OF THE CASE
Claims 1-3 are pending and on appeal (App. Br. 2). Because
Appellant did not argue the patentability of the claims separately, they stand
or fall together. See 37 C.F.R. § 41.37(c)(1)(vii).
Claim 1 is representative of the rejected claims, and reads as follows:
1. A method for treating a diabetic neuropathy, a spinal
cord injury or a crushed nerve in a subject, the method
comprising:
introducing a nucleic acid into a human subject,
wherein the nucleic acid encodes a polypeptide, wherein the
polypeptide comprises:
(i) a zinc finger DNA-binding domain that is
engineered to bind to a target site in the vascular endothelial
growth factor-A (VEGF-A) gene; and
(ii) a transcriptional activation domain; such that
the nucleic acid is expressed in one or more cells of the subject,
whereby the polypeptide binds to the target site and activates
transcription of the VEGF-A gene.

The sole rejection before us for review is the Examiner’s rejection of
claims 1-3 under 35 U.S.C. § 103(a) as obvious over Isner,2 Rebar,3 Hirai,4
McLaren,5 Beerli,6 Rebar II,7 and Koike8 (Ans. 3-5).9

2 Jeffrey M. Isner et al., CLINICAL PROTOCOL: VEGF Gene Transfer for
Diabetic Neuropathy, 12 HUMAN GENE THERAPY 1593-94 (2001).
3 U.S. Patent App. Publication, US 2003/0021776 A1 (published Jan. 30,
2003).
4 M. Hirai et al., Expression of Vascular Endothelial Growth Factors
(VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in Postmenopausal Uterine
Endometrial Carcinoma, 80 GYNECOLOGIC ONCOLOGY 181-188 (2001).
5 J. McLaren, Vascular endothelial growth factor and endometriotic
angiogenesis, 6 HUMAN REPRODUCTION UPDATE 45-55 (2000).
6 Roger R. Beerli et al., Positive and negative regulation of endogenous
genes by designed transcription factors, 97 PNAS 1495-1500 (2000).
Appeal 2010-004652
Application 11/101,287

3
OBVIOUSNESS
ISSUE
The Examiner cites Isner as disclosing a clinical trial proposal in
which a plasmid encoding VEGF-A was to be injected into patients to treat
diabetic neuropathy (Ans. 4). The Examiner concedes that, unlike claim 1,
Isner did not teach using a nucleic acid construct encoding a VEGF-A-
targeted zinc finger protein linked to a transcriptional activation domain as
the therapeutic agent (id.).
The Examiner cites Rebar as teaching the nucleic acid construct
recited in claim 1, and further notes that the construct was used to induce
angiogenesis (id.). Based on these teachings, the Examiner concludes that,
“[b]ecause both Isner et al. and Rebar et al. teach methods of increasing
VEGF-A expression and inducing angiogenesis, it would have been obvious

7 Edward J. Rebar et al., Induction of angiogenesis in a mouse model using
engineered transcription factors, 8 NATURE MEDICINE 1427-1432 (2002).
8 Hiromi Koike et al., Enhanced angiogenesis and improvement of
neuropathy by cotransfection of human hepatocyte growth factor and
prostacyclin synthase gene, 17 THE FASEB JOURNAL 779-781 (2003).

9 The Examiner appears to rely only on Isner, Rebar, and McLaren to show
prima facie obvious, and does not point to any disclosures in any of the other
cited references to support the prima facie case (see Ans. 4-5). Koike,
Beerli, and Rebar II are cited in the Examiner’s response to Appellant’s
arguments, apparently as rebuttal evidence (id. at 7, 13).
Hirai does not appear to be mentioned anywhere in the Examiner’s
Answer other than on page 3 (in the “Evidence Relied Upon” section and the
statement of rejection). According to Appellant, however, the Examiner
relied on Hirai in an Advisory Action to show that VEGF-A is the same
protein as VEGF-1 (App. Br. 3). Thus, the Examiner appears to have cited
Hirai in the Answer solely because it was relied on during earlier
prosecution.
Appeal 2010-004652
Application 11/101,287

4
to one skilled in the art to substitute the VEGF-A overexpression construct
taught by Isner et al. with that of the construct taught by Rebar” (id.).
Appellant contends that the Examiner has not “shown that VEGF-A
administration is a predictable, known element for treating diabetic
neuropathy, let alone that a zinc finger protein (ZFP) that modulates VEGF-
A expression treats this disease. Furthermore, the claimed invention solves a
long-felt need for treatment of diabetic neuropathy” (App. Br. 5). Appellant
also argues that the cited references do not teach or suggest all of the
claimed elements (Reply Br. 3-6).
In particular, Appellant urges that because Isner did not present any
actual data on the efficacy of the proposed treatment, Isner’s clinical trial
proposal would not have provided an ordinary artisan with a reasonable
expectation that administering a nucleic acid encoding VEGF-A, much less a
VEGF-A-stimulating zinc finger protein, would successfully treat diabetic
neuropathy (App. Br. 5-6; see also Reply Br. 6-7). Appellant urges that
none of the other cited references remedies Isner’s deficiency in this regard
(App. Br. 6-7; see also Reply Br. 7-8).
Moreover, Appellant argues, the apparent decision to conduct Isner’s
proposed clinical trial using a plasmid encoding VEGF-2, a different protein
than the originally proposed VEGF-A, and the failure of the VEGF-2
plasmid to successfully treat diabetic neuropathy, demonstrate that an
ordinary artisan lacked a reasonable expectation in treating diabetic
neuropathy with VEGF-A (App. Br. 8-9 (citing VEGF Gene Transfer
Appeal 2010-004652
Application 11/101,287

5
clinical trial webpage (App. Br. Appendix A);10 Corautus Genetics Press
Release of October 19, 2005 (Appendix B);11 Corautus Genetics Press
Release of October 10, 2006 (Appendix C);12 Corautus Genetics Press
Release of November 3, 2007 (Appendix D));13 see also Reply Br. 8-9).
Appellant argues that Rebar and Beerli would also have failed to
provide a reasonable expectation that VEGF-A-targeted zinc finger proteins
would treat diabetic neuropathy (App. Br. 9). Further, Appellant argues, the
evidence of record shows that the claimed methods meet a long-felt, but
unsolved need (id. at 10-11 (citing Sangamo BioSciences Press Release of
April 11, 2006 (App. Br. Appendix E));14 see also Reply Br. 9-11).
In view of the positions advanced by Appellant and the Examiner, the
issues with respect to this rejection are whether the evidence of record
supports the Examiner’s position that an ordinary artisan would have
considered it obvious that Rebar’s VEGF-A-stimulating nucleic acid

10 VEGF Gene Transfer for Diabetic Neuropathy,
http://clinicaltrials.gov/ct2/show/NCT00056290 (February 9, 2009).
11 Corautus Genetics Inc, (VEGF) Announces Collaboration And Licensing
Agreement For Treatment Of Diabetic Neuropathy With VEGF-2,
http://www.biospace.com/news_print.aspx?NewsEntityId=20849420
(October 19, 2005).
12 Corautus Genetics Announces Final Efficacy Results of GENASIS Phase
IIb Clinical Trial, http://www.prnewswire.com/cgi-
bin/stories.pl?ACCT=104&STORY=/www/story/10-10-20... (October 10,
2006).
13 Corautus Genetics Announces Redirection of Focus and Transition Of
Officers, http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=
104&STORY=/www/story/11-03-20... (November 3, 2007).
14 Diabetic Neuropathy Treatment Has Passed The First Clinical Trial,
http://www.medicalnewstoday.com/printerfriendlynews.php?newsid=41158
(April 11, 2006).
Appeal 2010-004652
Application 11/101,287

6
construct would successfully treat diabetic neuropathy when administered to
patients suffering from that disorder, and if so, whether the secondary indicia
of obviousness, in particular long-felt but unsolved need, are sufficient to
outweigh the evidence of prima facie obviousness.
FINDINGS OF FACT (“FF”)
Isner
1. Isner discloses:
Among diabetics, peripheral neuropathy is common and
ultimately accounts for significant morbidity. The ultimate
consequence of such sensory defects involving the lower
extremities may be foot ulceration initiated by trauma that is
inapparent to the patient. Such ulcerations often lead to lower
extremity amputation, a complication that is 15 times higher in
diabetic versus non- diabetic patients.

(Isner 1594.)
2. Isner discloses:
Preliminary clinical studies have demonstrated
improvement in signs and symptoms of sensory neuropathy in
patients with lower extremity vascular occlusive disease
following intramuscular injection of naked DNA encoding
vascular endothelial growth factor (VEGF). To determine if
such a strategy could be applied to diabetic patients, including
those without evidence of large vessel occlusive disease, we
investigated the hypothesis that experimental diabetic
neuropathy results from destruction of the vasa nervorum and
can be reversed by administration of an angiogenic growth
factor.

(Id.)
3. Isner discloses:
In two different animal models of diabetics, nerve blood flow
and the number of vasa nervorum were found to be markedly
Appeal 2010-004652
Application 11/101,287

7
attenuated resulting in severe peripheral neuropathy. In
contrast, following VEGF gene transfer, vascularity and blood
flow in nerves of treated animals were similar to those of non-
diabetic controls; constitutive overexpression of VEGF resulted
in restoration of large and small fiber peripheral nerve function.
These findings implicate microvascular disruption as the basis
for diabetic neuropathy and suggest that angiogenic growth
factors may constitute a novel treatment strategy for this
pernicious disorder.

(Id.)
4. Based on the preliminary results, Isner describes its proposed clinical
trial:
The protocol outlined in this Investigational New Drug
Application has been designed as a Phase I/II, single-site, dose
escalating, double-blind, placebo controlled study to evaluate
the safety and impact of phVEGF165 gene transfer on sensory
neuropathy in patients with diabetes with or without
macrovascular disease involving the lower extremities. . . . A
total of 192 patients will be recruited into two arms of the study
. . . .
(Id.)

5. It is undisputed that Isner’s phVEGF165 is a plasmid encoding the 165
amino acid isoform of VEGF-A which was to be injected into the foot, calf,
or thigh muscle of the affected extremity (see id. at 1593).

Rebar
6. Rebar discloses, as background to its invention, that “VEGF-A acts to
regulate the generation of new blood vessels during embryonic
vasculogenesis and then subsequently plays an important role in regulating
angiogenesis later in life” (Rebar [0008]).
Appeal 2010-004652
Application 11/101,287

8
7. Rebar discloses, in particular, that “the VEGF-A165 isoform is a 165
amino acid species and has a molecular weight of approximately 46 kD; this
isoform is the predominant molecular form found in normal cells and
tissues” (id. at [0009]).
8. Rebar further discloses that “VEGF-C is also referred to as VEGF-
related protein (hence VRP) or VEGF-2. The protein is roughly 30%
identical to the amino acid sequence of VEGF-A . . . . Although the protein
induces vascular permeability and promotes endothelial growth, it is less
potent than VEGF-A” (id. at [0012]).
9. Rebar describes its inventions as “methods and compositions for
regulating angiogenesis” (abstract).
Rebar’s methods use “various zinc finger proteins that bind to
particular target sites in one or more VEGF genes. Nucleic acids encoding
the zinc finger proteins are also disclosed. Methods for modulating the
expression of one or more VEGF genes with the zinc finger proteins and
nucleic acids are also disclosed” (id.).
10. Rebar discloses that its VEGF-targeted zinc finger proteins can act to
increase or repress angiogenesis, in the appropriate situation:
[W]ith angiogenesis, for example, by attaching an activation
domain to a ZFP [zinc finger protein] that binds to a target
sequence within a gene that affects angiogenesis, one can
enhance certain beneficial aspects associated with angiogenesis
(e.g., alleviation of ischemia). In contrast, if angiogenesis is
associated with harmful processes (e.g., delivery of blood
supply to tumors) one can reduce angiogenesis by using ZFPs
that are fused to a repressor. Hence, binding of this type of ZFP
to a gene involved in angiogenesis can significantly reduce
angiogenesis.

(Id. at [0021].)
Appeal 2010-004652
Application 11/101,287

9
11. Accordingly, where undesired angiogenesis contributes to a disease,
Rebar’s “ZFPs find use in preventing unwanted processes by repressing
vessel formation. Thus, for example, ZFPs can be used in treating diabetic
retinopathy, psoriasis, arthropathies and tumor growth” (id. at [0027]; see
also [0160]).
12. In contrast, Rebar discloses that its zinc finger proteins can also be
used to increase angiogenesis in conditions that warrant such treatment:
[T]he ZFPs can be used to activate expression of VEGF genes
to trigger beneficial angiogenesis in cell populations, both in
vitro and in vivo. Such activation can be utilized for example
to promote the formation of new blood vessels and capillaries
in treatments for ischemic conditions. For instance, the ZFPs
can be used to stimulate the development of collateral
circulation in individuals having any of a variety of arterial or
venous obstructions, such as individuals having arthrosclerosis.
The ZFPs can also be used to promote lymphogenesis (the
formation of lymphatic vessels) and myelopoiesis (the
formation of the tissue elements of bone marrow and/or types
of blood cells derived from bone marrow), and can be used to
regenerate blood vessels and tissue in wounds.

(Id. at [00159].)
13. Rebar discloses that its angiogenesis-modulating zinc finger proteins
can be introduced into cells and tissues by way of nucleic acid constructs
encoding the proteins:
Conventional viral and non-viral based gene transfer
methods can be used to introduce nucleic acids encoding the
present ZFPs in mammalian cells or target tissues. Such
methods can be used to administer nucleic acids encoding ZFPs
to cells in vitro. In some instances, the nucleic acids encoding
ZFPs are administered for in vivo or ex vivo gene therapy uses.

(Id. at [0253].)
Appeal 2010-004652
Application 11/101,287

10
14. Rebar thus discloses preparation of a nucleic acid construct encoding
a VEGF-A-targeted zinc finger protein linked to a viral transcription
activation domain (see id. at [0381]), and further discloses that injection of
that nucleic acid into a mouse resulted in stimulation of angiogenesis:
E. Induction of Angiogenesis
Subcutaneous injection of recombinant adenovirus
encoding VEGF regulating zinc finger proteins induces
angiogenesis in the mouse ear. To assess the ability of VEGF-
A regulating zinc finger proteins to induce angiogenesis in vivo
we injected recombinant adenovirus encoding VEGF-A
regulating ZFP's subcutaneously into the mouse ear. . . . Three
days and six days later the animals were visualized and digital
photographs of the ears were taken. As shown in FIGS. 18A-D,
adenovirus-mediated delivery of genes encoding VEGF-A
regulating ZFP's (VOP30A or VOP 32B) resulted in augmented
ear vascularization. These results were correlated with data
from formal vessel counts, as shown in FIG. 18E.

(Id. at [0414]-[0415].)
15. Rebar describes the advantages of its compositions:
[T]he designed ZFPs disclosed herein upregulate each
major splice variant of VEGF-A, in proportions similar to those
observed under physiological conditions (e.g., hypoxia). This
is important because recent studies suggest that proper isoform
balance is crucial for VEGF-A function. . . . . Currently, most
VEGF-A gene therapy trials involve the application of just a
single VEGF-A splice variant cDNA or protein isoform. Isner
et al. (1996) Lancet 348: 370-374; Esakof et al. (1999) Hum.
Gene Ther. 10: 2307-2314; Rosengart et al. (1999a) Ann.
Surg. 230: 466-470, discussion 470-472; Rosengart et al.
(1999b) Circulation 100: 468-474; Hendel et al. (2000)
Circulation 101: 118-121. It has been suggested that an ideal
gene therapy agent should be able to recapitulate natural ratios
of various different VEGF-A isoforms. Activation of VEGF-A
using the designed ZFPs disclosed herein therefore offers
Appeal 2010-004652
Application 11/101,287

11
advantages in this regard, providing key components of pro-
angiogenic gene therapy agents.

(Id. at [0361].)
VEGF Gene Transfer for Diabetic Neuropathy (App. Br. Appendix A)
16. This document, presented at the ClinicalTrials.gov website, describes
the following clinical trial:
This gene therapy study is being conducted to evaluate
intramuscular gene transfer using VEGF (Vascular Endothelial
Growth Factor) in patients with diabetic neuropathy in the legs.
This condition causes a decrease in feeling and sensation due to
diabetes. VEGF is DNA, or genetic material that is injected
into the muscles of the leg. Once in the leg, it has been shown
to cause new blood vessels to grow under a variety of
conditions.

(http://clinicaltrials.gov/ct2/show/NCT00056290 (February 9, 2009).)

Corautus Genetics Inc, (VEGF) Announces Collaboration And Licensing
Agreement For Treatment Of Diabetic Neuropathy With VEGF-2 (App. Br.
Appendix B)
17. This document describes a clinical trial in which “Corautus will
provide its proprietary vascular endothelial growth factor, VEGF-2 for
evaluation in the 64-patient, Phase I trial for treating diabetic neuropathy
now underway at CSEMC that is funded by a grant from the National
Institutes of Health (‘NIH’)” (http://www.biospace.com/news
_print.aspx?NewsEntityId=20849420 (October 19, 2005)).

Corautus Genetics Announces Final Efficacy Results of GENASIS Phase IIb
Clinical Trial (App. Br. Appendix C)
Appeal 2010-004652
Application 11/101,287

12
18. This document describes an announcement from Corautus Genetics
Inc. regarding termination of a clinical trial using the VEGF-2 gene as the
therapeutic agent:
Corautus Genetics Inc. (Nasdaq: VEGF), a clinical stage
biopharmaceutical company, announced today that the final
efficacy results from its GENASIS Phase IIb clinical trial did
not achieve a statistically significant difference from placebo in
any active dose group for the primary efficacy endpoint. . . . .
The data indicated considerable overlap in results between the
active and placebo groups for the secondary endpoints as well,
and no clear dose effect was seen.

(http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/
www/story/10-10-20... (October 10, 2006).)

Corautus Genetics Announces Redirection of Focus and Transition Of
Officers (App. Br. Appendix D)
19. This document describes an announcement from Corautus Genetics
explaining that it “does not plan to conduct further clinical trials for VEGF-2
for the treatment of cardiovascular and peripheral vascular disease and is
redirecting its focus to other life sciences opportunities”
(http://www.prnewswire.com/cgi-bin/stories.pl?ACCT= 104&STORY=
/www/story/11-03-20... (November 3, 2007)).

Medical News Today Article: “Diabetic Neuropathy Treatment Has Passed
The First Clinical Trial” (App. Br. Appendix E)
20. The Medical News Today article describes the following
announcement:
Appeal 2010-004652
Application 11/101,287

13
Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced
today positive results from the Phase 1 human clinical trial of
SB-509, the Company’s ZFP Therapeutic for the treatment of
diabetic neuropathy. Safety data and preliminary findings
regarding improvement of symptoms were presented at the 58th
Annual Meeting of the American Academy of Neurology in
San Diego by David Cornblath, M.D., Professor of Neurology
at The Johns Hopkins University School of Medicine and a
consultant to Sangamo. The results are the first publicly
reported data from a human clinical trial of a ZFP Therapeutic.

(http://www.medicalnewstoday.com/printerfriendlynews.php?newsid=41158
(April 11, 2006).)
21. The Medical News Today article describes SB-509, the therapeutic
agent, as follows:
SB-509 is administered as an injectable formulation of plasmid
DNA that encodes a zinc finger DNA- binding protein
transcription factor (ZFP TFTM), designed to upregulate the
VEGF-A gene. VEGF-A has been demonstrated to have direct
neurotrophic and neuroprotective properties. In preclinical
animal efficacy studies in a diabetic rat model, SB-509 has
proven effective in protecting motor and sensory nerve function
from disease-induced nerve damage.

(Id.)
22. The Medical News Today article discloses:
Dale Ando, M.D., Sangamo’s vice president of therapeutic
development and chief medical officer [stated] . . . “that a single
treatment of our ZFP Therapeutic resulted in improvements in
symptoms of pain, numbness and nerve testing in a number of
subjects. Most significantly, we did not observe any dose-
limiting toxicity, and we were able to treat subjects within the
pharmacologically effective dose range that we had
demonstrated to be efficacious in preclinical animal studies.
This is important, as previous therapies designed to halt or
reverse the nerve deterioration that is characteristics of this
Appeal 2010-004652
Application 11/101,287

14
condition had dose-limiting toxicities that prevented testing at
dosing proven to be effective and tolerated in animal studies.” .
. .
“Existing treatments for diabetic neuropathy are limited
to the use of antidepressants, analgesics or other agents for the
management of pain,” commented Mark Kipnes, M.D., a
principal clinical investigator for Sangamo and Endocrinologist
at the Diabetes and Glandular Disease Clinic in San Antonio,
Texas.

(Id.)
PRINCIPLES OF LAW
As the Supreme Court pointed out in KSR Int'l Co. v. Teleflex
Inc., 550 U.S. 398 (2007), when determining whether the prior art supplied a
reason for practicing the claimed subject matter, the analysis “need not seek
out precise teachings directed to the specific subject matter of the challenged
claim, for a court can take account of the inferences and creative steps that a
person of ordinary skill in the art would employ.” Id. at 418; see also id. at
421 (“A person of ordinary skill is . . . a person of ordinary creativity, not an
automaton.”).
The Court also reaffirmed that prima facie obviousness requires a
reasonable expectation of success:
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that it was obvious under § 103.

Id. at 421 (emphasis added).
Appeal 2010-004652
Application 11/101,287

15
The KSR Court further reaffirmed that secondary considerations of
non-obviousness, including long-felt but unsolved needs, should be weighed
in the ultimate obviousness evaluation. Id at 406-407.
ANALYSIS
Appellant’s arguments do not persuade us that the cited references
would have failed to provide an ordinary artisan with a reasonable
expectation that Rebar’s VEGF-A-stimulating nucleic acid construct would
successfully treat diabetic neuropathy when administered to patients
suffering from that disorder. Nor are we persuaded that the cited references
fail to suggest all of the claimed elements.
Regarding Isner, we first note that the reference appears to present
encouraging preliminary clinical, i.e. human, data in addition to the animal
data that prompted the clinical trial proposal (FF 2, 3). Moreover, we are not
persuaded that the document’s status as a clinical trial proposal undermines
its value as a teaching that would have provided an ordinary artisan with a
reasonable expectation that a plasmid encoding VEGF-A would successfully
treat diabetic neuropathy.
Rather, given that the preliminary data had so convinced the
investigators of success that they were willing to subject a relatively large
number of human patients to treatment with the VEGF-A-encoding plasmid
(FF 4, 5), we agree with the Examiner that Isner would have prompted an
ordinary artisan to treat diabetic neuropathy in humans using methods that
increased the amount of VEGF-A in the target tissue. Cf., In re Merck &
Co., Inc., 800 F.2d 1091, 1096-97 (Fed. Cir. 1986) (similarity of claim-
designated compound to prior art compound, combined with prior art
Appeal 2010-004652
Application 11/101,287

16
suggestion for testing in humans held sufficient to support prima facie case
of obviousness for claims directed to human therapeutic treatment).
We note, as Appellant argues, that Isner does not appear to describe
administering a nucleic acid construct encoding a VEGF-A-targeted zinc
finger protein, as recited in claim 1. However, as the Examiner points out,
Isner teaches that its plasmid was useful for treating diabetic neuropathy
because it stimulated angiogenesis (FF 3).
As the Examiner also points out, Rebar’s nucleic acid construct,
which encodes a VEGF-A-targeted zinc finger protein, stimulated
angiogenesis in an animal model (FF 14). Thus, we agree with the Examiner
that an ordinary artisan, advised by Isner that VEGF-A-generating,
angiogenesis-stimulating nucleic acids were useful for treating diabetic
neuropathy, and further advised by Rebar that nucleic acids encoding
VEGF-A-targeted zinc finger proteins stimulated angiogenesis in an animal
model by upregulating VEGF-A, would have been prompted to use Rebar’s
VEGF-A-activating nucleic acids to stimulate angiogenesis and thereby treat
diabetic neuropathy in humans.
We also note Rebar’s disclosure that certain prior art suggests that
proper VEGF-A isoform ratios are required to provide pro-angiogenic
therapy (FF 15). However, Rebar explicitly discloses that its VEGF-A-
targeted zinc finger proteins actually solve the isoform ratio problem (id.),
and further discloses that administering the same nucleic acid as that recited
in Appellant’s claim 1 actually stimulated angiogenesis in a mouse (FF 14).
Thus, given Rebar’s teachings and successful in vivo experiments, we
are not persuaded that concerns over VEGF-A isoform ratios would have
dissuaded an ordinary artisan from administering VEGF-A-activating
Appeal 2010-004652
Application 11/101,287

17
nucleic acid constructs to treat disorders disclosed as benefiting from
angiogenesis-stimulating therapy, such as diabetic neuropathy. Nor are we
persuaded that such concerns would have undermined the artisan’s
reasonable expectation of success, given Rebar’s positive in vivo results.
We also note Rebar’s disclosure that nucleic acid constructs encoding
VEGF-A-suppressing zinc finger proteins can be used to treat diabetic
retinopathy by suppressing, rather than activating, VEGF-A-generated
angiogenesis (FF 10, 11).
We acknowledge that diabetes underlies both diabetic retinopathy and
diabetic neuropathy. However, Appellant presents no direct evidence that
the specific symptomology of diabetic retinopathy would have been treated
in the same way as the claimed disorder, diabetic neuropathy. To the
contrary, Isner specifically teaches that angiogenesis-stimulating agents
should be used to treat diabetic neuropathy (FF 3).
Accordingly, the evidence of record does not suggest that an ordinary
artisan would have considered Rebar’s disclosure regarding suppressing
angiogenesis in diabetic retinopathy clearly relevant, much less predictive,
of whether stimulating angiogenesis in the manner taught by Rebar and Isner
would be useful in treating diabetic neuropathy. Rather, for the reasons
discussed, we agree with the Examiner that an ordinary artisan would have
been prompted by the cited references to treat diabetic neuropathy using
agents that stimulate angiogenesis, such as Rebar’s nucleic acid constructs
encoding VEGF-A-stimulating zinc finger proteins.
Regarding the various press releases urged by Appellant as showing
that an ordinary artisan would have lacked a reasonable expectation that the
claimed nucleic acid construct would have treated diabetic neuropathy, we
Appeal 2010-004652
Application 11/101,287

18
first note that every press release appears to have a publication date after the
April 7, 2005 filing date of the instant application (see App. Br. Appendices
A through E). Appellant has not adequately explained how or why these
post-filing disclosures demonstrate the state of the art at the time the instant
application was filed.
Nor are we persuaded that the various press releases demonstrate that
an ordinary artisan, prompted by Isner to administer angiogenesis-inducing
therapeutic agents to diabetic neuropathy patients, would have lacked a
reasonable expectation that Rebar’s angiogenesis-inducing nucleic acid
would be useful in treating diabetic neuropathy.
We note that the press release in Appendix A announces a clinical
trial, apparently of VEGF-A (FF 16), and that the press release in Appendix
B announces a clinical trial of VEGF-2 (FF 17), a very different protein than
VEGF-A (see FF 8). However, Appellant points to no specific language in
Appendix B’s press release mentioning any VEGF-A trial, nor does
Appellant point to any specific teaching in either press release suggesting
that any VEGF-A clinical trial failed to provide positive results. Thus, we
are not persuaded that Corautus’ decision to perform a clinical trial using
VEGF-2 would have suggested to an ordinary artisan that VEGF-A would
be inactive in treating diabetic neuropathy.
We also note Corautus’ decision, announced in the press releases in
Appendices C and D, to abandon clinical trials for VEGF-2 (FF 18, 19).
However, as noted above, VEGF-2 is a very different protein than the
VEGF-A of Isner and Rebar, and is, in fact, “less potent than VEGF-A”
(Rebar [0012] (FF 8)). Thus, we are not persuaded that Corautus’ decision
to abandon its VEGF-2 clinical trials would have undermined an ordinary
Appeal 2010-004652
Application 11/101,287

19
artisan’s reasonable expectation that VEGF-A-activating, angiogenesis-
stimulating, nucleic acids would be useful for treating diabetic neuropathy.
Nor are we persuaded that the secondary considerations of
non-obviousness outweigh the Examiner’s prima facie case. We
acknowledge Isner’s disclosure that diabetic neuropathy is a pernicious
disorder (FF 3), and also acknowledge Sangamo’s press release regarding
the positive results obtained using, apparently, a nucleic acid encompassed
by claim 1 (FF 20, 21). We further acknowledge the statements in the
Sangamo press release to the effect that the described agent is advantageous
when compared to other therapies (FF 22).
We are not persuaded, however, that this evidence shows that treating
diabetic neuropathy was an unmet need. Specifically, the Sangamo press
release concedes that “previous therapies” and “[e]xisting treatments” for the
disorder were available (FF 22).
Moreover, at the time Appellant’s application was filed, Isner had also
already met this need by teaching that diabetic neuropathy should be treated
using VEGF-A-generating, angiogenesis-stimulating, nucleic acids (FF 2-4).
Accordingly, we are not persuaded that the evidence proffered by Appellant
to show a long-felt but unmet need is sufficient to overcome the Examiner’s
prima facie case of obviousness.
In sum, for the reasons discussed, we agree with the Examiner that an
ordinary artisan would have been prompted by Isner and Rebar to administer
a nucleic acid construct encoding a VEGF-A-activating zinc finger protein
to human patients suffering from diabetic neuropathy. As discussed above,
we are not persuaded that the evidence regarding the secondary
considerations of non-obviousness is sufficient to outweigh the Examiner’s
Appeal 2010-004652
Application 11/101,287

20
prima facie case. Accordingly, we affirm the Examiner’s obviousness
rejection of claim 1, as well as claims 2 and 3, which fall with claim 1.
TIME PERIOD
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

alw

ROBINS & PASTERNAK
1731 EMBARCADERO ROAD
SUITE 230
PALO ALTO, CA 94303