THE UNIVERSITY OF BIRMINGHAM

Patent Trials and Appeals Board

Mar 23, 2021

2020004240 (P.T.A.B. Mar. 23, 2021)

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.
14/431,534 03/26/2015 Zsuzsanna Nagy UB-02-US 2010
50446 7590 03/23/2021
HOXIE & ASSOCIATES LLC
75 MAIN STREET
SUITE 203
MILLBURN, NJ 07041
EXAMINER
CHONG, YONG SOO
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
03/23/2021 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
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PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ZSUZSANNA NAGY and TIMOTHY BARRETT

Appeal 2020-004240
Application 14/431,534
Technology Center 1600
____________

Before ULRIKE W. JENKS, JOHN G. NEW, and RYAN H. FLAX,
Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims directed to a method of treating Wolfram
Syndrome-related neurodegeneration as obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42(a). Appellant identifies the real party-in-interest as
University of Birmingham, United Kingdom. Appeal Br. 2. Herein we refer
to the Final Office Action mailed March 25, 2019 (“Final Act.”), Appeal
Brief filed October 11, 2019 (“Appeal Br.”), Examiner’s Answer mailed
March 17, 2020 (“Ans.”), and Reply Brief filed May 18, 2020 (“Reply Br.”).
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BACKGROUND
According to the Specification, Wolfram Syndrome is a rare
autosomal recessive disorder characterized by neurodegeneration and
diabetes mellitus (caused by gene “WFS1”, which encodes WFS1 protein).
Spec. 1. The Specification acknowledges that the precise function of the
WFS1 protein is unknown, but “WFS1 protein deficiency affects the
unfolded protein response, intracellular ion homeostasis, cell cycle
progression, and granular acidification.” Id. In “WFS1 depleted neuronal
cells increased levels of p21 (CIP1/WAF1) is able to prevent neuronal
apoptosis and reverse the cell cycle disturbance caused by the WFS1
depletion.” Id. at 2.
According to the Specification, p21 is a protein that in humans is
primarily known from investigations into its role in cell cycle regulation. Id.
at 1. “Its clinical importance is associated mainly with cancer and resistance
against HIV infection.” Id. Experimental evidence shows that “WFS1
depleted cells that retain their p21 expression are protected against cell death
(apoptosis).” Id. at 3, 17 (“an increased p21 expression and/or functional
activity leads to a reduced neuronal apoptosis (i.e. reduced neurone cell
death) and correction of the cell cycle deficiency in WFS1 depleted cell
lines.”).
STATEMENT OF THE CASE
Claims 14 and 21–26 are on appeal, and can be found in the Claims
Appendix of the Appeal Brief. Claim 14 is representative of the claims on
appeal, and reads as follows:
14. A method of treating Wolfram Syndrome (WS)-related
neurodegeneration, comprising administering to a patient in need
thereof a compound selected from one or more of the group
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consisting of valproic acid and a salt thereof, wherein the (WS)-
related neurodegeneration is caused by or linked to loss of
function mutations in WFS1 genes, and wherein the compound
is administered at an amount effective to increase the expression,
increase the binding, increase the activation, increase the
accumulation and/or increase the induction of p21.
Appeal Br. 11 (Claims Appendix).
REJECTION
Appellant requests review of Examiner’s rejection of claims 14 and
21–26 under 35 U.S.C. § 103 as obvious over Glimcher2 in view of Shang3
and Kakiuchi.4
ANALYSIS
Examiner finds that Glimcher teaches “the treatment of
neurodegenerative disease” (abstract), for example Wolfram Syndrome,
where there is a mutation in the WFS1 protein of the ER membrane
(paragraph 0186). Ans. 4. “An example of an art recognized agent useful in
the treatment of a neurodegenerative disease associated with protein
aggregation is valproate (paragraph 0369).” Id. Examiner, however,
acknowledges that Glimcher does not “disclose a single embodiment of
treating Wolfram Syndrome (WS)-related neurodegeneration by
administering valproate.” Id.
Examiner looks to the teachings of Shang and Kakiuchi to make up
for this deficiency in Glimcher. Examiner relies on Shang for teaching that

2 Glimcher et al., US 2011/0142799 A1, published June 16, 2011
(“Glimcher”).
3 Shang et al., WO 2013/055834 A2, published Apr. 18, 2013 (“Shang”).
4 Kakiuchi et al., Valproate, a Mood Stabilizer, Induces WFS1 Expression
and Modulates Its Interaction with ER Stress Protein GRP94, 4 PLOS ONE
e4134 (1–6) (January 2009) (“Kakiuchi”).
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“WFS1 deficiency leads to activation of the unfolded protein response
(UPR) components, which coordinates protein-folding capacity with
transcriptional regulation and protein synthesis to mitigate ER stress.”
Ans. 4. Shang teaches that failure to deal with the UPR results in cell death
by apoptosis. Id. at 5; Shang ¶ 5. Therefore, Examiner finds that Shang
“confirms that Wolfram Syndrome (WS)-related neurodegeneration is
caused by [a] deficiency in the WFS1 gene, which leads to upregulation of
ER stress markers, and ultimately loss of cellular functionality or cell death
by apoptosis.” Ans. 5.
Examiner finds that Kakiuchi “teaches that valproate modulates the
ER stress response through regulation of WFS1, an important component for
mitigating ER stress. . . . [V]alproate induce expression of WFS1 mRNA
and activate the WFS1 promoter.” Ans. 5. Based on the combined teaching
of Glimcher, Shang, and Kakiuchi, Examiner concludes that one of ordinary
skill in art at the time the invention was made would have reasonably
expected to treat Wolfram Syndrome-related neurodegeneration in a patient
in need thereof by administering valproate. Id. at 6.
Appellant contends that (1) Examiner has not presented a prima facie
case of obviousness, (2) Examiner’s claim interpretation does not give the
preamble proper weight, and (3) Examiner ignores the “wherein clause” of
the claim. See generally Appeal Br. We address these arguments below.
According to Appellant, Glimcher teaches the use of valproate as a
secondary compound that functions as a mood stabilizer, but was not shown
to affect XBP-1 (a polypeptide), which is the focus of the Glimcher
reference. See Reply Br. 4; Appeal Br. 4. Appellant contends that Kakiuchi
does not provide motivation for one of ordinary skill in the art to administer
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valproate to a patient population that is homozygous for the defective WFS1
gene, because increasing expression of a defective protein would not be
expected to provide any benefit. See Reply Br. 6; Appeal Br. 7 (“increased
expression of a dysfunctional protein would not be expected to improve the
[Wolfram Syndrome] condition.” (emphasis removed)). In other words,
Appellant contends that there is no reasonable expectation of success in
administering valproate to a patient population that has Wolfram Syndrome
“caused by or linked to loss of function mutations in WFS1 genes” as
claimed, because Wolfram Syndrome is an autosomal recessive disorder
meaning that both forms of the gene are non-functional (the gene does not
express the protein, rather than functioning to express a dysfunctional
protein). Reply Br. 6; see Spec. 1.
On this record, we find that Appellant has the better position.
Glimcher teaches:
XBP-1 activation is known to control expression of several other
genes. . . . [Such as e]xpression of WFSl protein, an ER resident
membrane protein, is up-regulated by ER stress-inducing agents
and is a component of the IREI and PERK signaling pathways.
In addition, mutations in the gene encoding this protein are
responsible for Wolfram syndrome.
Glimcher ¶ 186. Glimcher suggests the administration of a compound that
modulates an XBP-1, IRE-I alpha, and/or EDEM signal transduction
pathway (e.g., by directly modulating XBP-1 activity) in conjunction with
another compound known in the art to be useful in treatment of a particular
condition or disease, such as, for example, mood-stabilizers (lithium,
valproate, carbamazepine). Id. ¶ 369. Glimcher teaches that XBP-1
deficiency protects against neurodegenerative disease associated with
protein aggregation. Id. ¶ 11. Glimcher teaches the use of inhibitory
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compounds, which inhibit the expression and/or activity of spliced XBP-1,
in the prevention and/or treatment of disorders associate with aberrant
protein aggregation. Id. ¶ 372. Glimcher provides a list of diseases that can
be treated with these XBP-1 inhibitors, and that list does not include
Wolfram Syndrome. Id. Glimcher does disclose that Wolfram Syndrome
exists and that it is caused by mutation in the WFS1 gene; however, the
reference does not connect administration of valproic acid with treating this
disease. Id. ¶ 186.
Shang teaches that “WFS1 deficiency leads to the activation of the
unfolded protein response (UPR) components, such as GRP78 (Bip) and
XBP-1 and decreases the ubiquitination of ATF6a. The unfolded protein
response coordinates protein-folding capacity with transcriptional regulation
and protein synthesis to mitigate ER stress.” Shang ¶ 5. Shang teaches that
Wolfram Syndrome is associated with intracellular ER stress. Id. ¶ 8. Shang
explains that when WFS1 levels are deficient this leads to activation of the
unfolded protein response, which includes increasing levels of XBP-1.
Shang ¶ 5.
The teachings of Glimcher and Shang, therefore, suggest keeping
XBP-1 expression at low levels in order to avoid protein aggregation leading
to neurodegeneration via cell death. At most, the combination Glimcher and
Shang would suggest that the ordinary artisan administer XBP-1 inhibitors
in order to prevent neurodegeneration, including in patients with Wolfram
Syndrome. Glimcher’s additional teaching of co-administering valproate
with XBP-1 modulators does not specifically address which conditions could
be treated in this manner (other than mood-instability). Glimcher ¶ 369. We
agree with Appellant that Glimcher’s long list of neurodegenerative diseases
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that could be treated with the XBP-1 inhibitors does not include Wolfram
Syndrome. See id. ¶ 372.
Examiner, however, does not rely solely on the combination of
Glimcher and Shang, Examiner also looks to Kakiuchi to provide motivation
to administer valproate to patients. Kakiuchi teaches that “[v]alproate
activates the WFS1 promoter and induces WFS1 mRNA expression in
neuronal cells. Under normal conditions, WFS1 forms a complex with
GRP94 and valproate enhances its dissociation from GRP94” allowing for
higher expression. Kakiuchi 2. Figure 4 of Kakiuchi, reproduced below,
provides model of action of valproate and XBP-1 in regulating WFS1.

Figure 4, shows a model of action of valproate on the regulation of WFS1.
Id. at 5. Specifically, Kakiuchi suggests that transcription factor XBP-1 as
well as valproate activates the WFS1 promoter in neuronal cells. Id. 3
(“Collectively, these results indicate that valproate can strongly activate the
WFS1 promoter together with XBP-1 specifically in neuronal cells.”). Thus,
Kakiuchi suggests that both XBP-1 and valproate activate the same WFS1
promoter leading to an increase in WFS1 protein expression.
Appellant contends that, at best, Kakiuchi teaches that valproate can
increase expression of WFS1 in a heterozygous patient population, i.e. those
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suffering from bipolar disorder. Reply Br. 5. However, this patient
population has one functional gene and increasing expression using
valproate would increase both functional and non-functional proteins in this
patient population. Id. Patients with Wolfram Syndrome only carry defective
WFS1 genes. Appellant contends that increasing the expression of a
dysfunctional protein from a defective gene, however, would not be
expected to improve the Wolfram Syndrome condition, therefore, there is no
reason to administer valproate to this patient population. See Appeal Br. 7;
Reply Br. 5.
We agree with Appellant, Kakiuchi teaches that valproate activates
the WFS1, and Examiner has not articulated why increasing the expression
of a defective protein would reasonably result in a method of treating
Wolfram Syndrome-related neurodegeneration. In other words, having more
protein that does not function would result in increased intracellular ER
stress, which then leads to an increase in XBP-1 levels, a condition which is
implicated in the development neurodegenerative disease. See Shang ¶ 8;
Glimcher ¶ 11 (“XBP-1 deficiency in motor neurons in an animal model of
neurodegenerative disease associated with protein aggregation, increases the
life span of the animals and reduces motor neuron apoptosis.”). The record,
therefore, supports the position that one of ordinary skill in the art would
want to reduce XBP-1 expression in order to reduce neurodegeneration.
Glimcher ¶ 372.
Kakuichi, however, teaches that both XBP-1 and valproate activate
the WFS1 promoter. Activation of the gene leading to the production of a
dysfunctional WFS1 protein would further increase the levels XBP-1 in
response to ER stress. Shang ¶ 5. Adding valproate into this cycle would
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lead to the accumulation of more dysfunctional WFS1 protein in the system.
See Kakiuchi 5 (Figure 4). Because valproate and XBP-1 activate the same
promoter on the WFS1 gene this would lead to the accumulation of more
dysfunctional WFS1 protein in patients having Wolfram Syndrome resulting
in increased ER stress because the cells still experience this as a WFS1
deficiency. Therefore, based on the teaching of Kakiuchi and Shang one of
ordinary skill in the art would not be motivated to add valproate to a system,
because to do so would increase the level of dysfunctional WFS1 protein,
leading to ER stress. See Kakiuchi 5 (Figure 4); Shang ¶ 5.
Taken together, the combination Glimcher, Shang, and Kakiuchi does
not support Examiner’s conclusion that the claims are obvious, because
Examiner has not articulated why in the Wolfram Syndrome patient
population one of ordinary skill in the art would want to simultaneously
decrease XBP-1 while administering valproate. Here, both XBP-1 and
valproate are known to activate the WFS1 promoter leading to the
production of dysfunctional protein which is bad. Accordingly, we agree
with Appellant that Examiner has not provided a sufficiently articulated
rationale based on the teachings in the art that suggests administering
valproate to patients suffering from Wolfram Syndrome.
Appellant also contends that Examiner is not giving weight to the
preamble of “treating Wolfram Syndrome (WS)-related neurodegeneration”
and instead is solely focusing on similarity in the prior art based on the
“neurodegeneration” aspect of the claim preamble. Appellant contends that
in this case the preamble should be treated like a claim limitation because
the phrase “to a patient in need thereof” would otherwise not have proper
antecedent basis in the body of the claim. See Appeal Br. 8 (citing Jansen v.
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Rexall Sundown, 342 F.3d 1329, 1333-34 (Fed. Cir. 2003); Rapoport v.
Dement, 254 F.3d 1053, 1060-61 (Fed. Cir. 2001)). Our reviewing court in
both Rapoport and Jansen considering similarly structured claims
determined that these claims should be interpreted to require that the method
be practiced with the “intent to achieve the objective stated in the preamble.”
Jansen, 342 F.3d 1333. “The preamble is therefore not merely a statement of
effect that may or may not be desired or appreciated. Rather, it is a statement
of the intentional purpose for which the method must be performed.” Id.
Applying the same claim interpretation to the present claims requires
that the combination of references suggests treating neurodegeneration in
patients having Wolfram Syndrome. Given this construction, we agree with
Appellant that the combination of references does not disclose treating
patients having Wolfram Syndrome-related neurodegeneration with
valproate. See e.g. Glimcher ¶ 372 (providing a list of neurodegenerative
disorder that can be treated with the inhibitors - Wolfram Syndrome is
notably missing from that list).
Appellant also contends that Examiner is not giving weight to the last
clause of the claim: “wherein the compound is administered at an amount
effective to increase the expression, increase the binding, increase the
activation, increase the accumulation and/or increase the induction of p21.”
Appeal Br. 7–8 (citing In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970);
CFMT, Inc. v. Yieldup Intern. Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003))
(citing In re Royka, 490 F.2d 981, 985 (CCPA 1974)); MPEP 2143.03).
The issue is whether the combination of references as applied by
Examiner treats the same patient population — those suffering from
neurodegeneration due to Wolfram Syndrome — with valproate in order to
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reach the conclusion that the effect on p21 would be expected to be the
same. See Ans. 6. Examiner reasons that “the cited prior art references teach
the same patient population and the same active agent, it is obvious to one of
ordinary skill in the art that the same mechanism of action [on p21] will
obviously occur.” Ans. 8. Examiner’s position, therefore, is if there is a
reason to administer valproate to the same patient population, those suffering
from neurodegeneration, then the mode of action on the p21 would occur
regardless of whether the art recognizes this compound to be a target of
action. Here, the problem is that the art does not suggest administering
valproate to the claimed patient population.
Kakiuchi suggests that both valproate and XBP-1 activate the same
promoter leading to an increase WFS1 expression. See Kakiuchi 5 (Figure
4). The bipolar patient population of Kakiuchi is a different patient
population from those suffering from Wolfram Syndrome. Here, there is no
evidence in the record that Kakiuchi’s bipolar patient population also suffer
from neurodegeneration, let alone neurodegeneration due to Wolfram
Syndrome. Thus, administration of valproate to a bipolar patient population
does not teach treating patients having Wolfram Syndrome. It also does not
explain why one of ordinary skill in the art would want to decrease
transcription factor XBP-1 that interacts with the same WFS1 promoter as
valproate while simultaneously administering a compound — valproate —
that activates transcription from the same promoter. Because Examiner has
not established that the art suggests treating the same patient population with
the same compound, we do not need to address whether the mode of action
is expected to be the same.
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We conclude that the preponderance of the evidence of record does
not support Examiner’s conclusion that the combination of Glimcher, Shang,
and Kakiuchi teaches a method having all the limitations of claims 14 and
21–26. We therefore reverse the rejection under 35 U.S.C. § 103(a) that
relies on the teachings of Glimcher, Shang, and Kakiuchi.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Basis/References Affirmed Reversed
14, 21–26 103 Glimcher, Shang,
Kakiuchi
14, 21–26

REVERSED