Ex Parte Mammen et al

Board of Patent Appeals and Interferences

Jul 1, 2008

10426270 (B.P.A.I. Jul. 1, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte MATHAI MAMMEN and DAVID OARE
____________

Appeal 2008-2051
Application 10/426,270
Technology Center 1600
____________

Decided: July 1, 2008
____________

Before DONALD E. ADAMS, LORA M. GREEN, and
JEFFREY N. FREEDMAN, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL

This appeal under 35 U.S.C. § 134 involves claims 50-63. Claim 64,
the only remaining claim pending in this application, was “withdrawn from
consideration as being drawn to a non-elected species and/or invention”
(App. Br. 2). We have jurisdiction under 35 U.S.C. § 6(b).

Appeal 2008-2051
Application 10/426,270

R2
K"
INTRODUCTION
Claims 50, 51, 55, 58, and 59 are illustrative:
50. A compound of the formula:
R1
K
N B" N H
O
BA

or a salt thereof; wherein
A is phenyl or pyridyl;
B is a heterocycloamino group selected from the group consisting of
pyrrolidinyl, piperidinyl, hexahydroazepinyl, quinuclidinyl, 1-
azabicyclo[2.2.1]heptyl and 1-azabicyclo[3.2.1]octyl;
B” is –NH-;
K is a bond or methylene group;
K" is a bond;
R1 is hydrogen or alkyl;
R2 is a group of formula (iii):

R7
R6
R8
(iii)

and
R6, R7, and R8 are independently selected from the group consisting of
hydrogen, halo, hydroxyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl and
alkyl optionally substituted with one, two or three substitutents selected from
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halo, hydroxyl, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amio and
substituted amino.
51. A compound of the formula:

NN
H
N
H
O
H

or a salt thereof.
55. The compound of Claims 50, wherein B is pyrrolidinyl.
58. The compound of Claim 50, wherein B is 1-
azabicyclo[2.2.1]heptyl.
59. The compound of Claim 50, wherein B is 1-
azabicyclo[3.2.1]octyl.

The Examiner relies on the following prior art references to show
unpatentability:
Mammen US 7,238,709 B2 Jul. 3, 2007
J. Büchi, “The Constitution-Effect Relationships From a New Viewpoint,”
Deutsche Apotheker-Zeitung 1695-1700 (1966) (as translated Oct. 2002).

Charles H. Mitch, “Muscarinic Analgesics with Potent and Selective Effects
on the Gastrointestinal Tract: Potential Application for the Treatment of
Irritable Bowel Syndrome,” 40 J. Med. Chem. 538-46 (1997).

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Ryo Naito, “Selective Muscarinic Antagonists. II. Synthesis and
Antimuscarinic Properties of Biphenylylcarbamate Derivatives,” 46(8)
Chem. Pharma. Bull. 1286-94 (1998).1

David P. Marriott, “Lead Generation Using Pharmacophore Mapping and
Three-Dimensional Database Searching: Application to Muscarinic M3
Receptor Antagonists,” 42 J. Med. Chem. 3210-16 (1999).

The rejection as presented by the Examiner is as follows:
1. Claims 50-63 stand rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Naito, Marriott, Mitch, and Büchi.
2. Claims 50-63 stand rejected under the judicially created doctrine of
obviousness-type double patenting as being unpatentable over claim 51 of
U.S. Patent 7,238,709 in view of Marriott, Mitch, Buchi, and Naito.
We affirm.

DISCUSSION
Obviousness:
Appellants provide separate arguments for the following five groups
of claims: I. Claims 50, 52, 57, and 60-63; II. Claims 51, 53, and 54; III.
Claims 55 and 56; IV. 58, and V. 59. Therefore, we limit our discussion to
representative claims 50, 51, 55, 58, and 59. 37 C.F.R. § 41.37(c)(1)(vii).

1 There are two Naito references of record and the Examiner’s statement of
the references relied upon appears to blend the title of the first with the
journal, volumne and page citation of the second. We have cited and relied
upon the correct version of Naito herein.
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Claim 50:
The Examiner finds that Naito teaches “many Muscarinic M3
antagonists including YM-46303” (Ans. 4.) YM-46303 (compound 8I) has
the following structure:

(Naito 1288: Table 2, compound 8I.)
N
N
H
O
O
The Examiner finds that YM-46303 “falls entirely within the scope of
Appellants’ claims (wherein A + R2 = biphenyl (i.e., R6, R7 and R8 = H), K =
bond, R1 = H and B = quinuclidinyl) with the exception that YM-46303
contains a carbamate linkage and not the requisite urea linkage” (Ans. 4).
Stated differently, the Examiner finds that Naito fails “to teach an ‘NH’ at
the B” position to form the requisite urea linkage (i.e., Naito et al. teach –
NH-(C=O)-O- instead of –NH-(C=O)-NH-” (id.).
The Examiner relies on Marriott, Mitch and Büchi to make up for this
deficiency in Naito. Specifically, the Examiner finds that:
[T]he combined references of Marriott et al., Mitch et al. and
Buchi [sic] (e.g., see entire documents) teach the use of an
“NH” group at the B” position to form a urea linkage (e.g., see
Marriott et al., page 3213, column 1, last full paragraph,
“Replacement of the oxygen atom for a nitrogen atom [i.e.,
formation of a urea] in the carbamate moiety . . . would lead to
further combinatorial opportunities [for identification of a lead
Muscarinic M3 receptor antagonist]”; see also abstract, “By
using Muscarinic M3 receptor antagonists as an example, we
show that it is possible to identify potent novel lead compounds
using this [combinatorial] approach”). In addition, the similar
physiocochemical properties would have been expected for the
“NH” to “O” substitution at the B” position because this
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represents an “isosteric” substitution (e.g., see Buchi [sic], page
3, Table 8, “O” and “NH” entries; see also paragraph bridging
pages 2-3, “By exchanging isosteric groups in active-ingredient
molecules [e.g., Muscarinic activity], it should be possible to
produce effective analogs, since the electronic charge and
physical/chemical properties of such a molecule should hardly
change”).

(Ans. 5-6).
Based on this evidence the Examiner concludes that it would have
been prima facie obvious to one of ordinary skill in the art at the time the
invention was made to substitute the “NH” for the “O” at the B” position of
YM-46303 as the “[r]eplacement of the oxygen atom for a nitrogen atom
[i.e., formation of a urea] in the carbamate moiety . . . would lead to further
combinatorial opportunities [for identification of a lead Muscarinic M3
receptor antagonist]” (Ans. 8). According to the Examiner “one of ordinary
skill in the art would have been motivated to use [sic] make such
substitutions because ‘. . . it is possible to identify potent novel lead
compounds’ using this approach” (id.). In addition, the Examiner finds that
“a person of skill in the art would also have been motivated to produce these
homologs as a result of their favorable physiochemical properties” (Ans. 9).
In this regard, the Examiner finds that “‘[a]n obviousness rejection based on
similarity in chemical structure and function entails the motivation of one
skilled in the art to make a claimed compound, in the expectation that
compounds similar in structure will have similar properties’ In re Payne,
606 F.2d 303, 313 . . . (CCPA 1979)” (id.).
Appellants disagree. According to Appellants while Marriott suggests
“the replacement of the oxygen atom for a nitrogen atom in compound 6
would lead to further combinatorial opportunities” and “that compounds
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such as 5, 6 and 7[ ]2 should be amenable to further optimization in order to
improve M3 antagonist potency”, Appellants assert that “this is merely an
invitation to modify these specific compounds in an attempt to optimize their
properties” (App. Br. 9).
Further Appellants assert that:
Marriott only suggests modifying one of its compounds by
changing the carbamate to a urea in the context of generating a
larger and more diverse combinatorial library. However, one
skilled in the art would not necessarily have a reasonable
expectation that the compounds in the library would have the
desired properties.

(App. Br. 9-10.) In this regard, Appellants “point out that Marriott found
only 3 of the 172 hit compounds to have any significant muscarinic activity”
and while “absolute predictability is not required . . . an obviousness
determination does require a reasonable expectation of success” (App. Br.
10). According to Appellants “one skilled in the art, observing Marriott’s
less than 2% success rate, would not have a reasonable expectation of
success of discovering a muscarinic antagonist should they choose to
combine the Marriott teachings with those of the Naito reference” (id.). We
disagree. Appellants’ position is contrary to Marriott who teaches that the
three compounds [structures 5, 6, 7] they identified “were found to exhibit
potency in our screen” and the “hit rate for leads from this study is . . .

2 The structure of Mariott’s compounds 5, 6, and 7 are as follows:

(see App. Br. 9.)
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several orders of magnitude greater than from high-throughput screening”
(Marriott 3213: col. 2, ll. 26-28).
Therefore, the question before us is not whether a person of ordinary
skill in the art would obtain compounds from a library based on a core
molecule that is taught by the references relied upon. To the contrary, the
question before us is whether the claimed compound is prima facie obvious
to a person of ordinary skill in the art. On this record, the evidence relied
upon by the Examiner teaches a muscarinic M3 antagonist that differs from
the claimed compound by containing a carbamate linkage and not the
requisite urea linkage (Ans. 4). Marriott “sought to identify novel
antagonists of the muscarinic M3 receptor” (Marriott 3210: col. 2, ll. 13-14).
Marriott teaches that “[p]harmacophore generation based on the structures of
known M3 receptor antagonists, 3D database searching, and medium-
throughput screening were used successfully to identify a small set of
simple, novel lead compounds” (Marriott 3211: col. 1, ll. 28-32). Marriott
found three compounds (compounds 5, 6, and 7) “constitute quality lead
structures ripe for optimization” (Marriott 3213: col. 2, ll. 25-26). Like the
claimed compound, Marriott’s compound 6 contains a carbamate moiety.
Marriott teaches that the “[r]eplacement of the oxygen atom for a nitrogen
atom in the carbamate moiety of structure 6, such that a central urea moiety
is generated, would lead to further combinatorial opportunities, with various
amine libraries open to exploration” (Marriott 3213: col. 1, ll. 28-32).
Thus, a person of ordinary skill in the art reading Naito and Marriott
in combination would realize that Naito’s compound (a M3 receptor
antagonist) can be used as a lead compound, as taught by Marriott, and that
by replacing the oxygen atom for a nitrogen atom in the carbamate moiety
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further combinatorial opportunities would be open to exploration as taught
by Marriott. In sum, we agree with the Examiner’s conclusion that the
claimed compound would have been prima facie obvious in view of the
combined teachings of Naito and Marriott.
Appellants’ arguments concerning the reasonable expectation of
successfully identifying other M3 receptor antagonists from a library based
on a compound taught by the combined teachings of Naito and Marriott puts
the cart before the horse. The issue is not whether it would have been
obvious to try screening a library based on such a compound in the hope of
identifying other M3 receptor antagonists. To the contrary, the issue is
whether the combination of prior art relied upon by the Examiner teaches the
claimed compound. For the foregoing reasons, we find that it does.
Accordingly, we are not persuaded by Appellants’ assertion’s regarding the
reasonable expectation of success in “discovering a muscarinic antagonist
should they choose to combine the Marriott teachings with those of the
Naito reference” (App. Br. 10). For the same reasons we are not persuaded
by Appellants’ assertion that “even if the secondary Marriott and/or Büchi
references were combined with Naito, there is no reasonable expectation of
success. While combinatorial chemistry is an excellent research tool, it is no
a roadmap to success.” (App. Br. 11).
We are also not persuaded by Appellants’ assertion that “there is
nothing in Büchi that teaches that ureas and carbamates are interchangeable”
or “that such isosteric changes can be done in a linker positioned at the core
of a complex structure” (App. Br. 10). Marriott addresses both of these
points by teaching the “[r]eplacement of the oxygen atom for a nitrogen
atom in the carbamate moiety of structure 6, such that a central urea moiety
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is generated, would lead to further combinatorial opportunities, with various
amine libraries open to exploration” (Marriott 3213: col. 1, ll. 28-32).
We recognize Appellants assertion that Mitch fails to support “that an
‘NH’ for ‘O’ substitution should be made for compounds with M3
Muscarinic activity” (App. Br. 12). However, as the Examiner points out
“Mitch is not being relied upon to show the obviousness of the O/N
substitution” (Ans. 24). Accordingly, we are not persuaded by Appellants’
arguments regarding Mitch.
For the foregoing reasons we find no error in the Examiner’s prima
facie case of obviousness. Accordingly, we affirm the rejection of claim 50
under 35 U.S.C. § 103(a) as unpatentable over the combination of Naito,
Marriott, Mitch, and Büchi. Claims 52, 57, and 60-63 fall together with
claim 50.

Claim 51:
The compound of claim 51 is similar to that of Naito’s muscarinic M3
antagonists YM-46303 except that the bicycle[2.2.2]octane groups is
replaced by a piperidin-4-yl group and YM-46303 contains a carbamate
linkage and not the requisite urea linkage. Naito does, however, teach a
compound (compound 14) which contains a piperidin-4-yl group in the
appropriate location (Naito 1287: Chart 3). Naito further illustrates this
compound as an intermediate in the formulation of compounds 15a-o (id.).
Accordingly, the question is whether it would have been prima facie obvious
to substitute the carbamate linkage with an urea linkage. For the reasons
discussed above, based on the teachings of Marriott we find that it would
have been prima facie obvious to make this substitution. Accordingly, we
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disagree with Appellants’ assertion that “there is nothing to suggest
combining the teachings of Marriott and Naito” (App. Br. 15).
For the foregoing reasons we affirm the rejection of claim 51 under 35
U.S.C. § 103(a) as unpatentable over the combination of Naito, Marriott,
Mitch, and Büchi. Claims 53 and 54 fall together with claim 51.

Claim 55:
The Examiner finds that the pyrrolidinyl ring is a homolog “of the
piperidinyl ring disclosed by Niato et al. (e.g., see Naito et al., Table 3,
compound 14)” (Ans. 7).
In response, Appellants assert that the change in ring structure,
coupled with “[t]he additional ‘carbamate to urea’ change that is required,
diminishes any possibility that homologous portions may function in a
similar manner” (App. Br. 17). We are not persuaded. Marriott teaches the
carbamate to urea substitution. Therefore, the question is whether the
modification of the piperidin-4-yl ring in compound 14 of Naito for a
pyrrolidinyl ring would have been obvious to a person of ordinary skill in
the art. In this regard, we note that:
Structural relationships may provide the requisite motivation or
suggestion to modify known compounds to obtain new
compounds. For example, a prior art compound may suggest its
homologs because homologs often have similar properties and
therefore chemists of ordinary skill would ordinarily
contemplate making them to try to obtain compounds with
improved properties. Similarly, a known compound may
suggest its analogs or isomers, either geometric isomers (cis v.
trans) or position isomers (e.g., ortho v. para).

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In re Deuel, 51 F.3d 1552, 1558 (Fed. Cir. 1995). Similarly, in Shetty the
Examiner noted that the claimed compound differed from the prior art
compound by “a mere methylene group . . . and concluded that ‘this minor
molecular modification would clearly be obvious to the pharmaceutical
chemist.’” The Shetty court, agreed with the Examiner’s position, finding
“that a person skilled in chemical and/or pharmaceutical arts would not
hesitate to extend the alkylene linkage of the prior art compound.” In re
Shetty, 566 F.2d 81, 85 (CCPA 1977). Accordingly, absent evidence to the
contrary, which there is none, we are not persuaded by Appellants’
argument. Attorney argument cannot take the place of evidence lacking in
the record. Meitzner v. Mindick, 549 F.2d 775, 782 (CCPA 1977).
For the reasons set forth above, we are not persuaded by Appellants
arguments concerning Büchi.
Accordingly, we affirm the rejection of claim 55 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Naito, Marriott, Mitch, and
Büchi. Claim 56 falls together with claim 55.

Claim 58:
The Examiner finds that “the 1-azabicyclo[2.2.2]octyl portion of the
YM-46303 muscarinic antagonist disclosed by Naito et al. represents, for
example, a [homology] of the currently claimed 1-azabicyclo[2.2.1]heptyl
‘B’ group” (Ans. 7).
Appellants assert that “more modifications have to be made to the
Naito compound to render the claimed compound obvious. The additional
‘carbamate to urea’ change that is required, diminishes any possibility that
homologous portions may function in a similar manner” (App. Br. 18). For
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the reasons set forth above, we disagree. For the same reasons we are not
persuaded by Appellants’ arguments regarding Büchi.
Accordingly, we affirm the rejection of claim 58 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Naito, Marriott, Mitch, and
Büchi.

Claim 59:
The Examiner finds that:
The 1-azabicyclo[2.2.2]octyl portion of the YM-46303
muscarinic antagonist disclosed by Naito et al. represents, for
example, a positional isomer with regard to the bridgehead
linkage (bound either meta or para to the ring nitrogen).
Compounds that are position isomers are generally of
sufficiently close structural similarity that there is a presumed
expectation that such compounds possess similar properties. In
re Wilder, 563 F.2d 457 . . . (CCPA 1977).

(Ans. 7-8.)
Appellants assert that that “the combined teachings do not
suggest taking the Naito muscarinic antagonist, changing its
carbamate to a urea, and then substituting the 1-azabicyclo[2.2.2]octyl
group with a 1-azabicyclo[3.2.1]octyl group to arrive at the claimed
compound” and “there is no reasonable expectation of success” in
doing so (App. Br. 19). For the reasons set forth above, we disagree.
Accordingly, we affirm the rejection of claim 59 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Naito, Marriott, Mitch, and
Büchi.

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Obviousness-type double patenting:
Claims 50-63 stand rejected under the judicially created doctrine of
obviousness-type double patenting as being unpatentable over claim 263 of
U.S. Patent 7,238,709 in view of Marriott, Mitch, Büchi, and Naito.
Claim 26 of the ‘709 patent is drawn to a compound having formula
(V)

or a salt thereof.
The Examiner finds that claim 26 of the ‘709 patent recites “a species
of Muscarinic antagonists that read (in part) on the currently claimed
invention. For example, claim [26 of ‘709] . . . recites N-[1,1’-biphenyl]-2-
yl-N’-4-methyl-4-piperidinyl-carbamate which reads (in part) on the
currently claimed ureas when R2=phenyl, K”=bond, A=phenyl,
R1=hydrogen and B=piperidinyl” (Ans. 12). The Examiner finds that the
muscarinic antagonist of ‘709’s claim 26 differs from the compound of
claim 50 by “reciting a ‘carbamate’ linkage instead of the requisite ‘urea’
linkage[ ]” and “a ‘4-methyl-4-piperidinyl’ group instead of the requisite
‘piperidinyl’ group” (id.).
The Examiner relies on Marriott, Mitch, Büchi, and Naito to teach the
substitution of an urea linkage for the carbamate in the compound of ‘709’s

3 As the Examiner explains U.S. Patent Application No. 09/732,241 issued
as U.S. Patent No. 7,238,709 (Ans. 11). Claim 51 of the ‘241 application
was renumbered as claim 26 in the ‘709 patent.
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claim 26. For the reasons discussed above, we find no error in the
Examiner’s conclusion that this substitution would have been prima facie
obvious to a person of ordinary skill in the art at the time the invention was
made (Ans. 12-13). The Examiner finds that piperidinyl is a homolog of 4-
methyl-4-piperidinyl and therefore the substitution of a 4-methyl-4-
piperidinyl group for a piperidinyl group would have been prima facie
obvious to a person of ordinary skill in the art at the time the invention was
made (Ans. 12-14). For the reasons set forth above, we find no error in the
Examiner’s prima facie case of obviousness.
In response, Appellants question why “one skilled in the art [would]
select the particular fragments mentioned by the Examiner from all the
possible fragments that could be used, to modify the teachings of the [‘709
patent] . . . or Naito, both of which describe compounds having central
carbamates” (App. Br. 23). For the reasons set forth above, we are not
persuaded.
The compound of ‘709’s claim 26 differs from Naito’s compound 14
by a methylene. Accordingly, a person of ordinary skill in the art would
have found it prima facie obvious to remove the methylene group from the
compound of ‘709’s claim 26 to use it as taught by Naito. As for the
substitution of the carbamate with an urea, as discussed above, Marriott
provides a person of ordinary skill in this art with a reason to make this
modification.
Absent evidence to the contrary, which there is none, we find no error
in the Examiner’s prima facie case.
Accordingly, we affirm the rejection of claim 50 under the judicially
created doctrine of obviousness-type double patenting as being unpatentable
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over claim 26 of U.S. Patent 7,238,709 in view of Marriott, Mitch, Büchi,
and Naito. Since they were not argued separately, claims 51-63 fall together
with claim 50. 37 C.F.R. § 41.37(c)(1)(vii).

CONCLUSION
In summary, we affirm the rejections of record.
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; 37 C.F.R. § 41.50(b)

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