Ex Parte Savola et al

Patent Trial and Appeal Board

Aug 23, 2013

10534091 (P.T.A.B. Aug. 23, 2013)

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.
10/534,091 05/06/2005 Juha-Matti Savola TUR-168 2654
32954 7590 08/23/2013
JAMES C. LYDON
100 DAINGERFIELD ROAD
SUITE 100
ALEXANDRIA, VA 22314
EXAMINER
GEMBEH, SHIRLEY V
ART UNIT PAPER NUMBER
1628
MAIL DATE DELIVERY MODE
08/23/2013 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 PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JUHA-MATTI SAVOLA, PAIVI JUUJARVI,
and JUKKA ILKKA1
__________

Appeal 2011-013247
Application 10/534,091
Technology Center 1600
__________

Before DONALD E. ADAMS, ERIC GRIMES, and JOHN G. NEW,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of administering fipamezole, which have been rejected for obviousness. We
have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1 Appellants identify the Real Party in Interest as Santhera Pharmaceuticals
(Switzerland) Ltd. (Appeal Br. 1).
App
App

2-yl)
adren
disor
claim
ingre

wher
R3 is
adm
muc
yl)-1
U.S.
6). T

2 Hu
atipa
3 Ka
eal 2011-0
lication 10
Accordin
-1H-imida
oceptors,
ders” (Spe
Claims 2
and read
23. A m
dient a su
e Y is -CH
H or lowe
administ
inistration
osa, and w
H-imidazo

The Exa
C. § 103(a
he Exami

upponen e
mezole, in
rjalainen e
13247
/534,091
ST
g to the S
zole) is a
and is “es
c. 1:17-22
3 and 25-
s as follow
ethod of ad
bstituted im
2- or -CO
r alkyl, or
ering said
, wherein o
herein said
le or its a
miner has
) as obvio
ner has als

t al., Bucc
humans,
t al., US 5
ATEMEN
pecificatio
highly sele
pecially va
).
33 are on a
s:
ministerin
idazole o
-, R1 is hal
an acid ad
formulatio
romucosa
active in
cid salt.
rejected cl
us based o
o rejected

al delivery
58 CLIN. P
,498,623, i
2
T OF TH
n, fipame
ctive and
luable in t
ppeal. Cl
g a formu
f formula
ogen or hy
dition salt
n to a pat
l administ
gredient is
aims 23, 2
n Huuppon
claims 23
of an α2-a
HARM. TH
ssued Mar
E CASE
zole (4-(2-
long-actin
he treatme
aim 23 is t
lation com
(I)
droxy, R2
thereof, c
ient by oro
ration is ab
4-(2-ethy
5-29, and
en2 and K
and 25-33
drenergic
ER. 506-51
. 12, 1996
ethyl-5-flu
g antagoni
nt of cogn
he only in
prising as

is H or ha
omprising
mucosal
sorption v
l-5-fluoro-
31-33 und
arjalainen
under 35
receptor a
1 (1995).
.
oroindan-
st of α2-
itive
dependent
an active
logen and

ia oral
indan-2-
er 35
3 (Answer
U.S.C.
ntagonist

,
Appeal 2011-013247
Application 10/534,091

3
§ 103(a) based on Huupponen, Karjalainen, and De Proost4 (Answer 8). The
same issue is dispositive for both rejections.
The Examiner finds that Huupponen discloses oromucosal
administration of atipamezole (Answer 6) and that Karjalainen discloses
fipamezole (id. at 7). The Examiner concludes that it would have been
obvious to substitute Karjalainen’s fipamezole for Huupponen’s atipamezole
because both compounds are α2 adrenergic receptor antagonists (id. at 8).
Appellants do not dispute that the cited references support a prima
facie case of obviousness, but argue that they have provided evidence of
unexpected results that rebuts the prima facie case (Appeal Br. 8).
Appellants point to the Specification’s working examples showing that oral
administration of fipamezole caused prolongation of the QT interval, a
potential cardiac safety issue, while oromucosal administration did not cause
the same effect (id. at 5-6).
We agree with Appellants that the evidence of unexpected results
outweighs the evidence supporting the prima facie case of obviousness. The
Specification provides a working example stating that when dogs were
orally dosed with fipamezole, “QT prolongation was observed when the
systemic concentration of fipamezole reached about 2000 ng/ml” (Spec. 9:8-
10) while buccal delivery of the same drug “showed no apparent changes in
ECG” even at systemic concentrations of 3300 ng/ml (id. at 9:20-23).
Crouch5 states that “much attention [recently] has . . . focused on
drugs that prolong the QT interval, potentially leading to malignant cardiac

4 De Proost, US 6,413,988 B1, issued July 2, 2002.
Appeal 2011-013247
Application 10/534,091

4
rhythm disturbances” (Crouch 881, right col.), and that several drugs have
been withdrawn from the market for this reason (id.). Crouch states that
“drug-induced prolongation of the QT interval is directly linked to
modification of the action potential. . . . Factors that impair rapid inward or
outward ion movement . . . widen the action potential, prolong
repolarization, and hence lengthen the QT interval.” (Id. at 882-883.)
Appellants have provided a declaration under 37 C.F.R. § 1.132 of
Jürg P. Seiler (dated Dec. 4, 2009). Dr. Seiler declared that oral
administration of fipamezole induced a dose-dependent prolongation of the
corrected QT interval6 (Seiler Declaration, ¶ 6) and “one of ordinary skill in
the art would have expected fipamezole to prolong the QTc interval” (id. at
¶ 7). Dr. Seiler declared that, “[i]n [his] opinion, the inventors’ discovery
that oromucosal administration of fipamezole does not result in QTc
prolongation could not have been predicted by one of ordinary skill in the
art” (id. at ¶ 12).
Dr. Seiler also declared that “there is no known case, in [his] opinion,
of any other compound for which a change in the mode of application has
eliminated a QTc prolongating effect” (id. at ¶ 13), and that the “fact that
oromucosal administration of fipamezole does not prolong the QTc interval,
despite an even greater initial amount of fipamezole in the circulating blood,
is thus surprising and unexpected” (id.).

5 Crouch et al., Clinical Relevance and Management of Drug-Related QT
Interval Prolongation, 23 PHARMACOTHERAPY 881-908 (2003).
6 The QT interval corrected for heart rate is referred to as the “QTc” interval.
See Declaration of Juhta-Matti Savola, dated Jan. 15, 2009, page 7.
Appeal 2011-013247
Application 10/534,091

5
Appellants’ Reply Brief acknowledges one other instance in which the
mode of administration affected the QTc interval; specifically, Crouch “lists
amiodarone as an antiarrhythmic which has a definite association with QT
prolongation, and discloses that intravenous administration affects QTc less
than oral administration” (Reply Br. 8). However, the Examiner has not
pointed to any other instance in which the mode of administration affects
whether a drug causes QT prolongation.
While the Examiner does not provide evidence that a person of
ordinary skill in the art would have expected oromucosal administration of
fipamezole to fix the QT prolongation problem caused by oral
administration of the drug, she argues that the prior art does not disclose any
problem with QT prolongation associated with the closely related drug
atipamezole (Answer 11-12).
This argument, however, does not adequately address the question of
why, after having found that oral administration (as suggested by
Karjalainen) of fipamezole causes QT prolongation (a problem apparently
discovered by Appellants), a skilled worker would have expected
oromucosal administration of the drug to solve that problem. As the
Examiner noted “Crouch . . . shows nothing supporting that QTC [sic]
depends on the administration route” (Answer 12). We agree that the
evidence of record provides no reason to expect that oromucosal delivery of
fipamezole would change its effect on the QT interval, compared to oral
delivery, despite an increased amount of the drug in systemic circulation.
The Examiner also reasons that “[o]ne of ordinary skill in the art
would necessarily expect that the properties of the drug bioavailability will
Appeal 2011-013247
Application 10/534,091

6
change based on the route of administration, therefore expectation of
properties is reasonably changed” (Answer 13). This reasoning, however,
also does not address the dispositive issue. A skilled worker might
reasonably expect that an increased systemic amount of fipamezole would
lead to an increased effect of the drug across the board, including an
increased QT prolongation, regardless of the mode of administration.
Appellants, however, have provided evidence that oromucosal
administration of fipamezole does not cause the QT prolongation that results
from oral administration of the same drug, despite higher systemic
concentrations of the drug.
The Examiner has not provided a reasonable basis, based on evidence
or sound technical reasoning, for expecting that oromucosal administration
of fipamezole would not cause prolongation of the QT interval despite
higher systemic concentrations than result from oral administration of the
same drug. We therefore conclude that the evidence of unexpected results
outweighs the evidence supporting the prima facie case of obviousness.
SUMMARY
We reverse both of the rejections on appeal.

REVERSED

cdc