Ex Parte Torrens et al

Patent Trial and Appeal Board

Jul 15, 2013

11457720 (P.T.A.B. Jul. 15, 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.
11/457,720 07/14/2006 Antoni TORRENS 006444.00047 (ET0043) 7610
22907 7590 07/15/2013
BANNER & WITCOFF, LTD.
1100 13th STREET, N.W.
SUITE 1200
WASHINGTON, DC 20005-4051
EXAMINER
HAVLIN, ROBERT H
ART UNIT PAPER NUMBER
1626
MAIL DATE DELIVERY MODE
07/15/2013 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 ANTONI TORRENS, HELMUT BUSCHMANN,
JORDI QUINTANA, SUSANA YENES, and JOSEP MAS
__________

Appeal 2011-012659
Application 11/457,720
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
JOHN G. NEW, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal
1
under 35 U.S.C. § 134 involving claims to a
substituted pyrazoline compound. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We vacate and enter
a New Grounds of Rejection.

1
Appellants have identified the Real Party in Interest as
Laboratorios del Dr. Esteve S.A. (see App. Br. 4).
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Statement of the Case
Background
The Specification teaches compounds which “have a high affinity for
cannabinoid receptors, particularly for the CB1-receptor, and that they act as
modulators e.g. antagonists, inverse agonists or agonists on these receptors”
(Spec. 2, ll. 25-27).
The Claims
Claims 1, 17, 21-27, and 42-44 are on appeal. Claim 1 is
representative and is reproduced in the Appellants‟ Claims Appendix.
The Issues

A. The Examiner rejected claims 1, 17, 21-27, and 42-44 under 35
U.S.C. § 103(a) as obvious over Barth
2
and Lange „179
3
(Ans. 7-18).
B. The Examiner rejected claims 1, 17, 21-27, and 42-44 under 35
U.S.C. § 103(a) as obvious over Lange „04
4
and Lange „05
5
(Ans. 22-30).
We vacate the Examiner‟s rejections and enter the following new
ground of rejection in order to combine all of the relevant teachings from the
cited prior art into a single obviousness rejection.

2
Barth et al., US 5,624,941, issued Apr. 29, 1997.
3
Lange et al., US 2005/0171179 A1, published Aug. 4, 2005.
4
Lange et al., Synthesis, Biological Properties, and Molecular Modeling
Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selective CB1
Cannabinoid Receptor Antagonists, 47 J. MED. CHEM. 627-643 (2004).
5
Lange et al., Bioisosteric Replacements of the Pyrazole Moiety of
Rimonabant: Synthesis, Biological Properties, and Molecular Modeling
Investigations of Thiazoles, Triazoles, and Imidazoles as Potent and
Selective CB1 Cannabinoid Receptor Antagonists, 48 J. MED. CHEM. 1823-
1838 (2005).
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New Grounds of Rejection
Under the provisions of 37 C.F.R. § 41.50(b), we enter the following
new grounds of rejection.
Claims 1, 17, 21-27, and 42-44 are rejected under 35 U.S.C. § 103(a)
as obvious over Barth, Lange „179, and Lange ‟05.
The issues are:
(i) Does the evidence of record support a prima facie case of
obviousness for the elected species?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Appellants elected cis-5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid
azepan-1-ylamide hydrochloride, with the structure reproduced below:

(see Response to Election/Restriction, filed May 11, 2007; claim 17,
compound 3).
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2. Barth teaches the following compound (Example #64):

Barth teaches that this compound is “N-piperidino-5-(4-chlorophenyl)-1-
(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide), or one of its
pharmaceutically acceptable salts” (Barth, col. 26, ll. 42-44).
2. Barth teaches that:
In particular, the compound of formula (I) in which
g2,g3, g5, g6, w3, w5 and w6 are hydrogen, w2 and w4 are a
chlorine atom, R4 is methyl, X is a direct bond and R is 1-
piperidinylamino (namely N-piperidino-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide),
or one of its pharmaceutically acceptable salts, exhibits a
very good affinity for the central cannabinoid receptors. This
compound is a potent and selective antagonist of the central
cannabinoid receptors and has a Ki of about 2 nM. It is from
500 to 1000 times more active on the central receptor as on
the peripheral receptor; it is also active upon oral
administration and penetrates the blood-brain barrier. The
good penetration of this compound in the central nervous
system as well as its antagonist character are confirmed by
the results obtained with the model of the antagonism of
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hypothermia induced by an agonist of cannabinoid
receptors. Especially, this compound antagonizes the
hypothermia induced by WIN 55 212-2 in mice with an
ED50 of 0.3 mg/kg i.p. and 0.4 mg/kg per os. In this test . . .
the above compound exerted its action for 8 to 10 hours after
oral administration of a dose of 3 mg/kg.

(Barth, col. 26, ll. 39-61.)
3. Barth teaches that the “compounds of formula (I) can be
isolated in the form of one of their salts, where appropriate, for example the
hydrochloride or the oxalate” (Barth, col. 20, ll. 19-21).
4. Lange „179 teaches compounds, identified as compounds 2 and
3 in the text (and compound 2 was erroneously listed as compound 1 in the
figure legend) which are reproduced below:

“Compound 2: N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-
dichloropheny1)-4,5 -dihydro-( lH)-pyrazole-3-carboxamide” (Lange 7 ¶
0071).
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“Compound 3: N-(Piperidin-1-yl)-1-(2,4-dichloropheny 1)-5 -phenyl-4,5 -
dihydro-( 1H)-pyrazole-3-carboxamide” (Lange 7 ¶ 0072).
5. Lange „179 teaches “that potent and selective antagonism or
inverse agonism of cannabinoid CB1 receptors is present in the novel 1,3,5-
trisubstituted 4,5-dihydro-1H-pyrazole derivatives of the formula (I)”
(Lange ‟179 1 ¶ 0003).
6. Table I of Lange „179 is reproduced below:

Table I shows “Cannabinoid receptor affinity and functional in vitro data
data” (Lange „179 10 ¶ 0094).
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7. Lange ‟05 teaches that:
Bioisosteric replacement forms a rational medicinal
chemistry approach for the discovery of new leads or series,
based on existing key ligands. The three-dimensional
structures of thiazoles, triazoles, and imidazoles maintain a
high similarity to that of the pyrazole. As a consequence
they can be regarded as isosteres thereof and have been
applied in order to discover pyrazole bioisosteres.

(Lange ‟05 1823, col. 2.)
8. Lange ‟05 teaches the structure of compound 62, reproduced
below:

(Lange ‟05 1830, col. 2).
9. Lange ‟05 teaches a compound 69R as reproduced below:

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10. Lange ‟05 teaches that “[s]ubstitution of the piperidinyl group
in 62 by . . . the corresponding seven-membered azepanyl group containing
69 . . . elicited clearly decreased affinit[y]” (Lange ‟05 1826, col. 2).
11. Lange ‟05 teaches that “[f]ive- to seven-membered cycloalkyl
groups (72-74) were also good receptor binders” (Lange ‟05 1827, col. 1).
12. Lange ‟05 teaches that “[m]olecular modeling studies revealed
a close three-dimensional structural overlap between the key compound 62
and the known CB1 receptor antagonist rimonabant” (Lange ‟05 1830, col.
1).
13. Table 1 of Lange ‟05 is reproduced below:

“Table 1. In Vitro Results of Compounds 13, 14, 27, 28, 60-80, 82, 87, 91-
93, 97, and 103” (Lange ‟05 1827).
14. Lange ‟05 teaches that the “5-methylated imidazole 62 was
found very potent in both assays, indicating that a methyl group constitutes
the optimal substituent in this series. Its potent in vivo activity is in line with
that of 1 thereby again corroborating the bioisosteric concept” (Lange ‟05,
1828, col. 1).
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15. Lange ‟05 teaches that the “presence of more bulky bicyclic
moieties such as in 71, 77, and 78 was well tolerated.” (Lange ‟05 1826, col.
2.)
Principles of Law
The analysis for obviousness of chemical variations is based on a
long line of Federal Circuit and CCPA decisions. In In re Dillon, the
Federal Circuit noted:
In brief, the cases establish that if an examiner
considers that he has found prior art close enough to the
claimed invention to give one skilled in the relevant
chemical art the motivation to make close relatives
(homologs, analogs, isomers, etc.) of the prior art
compound(s), then there arises what has been called a
presumption of obviousness or a prima facie case of
obviousness. In re Henze, 181 F.2d 196, 37 CCPA 1009, 85
USPQ 261 (CCPA 1950); In re Hass, 141 F.2d 122, 127,
130, 31 CCPA 895, 60 USPQ 544, 548, 552 (CCPA 1944).
The burden then shifts to the applicant, who then can present
arguments and/or data to show that what appears to be
obvious, is not in fact that, when the invention is looked at
as a whole. In re Papesch, 315 F.2d 381, 50 CCPA 1084,
137 USPQ 43 (CCPA 1963). The cases of Hass and Henze
established the rule that, unless an applicant showed that the
prior art compound lacked the property or advantage
asserted for the claimed compound, the presumption of
unpatentability was not overcome.

In re Dillon, 919 F.2d 688, 696 (Fed. Cir. 1990).

Analysis
Prima facie case
The current facts fall squarely within the ambit of Dillon, Henze
and Hass. The elected species of claim 1 differs from compound 69 of
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Lange ‟05 in two ways. Lange ‟05 has an imidazole ring in the place of
the pyrazoline ring and the location of the methyl group on the central
ring differs (FF 1, 10). Both compounds bind to the cannabinoid receptor
(FF 13; Spec. 2, ll. 4-6).
The elected species of claim 1 (FF 1) also differs from compound
64 of Barth (FF 2) in two ways. The elected species has a pyrazoline ring
in the place of the pyrazole ring of Barth, representing a single bond, and
the elected species has the seven membered azepan ring in the place of a
six membered piperidino ring in Barth (FF 2). Both compounds bind to
the cannabinoid receptor (FF 2; Spec. 2, ll. 4-6).
Lange „179 teaches a compound 3 (FF 4) which has cannabinoid
receptor binding activity (FF 5) which also differs from the elected
species in three ways. Compound 3 of Lange „179 lacks the 4-methyl
group on the pyrazoline ring present in the elected species, and
compound 3 of Lang „179 lacks the 4-chloro group on the 5-phenyl ring
in the elected species, and and compound 3 of Lange „179 has a six
membered piperidino ring in the place of the seven membered azepan
ring in the elected species (FF 1, 4). Compound 2, not tested by Lange
„179, is actually more similar to the elected species, and differs in only
two ways, lacking the 4-methyl group and the azepan group, but having
the 4-chloro group. We note that Lange 179‟s compounds 2 and 3 would
reasonably anticipate claim 1, though they do not anticipate the elected
species.
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The ordinary artisan would have reasonably substituted the pyrazoline
ring of Lange „179 for the pyrazole ring of Barth and the imidazole ring of
Lange ‟05 since Lange ‟05 teaches that:
Bioisosteric replacement forms a rational medicinal
chemistry approach for the discovery of new leads or series,
based on existing key ligands. The three-dimensional
structures of thiazoles, triazoles, and imidazoles maintain a
high similarity to that of the pyrazole. As a consequence
they can be regarded as isosteres thereof and have been
applied in order to discover pyrazole bioisosteres.

(Lange ‟05 1823, col. 2; FF 7.) That is, Lange ‟05 teaches that in rational
drug design, substituting groups such as imidazoles and pyrazoles with the
structurally similar pyrazoline group would have been an obvious selection
(FF 7).
Further, the ordinary artisan would have been motivated to place the
methyl group on the pyrazoline group of Lange „179 at the 4-position since
Lange ‟05 teaches that “the “5-methylated imidazole 62 was found very
potent in both assays, indicating that a methyl group constitutes the optimal
substituent in this series. Its potent in vivo activity is in line with that of 1
thereby again corroborating the bioisosteric concept” (Lange ‟05 1828, col.
1; FF 14). Just like the 4-position on the pyrazoline group of Lange „179, the
5-methyl imidazole position in Lange ‟05 is placed on the only carbon of the
5 membered ring not linked to another substituent (see FF 2, 4, 8, 9).
All of these compounds share the same activity, binding to the
cannabinoid receptor (FF 2, 5, 13; Spec. 2, ll. 4-6). Activity of the claimed
and prior art compound plays a role in the obviousness inquiry. See Dillon,
919 F.2d at 696 (“Some of the cited cases also contained language
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suggesting that the fact that the claimed and the prior art compounds
possessed the same activity were added factors in the establishment of the
prima facie case.”). Because the prior art compounds all share the
cannabinoid receptor binding activity of the elected species, this common
function serves to further support the prima facie obviousness determination
(see FF 2, 5, 13).
Appellants contend that “[o]ne skilled in the art would therefore not
have reasonably expected that modifying (i) the degree of saturation of the
core ring, in the compounds disclosed in Barth, or (ii) the substitution
pattern about this ring, in the compounds disclosed in Lange „179, would
conserve cannabinoid-CB1 receptor inhibition activity” (App. Br. 15).
We are not persuaded. Lange „179 teaches that when the degree of
saturation of the core ring is changed from pyrazole to pyrazoline, the
reduction of a bond, the resulting compounds maintain cannabinoid-CB1
receptor inhibition activity (FF 4). In addition, Lange ‟05 teaches that
inclusion of a methyl on the imidazole ring resulted in optimal activity (FF
14) while Barth showed that inclusion of a methyl on the pyrazole ring
resulted in a “potent and selective antagonist of the central cannabinoid
receptors” (Barth, col. 26, ll. 46-47; FF 2). Thus, the ordinary artisan would
reasonably have expected the incorporation of a methyl group on the
pyrazoline ring of Lange „179 to improve the properties consistent with the
results shown by Lange ‟05 on the imidazole ring (FF 14).

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Secondary Considerations
The CabanesDeclaration I
6
does not include an example of the elected
species (see FF 1). In a supplemental Declaration, Cabanes Declaration II
7
,
Table I shows the tested parent compounds, corrected to include a
pyrazoline core ring (see Cabanes Dec. II ¶ 5), but none of these compounds
represents the elected species. While each of the compounds in the “a”
series comprises a 4-substituted pyrazoline core ring, even compound Va,
which also comprises the azepan ring of the elected species, differs from the
elected species in comprising a 4-oxygen in the place of the 4-chlorine on
the phenyl group of the elected species. Thus, none of the results shown in
the Cabanes Declaration I or II are commensurate in scope with the elected
species. See In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (Unexpected
results must also be “commensurate in scope with the degree of protection
sought by the claimed subject matter.”)
In addition, the Cabanes Declaration II lacks an explanation of the
data for compounds Va and Vb, the closest structures in the Cabanes
Declaration II, which data is shown in Appendix I, page 5. The table is not
clear whether the n.d. simply means not detected, that is not assayed for, or
undetectable as below the lowest limits of detection.
We recognize that the data for compounds I-IV demonstrate some
improvement, up to 62%, for the methyl substitution on the core ring (see,
e.g., Cabanes Dec II ¶ 8, table B). However, Lange ‟05 teaches that the “5-
methylated imidazole 62 was found very potent in both assays, indicating

6
Declaration of M
a
Teresa Serafini Cabanes, filed Jun. 26, 2008.
7
Declaration of M
a
Teresa Serafini Cabanes, filed Sep. 4, 2009.
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that a methyl group constitutes the optimal substituent in this series. Its
potent in vivo activity is in line with that of 1 thereby again corroborating
the bioisosteric concept” (Lange ‟05 1828, col. 1; FF 14). We therefore find
that rather than being unexpected, inclusion of a methyl substituent on the
core ring would have been expected by the ordinary artisan to improve
activity. See In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected
beneficial results are evidence of obviousness of a claimed invention. Just as
unexpected beneficial results are evidence of unobviousness.”)
We also find that the amount of improvement, 62% at most, is
substantially less than the variance shown by Lange ‟05 between the in vitro
results of compounds 71, 77, and 78 where Lange ‟05 teaches that the
equivalence of the results of these compounds, stating that the “presence of
more bulky bicyclic moieties such as in 71, 77, and 78 was well tolerated.”
(Lange ‟05 1826, col. 2; FF 15.) However, compound 71 shows a Ki of 40,
compound 77 a Ki of 34 and compound 78 a Ki of 19, so that the Ki of
compound 78 is twofold better than compound 71, but this difference is not
interpreted by Lange ‟05 as substantial or unexpected in any way (FF 15).
Consequently, the evidence of record does not clearly demonstrate that an
improvement of 62% represents an unexpected result relative to the prior art.
See In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (“[I]t is not enough to
show that results are obtained which differ from those obtained in the prior
art: that difference must be shown to be an unexpected difference”).
Conclusion of Law
(i) The evidence of record supports a prima facie case of obviousness
for the elected species.
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(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
In summary, we vacate the rejection of claims 1, 17, 21-27, and 42-44
under 35 U.S.C. § 103(a) as obvious over Barth and Lange „179. We vacate
the rejection of claims 1, 17, 21-27, and 42-44 under 35 U.S.C. § 103(a) as
obvious over Lange „04 and Lange ‟05.
This decision also contains new grounds of rejection pursuant to 37
C.F.R. § 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960
(August 12, 2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)). 37
C.F.R. § 41.50(b) provides “[a] new ground of rejection pursuant to this
paragraph shall not be considered final for judicial review.”
Claims 1, 17, 21-27, and 42-44 are rejected under 35 U.S.C. § 103(a)
as obvious over Barth, Lange „179, and Lange ‟05 under the New Grounds
of Rejection as discussed above.
37 C.F.R. § 41.50(b) also provides that the Appellants, WITHIN
TWO MONTHS FROM THE DATE OF THE DECISION, must exercise
one of the following two options with respect to the new ground of rejection
to avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment
of the claims so rejected or new evidence relating to the
claims so rejected, or both, and have the matter reconsidered
by the Examiner, in which event the proceeding will be
remanded to the Examiner.…

(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same record.…
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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

VACATED, §41.50(b)

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