Ex Parte Benedini et al

Patent Trial and Appeal Board

Sep 23, 2014

12492359 (P.T.A.B. Sep. 23, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte FRANCESCA BENEDINI, ENNIO ONGINI,
ANTONIO GUGLIETTA, DANIEL PALOP,
and MARTA PRINCEP
__________

Appeal 2012-004462
Application 12/492,359
Technology Center 1600
__________

Before TONI R. SCHEINER, DONALD E. ADAMS, and
LORA M. GREEN, Administrative Patent Judges.

PER CURIAM.

DECISION ON APPEAL
This is a decision on appeal1 under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 1-7. We have jurisdiction under 35 U.S.C.
§ 6(b).
We affirm.

1 The Real Parties in Interest are Nicox S.A. and Ferrer Internacional S.A.
(App. Br. 3).
Appeal 2012-004462
Application 12/492,359

2
STATEMENT OF THE CASE
The Specification discloses “nitrooxyderivatives of corticosteroids
having an improved pharmacological[ ] profile, better pharmacokinetic and
pharmacodynamic properties[,] and fewer adverse side effects” (Spec. 5:28-
33).
Claim 1 is as follows:
1. (11β-17-[(ethoxycarbonyl)oxy]-11-hydroxy-21-[1-oxo-[4-
(nitrooxymethyl) benzoxy] pregna-1,4-diene-3,20-dione.
The Examiner relies on the following evidence:
Del Soldato US 6,610,676 B1 Aug. 26, 2003
Del Soldato US 7,157,450 B2 Jan. 2, 2007
Del Soldato et al. WO 03/064443 A2 Aug. 7, 2003
F. Lawlor et al., Prednicarbate 0.25% ointment in the treatment of atopic
dermatitis: A vehicle-controlled double-blind study, 6 J. DERMATOL. TREAT.
233-235 (1995).

Reisch et al., Untersuchungen zur Photostabilitaet von Halometason und
Prednicarbat in kristallinem Zustand sowie Kristallstruktur von
Halometason, 62 PHOTOCHEMISCHE STUDIEN, LIEBIGS ANN. CHEM. 63-67
(1992) (reference cited in the Advisory Action of May 20, 2011).
In addition, Appellants rely on the following evidence:
Declaration of Francesco Impagnatiello, submitted Nov. 17, 2010, under the
provisions of 37 C.F.R. § 1.132 (“Decl.”).

The claims stand rejected as follows:
Claims 1-7 under 35 U.S.C. § 103(a) in view of Del Soldato ’443 and
Lawlor (Ans. 6-17);
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Application 12/492,359

3
Claims 1-7 under the doctrine of nonstatutory obviousness-type
double patenting over claims 1 and 2 of U.S. Patent No. 7,157,450 in view
of Del Soldato ’443 and Lawlor (Ans. 17-20); and
Claims 1-7 under the doctrine of nonstatutory obviousness-type
double patenting over claims 1 and 2 of U.S. Patent No. 6,610,676 in view
of Del Soldato ’443 and Lawlor (Ans. 20-24).
OBVIOUSNESS
Issue
The Examiner has rejected claims 1-7 under 35 U.S.C. § 103(a) as
obvious in view of Del Soldato ’443 and Lawlor (Ans. 6-17). As Appellants
do not provide separate arguments for the claims, we select claim 1 as
representative, and claims 2-7 will stand or fall accordingly. 37 C.F.R.
§ 41.37(c)(1)(vii).
The issue presented by this rejection is whether the Examiner has
established by a preponderance of the evidence that that the claimed
compound would have been obvious over the combined disclosures of Del
Sodato ’443 and Lawlor.
Findings of Fact
FF1. The Examiner finds, and Appellants do not dispute, that (11β-
17-[(ethoxycarbonyl)oxy]-11-hydroxy-21-[1-oxo-[4-(nitrooxymethyl)
benzoxy] pregna-1,4-diene-3,20-dione (“the claimed compound”) is a
prednicarbate derivative having the following structural formula:
App
App

(Ans
gene
with
(Ans
from
wher
Sold
“enc
the p
’443
eal 2012-0
lication 12
. 6; Spec.
FF2. De
ric formul
the follow
. 7; Del So
a group in
ein n3 is a
ato ’443 7
FF3. Th
ompasses
FF4. De
recursor o
9-10).
04462
/492,359
48).
l Soldato
a (I), B-X1
ing structu
ldato ’443
cluding th
n integer f
).
e Examine
the claime
l Soldato
f B” inclu
’443 disclo
-NO2” (An
re:
5), and X
e followin
rom 0 to 5
r finds tha
d species”
’443 disclo
de prednis
4
ses “a gen
s. 7), whe
1 is a biva
g structur
and n3' is
t Del Sold
(Ans. 7).
ses “prefe
olone and
us of com
rein “B is

lent linkin
e:
an intege
ato ’443’s
rred comp
prednicarb

pounds ha
a steroida
g group se

r from 1 to
generic f
ounds . . .
ate (Del S
ving
l radical”
lected
3 (Del
ormula I
wherein
oldato

App
App

pred
(Ans
pred
(Ans
pred
pred
the f
(Ans
eal 2012-0
lication 12
FF5. Th
nisolone h
. 10).
FF6. Th
nicarbate h
. 13).
FF7. Th
nisolone d
nisolone 2
ollowing s
. 11, 12; D
04462
/492,359
e Examine
as the follo
e Examine
as the foll
e Examine
erivative “
1-(4’-nitro
tructural f
el Soldato
r finds, an
wing stru
r further f
owing stru
r finds tha
within the
oxymethy
ormula:
’443 13,
5
d Appella
cture:
inds, and A
cture:
t Del Sold
scope of .
l)-benzoat
40).
nts do not

ppellants
ato ’443 d
. . formul
e” (“ Pred
dispute, th
do not di

iscloses a
a (I); spec
n-Ar-ONO

at
spute, that

ifically,
2”), with

App
App

comp
of de
dexa
vitro
deriv
ONO
Del
displ
displ
incre
eal 2012-0
lication 12
FF8. Ta
etitive bin
xamethas
methasone
Similarly
competiti
atives (pr
2) to displ
Soldato ’4
FF9. Th
acement o
acement .
ased in viv
04462
/492,359
ble 2 of D
ding assa
one, Dex-C
bound to
, Table 3
ve binding
edn-C4-ON
ace 3H-de
43 40, 47)
e Examine
f [the] fou
. . suggest
o potency
el Soldato
y measurin
4-ONO2 a
human mo
of Del Sol
assay me
O2; -Ar-O
xamethaso
. Table 3 i
r finds tha
r modified
s higher bi
” (Ans. 12
6
’443 prese
g the abil
nd Dex-A
nocytes (
dato ’443
asuring the
NO2; -pyp
ne bound
s reproduc
t Predn-A
prednisol
nding affi
).
nts the re
ity of two
r-ONO2, t
Del Soldat
presents th
ability of
er-ONO2;
to human
ed below:
r-ONO2 ex
one deriva
nity, whic
sults of an
nitrooxyde
o displace
o ’443 46)
e results o
four pred
and -pype
monocytes

hibited “t
tives” and
h in turn su
in vitro
rivatives
3H-
.
f an in
nisolone
r-C3-
(Ans. 12;

he highest
“[h]igher
ggests

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Application 12/492,359

7
FF10. The Examiner finds that one of ordinary skill in the art would
have recognized that “the -Ar-ONO2 modification (i.e., -X1-NO2 as defined
above) is responsible for this greatest increase in binding affinity, because
the test conditions are otherwise identical” (Ans. 12), and “would have been
motivated to select the group -X1-NO2 as defined above to achieve the
greatest increases in binding affinity (and in turn, increased in vivo
potency)” (id.).
FF11. Del Soldato ’443 teaches that “the connection between B and
X1 is . . . [generally] of ester or amidic type” and “for the formation of said
functional groups the synthesis methods described in the prior art are usable”
(Del Soldato ’443 17-18).
FF12. The Examiner further cites Reisch as evidence that “methods
of cleaving the terminal propionate group from prednicarbate to yield a free
21'-OH group were known in the art” (Ans. 25).
FF13. The Examiner finds that Del Soldato ’443 and Reisch
“establish that any additional synthetic steps required to modify the
preferred precursors of steroidal radical B, e.g., prednicarbate, to arrive at
compounds of formula B-X1-NO2 (e.g., the claimed compound) were within
the capability of an ordinarily skilled chemist” (Ans. 27).
FF14. The Examiner finds that Lawlor discloses that prednicarbate
ointment was known to be effective in treating atopic dermatitis at the time
of the invention (Ans. 16; Lawlor Abstract).
FF15. Appellants have provided the Declaration of Francesco
Impagnatiello. Mr. Impagnatiello explains that a compound’s “affinity for
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Application 12/492,359

8
the recombinant human glucocorticoid receptors [hGR] correlates with the
potency of the compound” (Decl. ¶ 3).
FF16. Mr. Impagnatiello declares that he supervised an experiment
conducted to compare the affinities of the claimed compound and Del
Soldato ’443’s Predn-Ar-ONO2 for hGR (Decl. ¶¶ 2, 3). The results of the
experiment are shown in the table reproduced below:

(Id. at ¶ 6.)
FF17. Mr. Impagnatiello declares that the claimed compound “was
found to be more potent” than Del Soldato ’443’s Predn-Ar-ONO2, as it
“inhibited 3H-dexamethasone specific binding from hGR to [a] greater
extent compared to [Predn-Ar-ONO2], in each of the tested concentrations”
(Decl. ¶ 6).
Principles of Law
The burden of demonstrating unexpected results rests on the party
asserting them. In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972).
In order for a showing of “unexpected results” to be
probative evidence of non-obviousness, it falls upon the
applicant to at least establish: (1) that there actually is a
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Application 12/492,359

9
difference between the results obtained through the claimed
invention and those of the prior art; and (2) that the difference
actually obtained would not have been expected by one skilled
in the art at the time of [the] invention.
In re Freeman, 474 F.2d 1318, 1324 (CCPA 1973) (internal citations
omitted).)
Analysis
The Examiner concludes that:
[I]t would have been prima facie obvious to one of ordinary
skill in the art at the time the invention was made to modify,
e.g., Predn-Ar-ONO2 by substituting prednisolone with
prednicarbate as the precursor to steroidal radical B as disclosed
by Del Soldato [’443] with a reasonable expectation of success,
because Del Soldato [’443] disclose[s] prednisolone and
prednicarbate as preferred precursors to steroidal radical B, and
the -Ar-ONO2 modification as the most effective group -X1-
NO2 for increasing binding affinity and in vivo potency. In
addition, the modified anti-inflammatory corticosteroids of Del
Soldato [’443] are disclosed to have the advantage of improved
tolerability and efficacy as compared to their precursor steroids;
and Lawlor et al. provides the motivation to select
prednicarbate as the precursor of steroidal radical B due to its
superior efficacy and fewer adverse events.
(Ans. 17.)
Appellants contend that one of ordinary skill in the art “would not be
motivated to arrive at the presently claimed invention based on the teachings
of Del Soldato [’443], because the claimed compound is not merely a known
base steroid with a 21-(4’-nitrooxymethyl)-benzoate group” like the cited
Del Soldato ’443 compounds (App. Br. 12), but “is a differently-modified
steroidal derivative” (id. at 13). Appellants argue “to achieve the claimed
App
App

comp
precu
(Id. a
comp
discl
i.e. t
wher
agre
a rea
obta
discu
meth
func
“an e
prop
(FF1
these
eal 2012-0
lication 12
osition, o
rsor comp
t 12).
That arg
ound that
oses a pre
he substitu
ein the mo
e with the
son to mo
in a predni
ssed abov
ods know
tional X1 g
xample of
ionate gro
2; Ans. 27
“referenc
04462
/492,359
ne would n
ound” as
ument is n
encompas
dnisolone
ent
dified pre
Examiner
dify predn
carbate de
e, the Exa
n in the art
roups (FF
one know
up (-C(O)C
). On this
es establis
eed to rep
shown bel
ot persuas
ses the co
derivative
dnisolone
that one o
icarbate w
rivative w
miner find
are suitab
11; Ans. 2
n method
H2CH3) t
record, w
h that any
10
lace the c
ow:
ive. Del S
mpound o
with a par
has enhan
f ordinary
ith this sam
ith enhanc
s that Del
le for synt
7), and fur
for cleavin
o yield a f
e agree wi
additional
ircled grou
oldato ’44
f claim 1 a
ticular sub

ced activit
skill in the
e substitu
ed activity
Soldato ’4
hesis of co
ther finds
g the pred
ree 21'-OH
th the Exa
synthetic
p of the st
3 disclose
nd specifi
stituent at
y (FF7-10
art would
ent in ord
. Moreov
43 disclos
mpounds
that Reisc
nicarbate
(hydroxy
miner’s fin
steps requ
eroidal
s a generic
cally
carbon 17
). We
have had
er to
er, as
es that
with the
h provides
terminal
) group”
ding that
ired to

,

Appeal 2012-004462
Application 12/492,359

11
modify the preferred precursors of steroidal radical B, e.g., prednicarbate, to
arrive at compounds of formula B-X1-NO2 (e.g., the claimed compound)
were within the capability of an ordinarily skilled chemist” (FF13; Ans. 27).
Appellants also argue that the claimed compound “was found to have
unexpected results not seen with [Del Soldato ’443’s Predn-Ar-ONO2]
compound” (App. Br. 8). Appellants contend that the Impagnatiello
Declaration compares the claimed compound with Del Soldato ’443’s Predn-
Ar-ONO2 compound and “the claimed compound was found to have greater
inhibition of 3H-dexamethasone specific binding at each of the tested
concentrations” (id. at 9). In particular, Appellants argue that at the 1 µM
concentration, “the claimed compound resulted in a 94% inhibition of 3H-
dexamethasone specific binding, compared to the 76% inhibition found
with” Predn-Ar-ONO2 (id.). Appellants argue further that, at the
concentration of 0.1 µM, the claimed compound resulted in 77% inhibition
of 3H-dexamethasone specific binding, compared to the 54% inhibition
found with Del Soldato ’443’s” Predn-Ar-ONO2 compound (id.).
Appellants argue that the Impagnatiello Declaration states that these results
show that the claimed compound “is more potent than Del Soldato [’443]’s”
Predn-Ar-ONO2 compound (id.), and that the cited references, “alone or in
combination, do not teach or suggest this unexpected result, and based on
the teachings of Del Soldato [’443] and Lawlor, one of ordinary skill in the
art would not have understood this benefit” (id.).
That argument is not persuasive. “Mere improvement in properties
does not always suffice to show unexpected results.” In re Soni, 54 F.3d
746, 751 (Fed. Cir. 1995). As discussed above, “in order for a showing of
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12
‘unexpected results’ to be probative evidence of non-obviousness, it falls
upon the applicant to at least establish . . . that the difference actually
obtained would not have been expected by one skilled in the art at the time
of [the] invention.” In re Freeman, 474 F.2d at 1324.
Here, however, nothing in the Specification indicates that the claimed
compound exhibits any properties that would have been unexpected to one
skilled in the art at the time of the invention. Moreover, Mr. Impagnatiello
merely states that the claimed compound “was found to be more potent”
than Predn-Ar-ONO2, and nowhere states that the observed difference would
have been unexpected. (Spec. 60-63; Decl. ¶ 6.) Thus, Appellants assertion
that the claimed compound “was found to have unexpected results (App. Br.
8) is not supported by the evidence relied on. Compare In re Geisler, 116
F.3d 1465, 1471 (Fed. Cir. 1997) (argument by counsel cannot be substituted
for actual evidence of unexpected results).
That being the case, Appellants’ proffered evidence is insufficient to
outweigh the Examiner’s evidence supporting a conclusion of obviousness.
Conclusion of Law
Having weighed the evidence proffered by the Examiner and
Appellants, we conclude that the Examiner has established by a
preponderance of the evidence that the claimed compound would have been
obvious over the combined disclosures of Del Sodato ’443 and Lawlor.
The rejection of claims 1-7 as obvious in view of Del Soldato ’443
and Lawlor is affirmed.
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13
DOUBLE PATENTING—THE ’450 PATENT
The Examiner has rejected claims 1-7 as unpatentable on the ground
of nonstatutory obviousness-type double patenting over claims 1 and 2 of
U.S. Patent No. 7,157,450 (“the ’450 patent”) in view of Del Soldato ’443
and Lawlor (Ans. 17-20).
Findings of Fact
FF18. Claim 1 of the ʼ450 patent reads, in part, as follows:
1. A compound of formula
B-R”-X1-NO2
or their esters or salts,
wherein B-R” has the following structure:

(ʼ450 patent, col. 14, ll. 44-60.)
FF19. Claim 2 of the ʼ450 patent is directed to a “[p]harmaceutical
composition comprising a compound according to claim 1 and a
pharmaceutically acceptable carrier” (id. at col. 16, ll. 40-42).
FF20. The Examiner finds that claim 1 of the ʼ450 patent recites
“compounds of formula B-R”-X1-NO2,” wherein B can be prednicarbate
(Ans. 17-18), and therefore ,“encompasses the species” of instant claim 1
(id. at 17).
Analysis
The Examiner concludes that it would have been obvious for one of
ordinary skill in the art “to select . . . [the claimed] species from the genus
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14
recited by reference claim 1 [of the ’450 patent] because Del Soldato
[’443]. . . claims the compound prednisolone 21-(4’-nitrooxy-methyl)-
benzoate, and teaches that the precursor steroid compound may be
prednisolone or prednicarbate” (Ans. 19).
Appellants reiterate the arguments made in connection with the
obviousness rejection over Del Soldato ’443 and Lawlor (App. Br. 14).
We conclude that the Examiner has established by a preponderance of
the evidence that that the claimed compound is not patentably distinct from
the subject matter of claims 1 and 2 of the ’450 patent, for the same reasons
discussed above in connection with the obviousness rejection over Del
Soldato ’443 and Lawlor.
The rejection of claims 1-7 as unpatentable on the ground of
nonstatutory obviousness-type double patenting over claims 1 and 2 of the
’450 patent is affirmed.
DOUBLE PATENTING—THE ’676 PATENT
The Examiner has rejected claims 1-7 as unpatentable on the ground
of nonstatutory obviousness-type double patenting over claims 1 and 2 of
U.S. Patent No. 6,610,676 (“the ʼ676 patent”) in view of Del Soldato [’443]
and Lawlor (Ans. 20-24).
Findings of Fact
FF21. Claim 1 of the ʼ676 patent reads, in part, as follows:
1. A method for treating arthritis, comprising
administering, to a patient in need thereof an effective amount
of a compound of formula
B-X1-NO2
or their esters or salts,
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15
wherein B has the following structure:

(ʼ676 patent, col. 14, ll. 42-60).
FF22. Claim 2 of the ʼ676 patent is directed to a “method according
to claim 1, wherein B is chosen from the group consisting of . . .
prednicarbate, prednisolone . . . wherein R” is as defined in claim 1” (id. at
col. 16, ll. 44-63).
FF23. The Examiner finds that the claims of the ʼ676 patent “are
drawn to methods of treating arthritis by administering a compound
belonging to a genus which encompasses the species recited by examined
claim 1” (Ans. 21).
FF24. The Examiner finds that the “reference claims recite
compounds of formula B-X1-NO2,” wherein B is prednicarbate (id.).
Analysis
The Examiner concludes that it “would have been predictable to one
of ordinary skill in the art to select . . . [the claimed] species from the genus
recited by the reference claims [of the ʼ676 patent] because Del Soldato
[’443] . . . claims the compound prednisolone 21-(4’-nitrooxy-methyl)-
benzoate, and teaches that the precursor steroid compound may be
prednisolone or prednicarbate” (Ans. 21).
Appellants reiterate the arguments made in connection with the
obviousness rejection over Del Soldato ’443 and Lawlor (App. Br. 15).
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16
We conclude that the Examiner has established by a preponderance of
the evidence that that the claimed compound is not patentably distinct from
the subject matter of claims 1 and 2 of the ’450 patent, for the same reasons
discussed above in connection with the obviousness rejection over Del
Soldato ’443 and Lawlor.
The rejection of claims 1-7 as unpatentable on the ground of
nonstatutory obviousness-type double patenting over claims 1 and 2 of the
’676 patent is affirmed.
SUMMARY
The rejection of claims 1-7 under 35 U.S.C. § 103(a) is affirmed.
The rejection of claims 1-7 under the doctrine of nonstatutory
obviousness-type double patenting over claims 1 and 2 of U.S. Patent No.
7,157,450 in view of Del Soldato ’443 and Lawlor is affirmed.
The rejection of claims 1-7 under the doctrine of nonstatutory
obviousness-type double patenting over claims 1 and 2 of U.S. Patent No.
6,610,676 in view of Del Soldato ’443 and Lawlor is affirmed.
TIME PERIOD FOR RESPONSE
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

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