Ex Parte Lange et al

Board of Patent Appeals and Interferences

Jun 18, 2010

10942021 (B.P.A.I. Jun. 18, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte JOSEPHUS H. M. LANGE,
CORNELIUS G. KRUSE,
HERMAN H. VAN STUIVENBERG,
and
LEONARDUS A. J. M. SLIEDREGT,
Appellants1
____________________

Appeal 2009-014494
Application 10/942,021
Technology Center 1600
____________________

Decided: June 18, 2010
____________________

Before CAROL A. SPIEGEL, TONI R. SCHEINER, and
FRANCISCO C. PRATS, Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

1 The real party in interest is SOLVAY PHARMACEUTICALS B.V.
(Appeal Brief under Board Rule § 41.37 filed 12 January 2009 ("App. Br.")
at 3). This decision also cites to the Examiner's Answer mailed 5 May 2009
("Ans.") and the Reply Brief under Board Rule § 41.41 filed 30 June 2009
("Reply Br.").

Appeal 2009-014494
Application 10/942,021

DECISION ON APPEAL
Appellants appeal under 35 U.S.C. § 134(a) from an Examiner's final
rejection of claims 2 and 4. Claims 1, 6-9, and 12-18 are withdrawn from
consideration as directed to a non-elected invention. Claims 10 and 11 are
objected to as being dependent upon a rejected base claim. (App. Br. 5; Ans.
3; Reply Br. 2.) We have jurisdiction under 35 U.S.C. § 134. We
REVERSE.
I. Statement of the Case
The subject matter on appeal is directed to certain thiazole derivatives
capable of binding to cannabinoid receptor(s) CB1 and/or CB2. Claims 2 and
4 read as follows (App. Br. 23-27):
2. A compound of formula (I), wherein:

-- R and R1 are the same or different and are independently chosen from
phenyl group, 3-pyridinyl group, and 4-pyridinyl groups, optionally
substituted with one, two, or three substituents Y, wherein Y is chosen from
a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy
group, a hydroxy group, a hydroxymethyl group, a hydroxyethyl group, a
trifluoromethyl group, a trifluoromethoxy group, a methylsulfonyl
group, a methylsulfanyl group, a trifluoromethylsulfonyl group, a phenyl
group, a cyano group, a chlorine atom, an iodine atom, a bromine atom, and
a fluorine atom, with the proviso that X does not represent the subgroup (ii);
or
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-- one of the moieties R or R1 is independently chosen from phenyl, 3-
pyridinyl, and 4- pyridinyl groups, optionally substituted with one, two, or
three substituents Y, wherein Y is chosen from a methyl group, an ethyl
group, a propyl group, a methoxy group, an ethoxy group, a hydroxy group,
a hydroxymethyl group, a hydroxyethyl group, a trifluoromethyl group, a
trifluoromethoxy group, a methylsulfonyl group, a methylsulfanyl
group, a trifluoromethylsulfonyl group, a phenyl group, a cyano group, a
chlorine atom, an iodine atom, a bromine atom and a fluorine atom, and
-- one of the moieties R and R1 is chosen from C2-8 branched or unbranched
groups, C3-8 heteroalkyl branched or unbranched groups having one
heteroatom chosen from a nitrogen atom, an oxygen atom and a sulfur atom,
a C3-7 cycloalkyl group, a C3-7- cycloalkyl-C1-3-alkyl group, and a C3-7-
heterocycloalkyl-C1-3-alkyl group, wherein each group may be optionally
substituted with a substituent chosen from a hydroxy group, a methoxy
group, a methyl group, a trifluoromethyl group, and a fluorine atom, and
wherein the C3-7-heterocycloalkyl-C1-3-alkyl group comprises at least one
heteroatom chosen from a nitrogen atom, an oxygen atom and a sulfur atom;
or
-- one of the moieties R and R1 is chosen from a benzyl group, optionally
substituted on its phenyl ring with one, two, or three substituents Y, wherein
Y is chosen from a methyl group, an ethyl group, a propyl group, a methoxy
group, an ethoxy group, a hydroxy group, a hydroxymethyl group, a
hydroxyethyl group, a trifluoromethyl group, a trifluoromethoxy group, a
methylsulfonyl group, a methylsulfanyl group, a trifluoromethylsulfonyl
group, a phenyl group, a cyano group, a chlorine atom, an iodine
atom, a bromine, and a fluorine atom;
and wherein
-- X is chosen from one of the subgroups (i) and (ii); and wherein

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-- R2 is chosen from C3-8 alkyl branched or unbranched groups, a C3-7
cycloalkyl group, a C3-7-cycloalkyl-C1-2-alkyl group, and a C3-7-
heterocycloalkyl-C1-2-alkyl group having at least one heteroatoms chosen
from a nitrogen atom, an oxygen atom and a sulfur atom, wherein each
group may be optionally substituted with a substituent chosen from a
hydroxy group, a methyl group, a trifluoromethyl group and a fluorine atom;
or
-- R2 is chosen from benzyl, phenethyl, and phenylpropyl groups, wherein
the phenyl ring of R2 may be optionally substituted with one, two, or three
substituents Y, wherein Y is independently chosen from a methyl group, an
ethyl group, a propyl group, a methoxy group, an ethoxy group, a hydroxy
group, a hydroxymethyl group, a hydroxyethyl group, a trifluoromethyl
group, a trifluoromethoxy group, a methylsulfonyl group, a methylsulfanyl
group, a trifluoromethylsulfonyl group, a phenyl group, a cyano group, a
chlorine atom, an iodine atom, a bromine atom and a fluorine atom; or
-- R2 is chosen from pyridyl, thienyl, and naphtyl groups, wherein the
napthyl group may be optionally substituted with a halogen atom, a methyl
group, a methoxy group and a trifluoromethyl group;
and wherein
-- R3 is chosen from a hydrogen atom and C1-3 alkyl branched or unbranched
groups;
and wherein
-- R4 is chosen from C1-10 alkyl branched or unbranched groups, a C3-8
cycloalkyl-C1-2- alkyl group, C1-10 alkoxy branched or unbranched groups, a
C3-8 cycloalkyl group, a C5-10 bicycloalkyl group, a C5-10-bicycloalkyl-C1-2
alkyl group, a C6-10 tricycloalkyl group, a C6-10 tricycloalkyl-methyl group,
C3-10 alkenyl branched or unbranched groups, a C5-8 cycloalkenyl group,
wherein each group may optionally comprise at least one heteroatom chosen
from a nitrogen atom, an oxygen atom and a sulfur atom, and wherein the R4
group may optionally be substituted with substituents chosen from a
hydroxy group, one, two, or three methyl groups, an ethyl group and one,
two or three fluorine atoms; or
-- R4 is chosen from phenyl, phenylamino, phenoxy, benzyl, phenethyl, and
phenylpropyl groups, optionally substituted on its phenyl ring with one, two,
or three substituents Y, wherein Y is chosen from a methyl group, an ethyl
group, a propyl group, a methoxy group, an ethoxy group, a hydroxy group,
a hydroxymethyl group, a hydroxyethyl group, a trifluoromethyl group, a
trifluoromethoxy group, a methylsulfonyl group, a methylsulfanyl group, a
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trifluoromethylsulfonyl group, a phenyl group, a cyano groups a chlorine
atom, an iodine atom, a bromine atom and a fluorine atom, or
-- R4 is chosen from pyridyl and thienyl groups, or
R4 is NR5R6, wherein R5 and R6, together with the nitrogen atom to which
they are bound, form a saturated or unsaturated, monocyclic or bicyclic,
heterocyclic group having 4 to 10 ring atoms, wherein the heterocyclic
group has at least one heteroatom chosen from a nitrogen atom, an oxygen
atom and a sulfur atom, and wherein the heterocyclic group is optionally
substituted with one substituent chosen from a C1-3 alkyl branched or
unbranched group, a phenyl group, a hydroxy group, a trifluoromethyl group
and a fluorine atom; or
-- R3 and R4, together with the nitrogen atom to which they are bound, form
a heterocyclic group having 4 to 10 ring atoms, that is either saturated,
unsaturated, monocyclic or bicyclic, and wherein the heterocyclic group
comprises at least one species chosen from a nitrogen atom, an oxygen atom
and a sulfur atom, and wherein the heterocyclic group is optionally
substituted with a substituent chosen from C1-3 alkyl branched or unbranched
groups, a phenyl group, an amino group, a hydroxy group, a methoxy group,
a cyano group, a trifluoromethyl group, a fluorine atom, and a chlorine
atom; or
pharmaceutically acceptable salts thereof, or prodrugs thereof.

4. A pharmaceutical composition comprising a carrier material and at least
one compound of Claim 2 as an active ingredient.

In response to a requirement for restriction/election of species mailed
August 3, 2006, Appellants elected compounds of formula (I) wherein
R and R1 are the same or different and are independently chosen from
phenyl, 3-pyridinyl,2 and 4-pyridinyl, optionally substituted; OR, one of R
and R1 is selected from phenyl, 3-pyridinyl, and 4-pyridinyl, optionally
substituted, and the other is a benzyl group, optionally substituted;
X is –C (=O) – R2; and,

2 This decision uses the terms "pyridyl" and "pyridinyl" interchangeably.
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all other variables are as defined in claim 2 (Ans. 7-8; see also OA3 4).
Therefore, only compounds comprising these species are before us.
The Examiner rejected claims 2 and 4 as unpatentable under 35 U.S.C.
§ 103(a) as obvious over Takasugi4 (Ans. 5-6). The Examiner found that
Takasugi teaches anti-inflammatory thiazole compounds substituted with
substituted phenyls at positions 4 and 5 and with – A – Z at position 2,
wherein A is a carbonyl group and Z is a heterocyclic group, e.g.,

(id. at 5 and 8-9). To wit, the Examiner deemed (a) the substituted phenyl
groups and (b) combined carboxyl group A and heterocyclic group Z of
Takasugi to correspond to (a) the elected R and R1 groups and (b) X group,
respectively, of the claimed compounds. The Examiner concluded that it
would have been obvious to arrive at the claimed compounds with the
expectation of obtaining similar thiazole compounds with similar anti-
inflammatory activity based on the teachings of Takasugi (id. at 6).
In particular, the Examiner found that Example 11 of Takasugi, i.e.,

3 Office Action mailed 15 November 2006 ("OA").
4 U.S. Patent 5,217,971, Thiazole Compounds and Pharmaceutical
Composition Comprising the Same, issued 8 June 1993 to Takasugi et al.
("Takasugi").
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,
differs in having the pyridyl (heterocylic Z) group attached directly to the
thiazole ring through a single bond instead of through a carbonyl group as
claimed (id. at 10-11). However, the Examiner maintains that Takasugi
teaches
the interchangeability of the A variable
representing a bond or carbonyl in formula (I) in
column 1 as well as in the subgenus of formula
(Id) found in column 4 (both reproduced below).

(Ans. 14-15.)
Thus, the Examiner concluded that the claimed compounds would have been
obvious to one of ordinary skill in the art (id. at 15-16).
Appellants argue that Takasugi's general formula encompasses an
enormous range of possible thiazole compounds and the Examiner has failed
to explain why one of ordinary skill in the art would have made the specific
structural modifications necessary to arrive at the claimed compounds (App.
Br. 16 and 20). Appellants further argue that claim 2 expressly excludes
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compounds where the carbonyl group is directly bonded to a nitrogen atom
of a nitrogen containing group, thereby excluding compounds such as
Takasugi Example 11 (id. at 17-18). In short, Appellants contend that (i)
structural similarity alone is insufficient to establish a prima facie case of
obviousness absent some reason that would suggest to one of ordinary skill
in the art to make the specific molecular modifications necessary to arrive at
the claimed invention and (ii) Takasugi fails to provide any motivation to
modify its general formula to produce species that would fall within the
claimed genus (id. at 20).
The dispositive issue, therefore, is whether Takasugi would have
suggested making the specific molecular modifications necessary to achieve
the claimed invention, i.e., to select the specifically elected R, R1, and
–C(=O)–R2 groups recited in claim 2.
II. Findings of Fact
The following findings of fact ("FF") are supported by a
preponderance of the evidence of record.
[1] Takasugi discloses compounds having the general formula

wherein R1 and R2 are each halogen, lower alkyloxy, lower alkylthio
or lower alkylsulfinyl,
A is lower alkylene, carbonyl or single bond, and
Z is a heterocylic group which may have a suitable substituent(s), a
group of the formula:
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in which R3 and R4 are each hydrogen, lower alkyl which may have a
heterocyclic group or piperidyl which may have suitable substituent(s),
or a group of the formula:

in which (1) R5, R6, and R7 are each hydrogen, lower alkyl, or
cyclo(lower)alkyl; (2) R5 is hydrogen, lower alkyl, or
cyclo(lower)alkyl, and R6 and R7 are linked together with the attached
nitrogen atom to form a heterocyclic group which may have suitable
substituent(s); or (3) R5 and R6 are linked together to form lower
alkylene, and R7 is hydrogen;
provided that when Z is a group of the formula:

wherein R3 and R4 are each defined above, then A is lower alkylene or
carbonyl (Takasugi col. 1, l. 36-col. 2, l. 38).
[2] According to Takasugi,
[s]uitable "heterocyclic group" in "heterocyclic
group which may have suitable substituent(s)" and
"lower alkyl which may have heterocyclic group" may
be aliphatic or aromatic, heteromonocyclic or
heteropolycyclic group containing at least one hetero
atom such as nitrogen, oxygen and sulfur atoms, and
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more suitable "heterocyclic group" thus defined may
include 5 to 7 membered aliphatic heteromonocyclic
group having one to three hetero atom(s) selected from
nitrogen, oxygen and sulfur or 5 to 6 membered aromatic
heteromonocyclic group having one to three hetero
atom(s) selected from nitrogen, oxygen and sulfur, such
as piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,
pyridyl, dihydropyridyl, tetrahydropyridyl,
perhydrodiazepinyl, tetrahydropyridazinyl, and the like
d. at col 9, ll. 43-57). (i

[3] According to Takasugi, compounds of its general formula possess
antithrombotic, vasodilating, antiallergic, anti-inflammatory, and 5-
lipoxygenase inhibitory activities (id. at col. 1, ll. 5-35).
[4] Illustrative compounds falling within the general formula of Takasugi
include
,
,
,
and
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(id. at col. 26, ll. 27-40; col. 27, ll. 37-50; col. 31, ll. 51-63; and col. 40, ll.
31-42).
[5] Forty-one of the forty-four specific examples falling within the
general formula of Takasugi have p-methoxyphenyl groups at
positions 4 and 5 of the thiazole ring.
[6] Takasugi describes a process for making a compound Ie, i.e.,
,
wherein X2 is an acid residue and R9 is a lower alkyl (Takasugi col. 4,
l. 38-l. 68 and col. 8, ll. 50 an 55).
III. Discussion
A. Legal principles
"[O]bviousness requires a suggestion of all limitations in a claim."
CFMT, Inc. v. Yieldup Int'l Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003)
(citing In re Royka, 490 F.2d 981, 985 (CCPA 1974)). In KSR Int'l Co. v.
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Teleflex, Inc., 550 U.S. 398, 418 (2007) (citing In re Kahn, 441 F.3d 977,
988 (Fed. Cir. 2006), the Supreme Court noted that "[t]o facilitate review,
this [obviousness] analysis should be made explicit."
In order to establish a prima facie case of obviousness for chemical
compounds, there need be "a showing that the 'prior art would have
suggested making the specific molecular modifications necessary to achieve
the claimed invention.'" Takeda Chemical Industries, Ltd. v. Alphapharm
Pty., Ltd., 492 F.3d 1350, 1356 (Fed. Cir. 2007), quoting In re Deuel, 51
F.3d 1552, 1558 (Fed. Cir. 1995). The court in Takeda noted that the "test
for prima facie obviousness for chemical compounds is consistent with the
legal principles enunciated in KSR," Takeda, 492 F.3d at 1356, and thus, "in
cases involving new chemical compounds, it remains necessary to identify
some reason that would have led a chemist to modify a known compound in
a particular manner to establish prima facie obviousness of a new claimed
compound." Id. at 1357.
B. Analysis
Thiazole compounds within the general formula of Takasugi have
halogen, lower alkyloxy, lower alkylthio, or lower alkylsulfinyl substituted
phenyl groups attached at positions 4 and 5 of the thiazole ring (FF 1).
Thiazole compounds within the general formula of Takasugi also have an
–A–Z moiety attached at position of 2 of the thiazole ring, wherein A can be
a lower alkylene or carbonyl group or a single bond, and Z can be (a) an
optionally substituted heterocyclic group, (b) an –NR3R4 group, wherein R3
and R4 are each hydrogen, lower alkyl which may have a heterocyclic group
or piperidyl which may have suitable substituent(s), or (c) an
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group wherein (1) R5, R6, and R7 are each hydrogen, lower
alkyl, or cyclo(lower)alkyl; (2) R5 is hydrogen, lower alkyl, or
cyclo(lower)alkyl, and R6 and R7 are linked together with the attached
nitrogen atom to form a heterocyclic group which may have suitable
substituent(s); or (3) R5 and R6 are linked together to form lower alkylene,
and R7 is hydrogen; provided that when Z is –NR3R4 and R3 and R4 are each
defined above, then A is lower alkylene or carbonyl (FF 1).
The Examiner opines that since the compounds of Takasugi are
structurally similar to the claimed compounds, a skilled artisan would have
been "motivated to prepare compounds embraced by the prior art to arrive at
the instant claimed products with the expectation of obtaining additional
beneficial products which would be useful in treating, for example,
inflammation" (Ans. 6). However, the Examiner has not explained how
Takasugi would have suggested making the specific molecular modifications
to its general formula necessary to achieve the claimed compounds. Takeda,
492 F.3d at 1356.
Forty-one of the forty-four specific examples falling within the
general formula of Takasugi have p-methoxyphenyl groups attached at
positions 4 and 5 of the thiazole ring (FF 5). As noted by Appellants, none
of the forty-one examples contain a combination of A and Z groups within
the scope of claim 2 (App. Br. 16), and the Examiner has not explained how
Takasugi would have suggested making compounds having the required
combination, i.e., claimed X moiety –C(=O)–R2.
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The Examiner maintains that Takasugi generically teaches an X
moiety within the scope of appealed claim 2 and directs our attention to
Takasugi Example 11 (Ans. 10). In Example 11, the Z group of Takasugi is
a pyridyl ring and the A group of Takasugi is a single bond, i.e., the
corresponding X moiety is a pyridyl group. According to claim 2, if R2 is a
heterocyclic group, then the heterocyclic group is selected from a
"C3-7-heterocycloalkyl-C1-2 alkyl group having at least one
heteroatoms chosen from a nitrogen atom, an oxygen atom and a sulfur atom,
…" or
"pyridyl, thienyl, and naphtyl [sic] groups"
with the proviso that "R and R1 are the same … and are … [a] phenyl
group, … optionally substituted with one … substituent[] Y, wherein Y is …
a methoxy group, an ethoxy group, …", then the carbonyl group is not
attached directly to a nitrogen atom which is part of heterocyclic group
having 4 to 10 ring atoms (i.e., "X does not represent the subgroup (ii)” [i.e.,
]). Thus, based on the proviso in claim 2, while the heterocyclic
group (i.e., the X group of Takasugi or the R2 group of claim 2) may be a
pyridyl group, the pyridyl group cannot be attached to the carbonyl group
through the nitrogen atom in the pyridyl group. Indeed, the Examiner states
that "a pyridyl ring does circumvent the proviso in instant claim 2 because it
is not possible for the nitrogen of the pyridyl ring to be connected to the
carbonyl … " (Ans. 13). According to the Examiner, however, Takasugi
teaches that a single bond and a carbonyl group are interchangeable linkers
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for attaching a heterocyclic group to a thiazole ring and directs our attention
to the general formula and compound (Id) of Takasugi (id. at 14-15).
The general formula of Takasugi encompasses many alternatives for
its R1, R2, A, and Z groups (FF 1). Compound Id, similar to Takasugi's
general formula, encompasses many alternatives for its R1, R2, and A groups
(FF 6). Specifically, compound Id has an unsubstituted pyridyl group
attached to the thiazole ring through an unspecified A group attached to an
unspecified carbon atom in the pyridyl ring and is used as a starting material
for attaching a lower alkyl substituent to the nitrogen atom in the pyridyl
ring (FF 6). Example 11 and compound Id suggest that whether or not an A
group, e.g., a single bond or a carbonyl group, can be used interchangeably
to attach a heterocyclic group to a thiazole ring according to Takasugi
depends at least in part on which atom in the heterocyclic ring is reacting
with a particular A group. Again, the Examiner has not explained how
Example 11, compound Id, or the general formula of Takasugi would have
suggested making the specific molecular modifications to the general
formula of Takasugi necessary to achieve the claimed compounds. Takeda,
492 F.3d at 1356.
In short, whether one of ordinary skill in the art "'would have been
able to produce'" the claimed compounds is not the appropriate standard for
an obviousness analysis. Orthokinetics, Inc. v. Safety Travel Chairs, Inc.,
806 F.2d 1565, 1575 (Fed. Cir. 1986). To establish a prima facie case of
obviousness for chemical compounds, there need be "a showing that the
'prior art would have suggested making the specific molecular modifications
necessary to achieve the claimed invention.'" Takeda, 492 F.3d at 1356.
C. Conclusion
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We will not sustain the rejection of claims 2 and 4 under § 103 over
Takasugi because the Examiner has failed to establish that Takasugi would
have suggested making the specific molecular modifications necessary to
achieve the claimed invention, i.e., to select the specifically elected R, R1,
and –C(=O)–R2 groups recited in claim 2.
V. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner to reject claims 2 and 4
as unpatentable under 35 U.S.C. § 103(a) as obvious over Takasugi is
REVERSED.
REVERSED

cdc

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