Ex parte OIDA et al.

Board of Patent Appeals and Interferences

Feb 5, 1998

08035915 (B.P.A.I. Feb. 5, 1998)

Application for patent filed March 23, 1993. According to applicants, this application is a continuation of1
Application 07/935,642, filed August 25, 1992, now abandoned; which is a continuation of Application 07/810,304, filed
December 19, 1991, now abandoned; which is a continuation of Application 07/697,532, filed April 30, 1991, now
abandoned; which is a continuation of Application 07/481,717, filed February 15, 1990, now abandoned; which is a
continuation of Application 07/018,794, filed February 19, 1987, now abandoned; which is a continuation of Application
06/873,856, filed June 11, 1986, now abandoned; which is a continuation of Application 06/742,132, filed June 6, 1985,
now abandoned; which is a continuation of Application 06/525,616, filed August 22, 1983, now abandoned.
-1-
THIS OPINION WAS NOT WRITTEN FOR PUBLICATION
The opinion in support of the decision being entered today (1) was not written for publication in a
law journal and (2) is not binding precedent of the Board.
Paper No. 89
UNITED STATES PATENT AND TRADEMARK OFFICE
_____________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
_____________
Ex parte SADAO OIDA, AKIRA YOSHIDA,
YAWARA TAJIMA, and NORIKO TAKEDA
_____________
Appeal No. 94-4265
Application 08/035,9151
______________
ON BRIEF
_______________
Before WILLIAM F. SMITH, WEIFFENBACH and WALTZ, Administrative Patent Judges.
WEIFFENBACH, Administrative Patent Judge.
Appeal No. 94-4265
Application 08/035,915
Although Oida is the second named inventor in the Japanese Kokai, the examiner identified the reference by “Oida2
III” early in the prosecution. Although it is customary for the Board to identify a reference by the last name of the first named
inventor only, since the examiner and appellants have used “Oida III” throughout the prosecution, we will use it for the sake
of consistency. The reference has been translated and it is the translation which has been relied upon by the examiner and
by us in our decision.
-2-
DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the examiner's final rejection of
claims 37, 39, 43, 45-48, and 50-59, the only claims remaining in the application. We reverse.
The Claimed Subject Matter
The claims on appeal are directed to a process for preparing azetidinone and carbapenem
derivatives. Claim 51 is illustrative of the claimed subject matter and is appended to this decision.
The Prior Art
The following prior art references are relied upon by the examiner in support of the rejection
of the claims:
Oki et al (Oida III ) Japanese Kokai 57-9784 Jan. 19, 19822
Morimoto (EP 45198) European Patent Application 0 045 198 Feb. 3, 1982
The following additional references, not relied upon in the stated rejection of the claims on appeal,
are cited by the examiner in the answer and the appellants in their reply brief:
International Tables for X-ray Crystallography, “Volume II Mathematical Tables,” The
Kynoch Press, Birmingham, England, pp. 60-64 (1959) (reply brief, appendix 4).
Handbook of Chemistry and Physics, The Chemical Rubber Co., 46th Edition, p. F-121
Appeal No. 94-4265
Application 08/035,915
We note that in the final rejection, the examiner made separate rejections of the claims over Oida III and EP3
45198, but combined them into a single rejection in the examiner’s answer.
-3-
(1965) (answer, p. 2).
Pine et al., Organic Chemistry, 4th Edition, McGraw-Hill International Book Company, pp.
79-82 (1981) (reply brief, appendix 2).
Pfaendler et al., “Structure, Reactivity, and Biological Activity of Strained Bicyclic $-Lac-
tams,” J. Am. Chem. Soc., Vol. 103, pp. 4526-4531 (1981) (reply brief, appendix 3).
Allen et al., “The Development of Versions 3 and 4 of the Cambridge Structural Database
System,” J. Chem. Inf. Comput. Sci., Vol. 31, pp. 187-204 (1991) (reply brief,
appendix 5).

The Rejection
All of the claims stand rejected under 35 U.S.C. § 103 as being obvious in view of either Oida
III or EP 45198. 3
Opinion
We have carefully considered the respective positions advanced by appellants and the
examiner. For the reasons set forth below, we will not sustain the examiner's rejection.
In essence, appellants’ process involves forming an azetidinone derivative which is then
cyclized by “conventional means,” a Witting condensation reaction, to form a carbapenem derivative
having formula (IV) as per the following reaction mechanism:
Appeal No. 94-4265
Application 08/035,915
-4-
wherein R can be, inter alia, hydrogen; R and R may be the same or different and each may be1 2 3
hydrogen, a C -C alkyl group or a phenyl group; R is, inter alia, a C -C alkyl group; R is, inter1 6 1 64 5
alia, a carboxy-protecting group; and R is, inter alia, a C -C alkoxy group or a phenoxy group.6 1 6
The method defined by claim 50 comprises cyclizing the compound of formula (I) to form the
compound of formula (IV). The method of claim 51 is essentially the reaction mechanism illustrated
above, but without identifying the compound having formula (I) as an intermediate. Claim 48 is
dependent on claim 51 and specifies that the method of claim 51 is effected without isolation of the
intermediate product (presumably the compound of formula (I)) produced by the reaction of
compounds having formulae (II) and (III).
Appeal No. 94-4265
Application 08/035,915
The examiner appears to hold that Oida III teaches a “Y” as being only a methylene group. However, as4
translated, the reference states on pages 2 and 6 that “Y represents an oxygen atom, sulfur atom, or methylene group.”
-5-
Oida III teaches a method of producing penemve-3-carboxylic acid derivatives in accordance
with the following reaction mechanism:
wherein R can be a hydroxy group, A can be ethylidene, R can be a C -C alkyl group, and R is a7 8 9 1 5
carboxy protecting group, R can be an alkoxy group, and Y can be a methylene group or sulfur10
atom (Oida III, pp. 4-7). The examiner’s position is that a methylene group (Y) and the sulfur atom4
bridging the carbonyl group and the nitrogen ring in the Oida III compounds (formulae (V-VIII)) are
known structural isosteres, i.e. the methylene group (Y) is interchangeable with the sulfur atom. The
examiner relies on Mead Johnson v. Premo Pharmaceutical Labs, 207 USPQ 820 (D.N.J. 1980) to
support his position.
Appeal No. 94-4265
Application 08/035,915
-6-
We agree with appellants that the Mead case does not support the examiner’s position. In
the Mead case, the court made a factual finding that
44. The only difference between the structure of isoxsuprine and that of
nylidrin is that isoxsuprine contains an oxygen atom adjacent to the right-hand phenyl
group or benzene ring whereas nylidrin has a methylene group (CH ) attached to the2
benzene ring instead of the oxygen atom in the same position.
The court considered testimony and other evidence before it and concluded that
87. One of the many classical molecular modifications, in accordance with
the principles of bioisosterism, is the replacement a methylene group with an oxygen
atom in biologically active compound. Such substitution was well known prior to
1955 to produce compounds of similar biological activity to the lead compound, and
it would have been obvious for a medicinal chemist in that time period to have made
the substitution when seeking to modify a compound containing a methylene group,
provided, of course, that the substitution was chemically feasible in that particular
position.
88. In terms of the priority which a medicinal chemist would have
accorded to the isosteric replacement of oxygen for methylene in the nylidrin
compound prior to 1955, a medicinal chemist would have considered that
modification to be the second out of four which would logically have been attempted
in the search for an improved cardiovascular drug.
89. Another theory known in the organic chemistry art prior to 1955 which
posited that oxygen and methylene could be interchanged in compounds without
greatly affecting their physical properties was Grimm*s Hydride Displacement Law
....
90. Oxygen was said by Grimm to be interchangeable with the methylene
group. The modification of nylidrin which resulted from the interchanging of oxygen
and methylene was within the replacement rules taught by Grimm, although Grimm*s
law does not postulate any compounds which specifically related to isoxsuprine or
nylidrin.
91. A medicinal chemist seeking in 1955 to modify the compound nylidrin
in order to improve its biological properties would have been motivated to substitute
oxygen for methylene adjacent to phenyl in nylidrin because of the teachings of the
Appeal No. 94-4265
Application 08/035,915
-7-
prior art as to the interchangeability of oxygen and methylene and the fact that
substitution had produced compounds of similar and sometimes improved activity.
We do not find in the record before us that the examiner has established that sulfur and
methylene in the Oida III compounds are isosteres. Drawing a conclusion from the Mead case that
sulfur and methylene are isosteres because evidence in Mead led the judge to conclude that oxygen
and methylene are isosteres for compounds such as nylidrin and isoxsuprine without any further
evidence is pure speculation. The examiner has not presented any evidence that sulfur and methylene
isosterism is known in the art for the claimed compounds and that such interchange would have been
considered to be within the skill of the art. The court in the Mead case based its decision on
isosterism on evidence. Here the examiner has provided no such evidence. The examiner is in error
in relying on the Mead case to establish isosterism rather than presenting scientific reasoning to show
that Oida III’s and appellants’ compounds are isosteric compounds. In re Brouwer, 77 F.3d 422,
425, 37 USPQ2d 1663, 1666 (Fed. Cir. 1996). Furthermore, the examiner’s reliance in this case on
In re Durden, 763 F.2d 1406, 226 USPQ 359 (Fed. Cir. 1985) and In re Albertson, 332 F.2d 379,
141 USPQ 730 (CCPA 1964) to support a conclusion of obviousness is also misplaced. See In re
Ochiai, 71 F.3d 1565, 1569-1572, 37 USPQ2d 1127, 1131-1133 (Fed. Cir. 1995). For these
reasons, we will not sustain the rejection of any of the claims over Oida III alone.
The examiner rejected all of the claims as being unpatentable under 35 U.S.C. § 103 over EP
45198 alone. The reference is directed to preparing carba-2-penem compounds having formula (XII)
made in accordance with the following reaction mechanism:
Appeal No. 94-4265
Application 08/035,915
-8-
wherein R can be a hydroxyalkyl group, R can be an alkoxycarbonyl group, R can be a C -C11 12 13 1 4
alkyl group or aryl group, R can be a C -C alkylthio group, R can be a lower alkoxy group, X14 15 1 4
is a halogen atom or a reactive ester residue, and COOR is a protected carboxyl group (EP 45198:
p. 2, line 4 to p. 3, line 1; p. 5, lines 8-29; p. 10, line 24 to p. 11, line 4; p.18, line 24 to p. 19, line 3).
The reaction mechanism in EP 45198 is similar to appellants’ claimed mechanism, the
principle differences being substituent R at the 1-position of the penem structure and the starting12
compound (formula (IX)) for the reaction. While appellants’ R and R in EP 45198 can be a C -C3 13 1 4
alkyl group or phenyl, appellants’ R and R in EP 45198 are different. Appellants’ compound2 12
defines R as being hydrogen, a C -C alkyl group or a phenyl group while EP 45198 defines R as2 121 8
being, for example, a C -C alkoxycarbonyl group or a C -C alkylcarbonyl (EP 45198: p. 5, lines1 4 1 4
Appeal No. 94-4265
Application 08/035,915
Upon the return of this application to the examining group, the examiner should consider the references cited on5
page 2 of EP 45198.
-9-
8-13). As for the other noted difference, EP 45198 has the following functional group in starting
formula (IX):
while the functional group in appellants’ starting formula (II) is
The examiner has not made out a prima facie case of obviousness over EP 45198 taken alone.
The examiner has not presented a reasoned analysis to explain why the teachings of EP 45198 would
have led one skilled in the art to appellant’s claimed starting compound having formula (II). EP
45198 does not disclose R as comprising moieties as set forth set forth in appellants’ claims for R .12 2
While we note that EP 45198 discloses on page 2 that carba-2-penems are known having no
substituents or two methyl groups at the 1- position, the reference does not disclose making5
compounds using the Wittig reaction where R is hydrogen or a methyl group. The examiner has not12
presented any reasoned analysis to explained how it would have been obvious to one skilled in the
Appeal No. 94-4265
Application 08/035,915
-10-
art from the teachings of EP 45198 for R to be hydrogen, a C -C alkyl group or a phenyl group as12 1 8
required by appellants’ claims on appeal. For the foregoing reasons, we will not sustain the rejection
of the claims over EP 45198 alone.
In summary, we find that the examiner has not established a prima facie case of obviousness
for the claimed subject matter over Oida III or EP 45198. Accordingly, the decision of the examiner
is reversed.
No time period for taking any subsequent action in connection with this appeal may be
extended under 37 CFR § 1.136(a).
REVERSED
WILLIAM F. SMITH )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
CAMERON WEIFFENBACH ) APPEALS AND
Administrative Patent Judge ) INTERFERENCES
)
)
)
THOMAS A. WALTZ )
Administrative Patent Judge )
Appeal No. 94-4265
Application 08/035,915
-11-
FRISHAUF, HOLTZ, GOODMAN,
LANGER & CHICK, P.C.
767 THIRD AVE.
25TH FLOOR
NEW YORK, NY 10017-2023
Appeal No. 94-4265
Application 08/035,915
-12-
APPENDIX
51. A process for preparing a compound of the formula (IV):
which comprises reacting a compound of the formula (II):
with a compound of the formula (III):
and cyclising the product of this reaction to prepare said compound of the formula (IV);
wherein
R represents hydrogen or a hydroxy-protecting group;1
R and R may be the same or different and each represents hydrogen, a C -C alkyl group or2 3 1 8
a phenyl group;
Appeal No. 94-4265
Application 08/035,915
-13-
R represents a C -C alkyl group;4 1 6
a non-aromatic heterocyclic group having from 4 to 8 ring carbon atoms and having one or
two ring nitrogen atoms and optionally containing an oxygen atom, a sulphur atom, a sulphinyl group,
a sulphonyl group or a carbonyl group, and optionally having one or more substituents attached to
the carbon atoms or to any nitrogen atom, selected from the group consisting of (1) substituents for
attachment to the ring carbon atoms selected from the group consisting of C -C alkyl groups,1 6
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, C -C alkoxyalkyl groups,2 8
methoxycarbonylmethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl, benzyloxycarbonylethyl,
methoxycarbonylpropyl groups, C -C cyanoalkyl groups, C -C haloalkyl groups, C -C alkoxy2 7 1 6 1 6
groups, halogen atoms, C -C aliphatic acyloxy groups, C -C aliphatic acylamino groups, cyano1 6 1 6
group, azido group, carboxy group, C -C alkoxycarbonyl groups, carbamoyl group, C -C alkylthio2 7 1 6
groups, C -C alkylsulphinyl groups, C -C alkylsulphonyl groups, nitro group; and (2) substituents1 6 1 6
for attachment to said ring nitrogen atom(s) selected from the group consisting of C -C alkyl groups,1 6
C -C alkenyl groups, C -C alkynyl groups, C -C cycloalkyl groups, cyclopropylmethyl, cyclo-2 6 2 6 3 8
butylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopentylethyl, 2-cyclo-
hexylethyl, 3-cyclopentylpropyl, 2-cyclopentylpropyl, 3-cyclohexylpropyl, 2-cyclohexylpropyl, 4-
cyclopentylbutyl, 3-cyclohexylbutyl, phenyl, naphthyl groups, benzyl, phenethyl, 3-phenylpropyl, C -1
C aliphatic acyl groups, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl,6
cyclohexanecarbonyl, cyclopropylacetyl, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl, 3-
cyclopentylpropionyl, 3-cyclohexylpropionyl, 4-cyclopentylbutyryl, 4-cyclohexylbutyryl benzoyl, l-,
naphthoyl, 2-naphthoyl groups, phenylacetyl, l-naphthylacetyl, 3-phenylpropionyl, hydratropoyl,
cinnamoyl, phenylpropioloyl, furoyl, thenoyl, nicotinoyl, isonicotinoyl, 4-thiazolecarbonyl, 5-
pyrimidinecarbonyl, 2-pyrazinecarbonyl, 2-thienylacetyl, 3-(2-thienyl)propionyl, 4-thiazolylacetyl, 2-
pyridylacetyl, 4-pyridylacetyl, 5-pyrimidinylacetyl, 1-aziridinylacetyl, 1-azetidinylacetyl, 3-
azetidinylacetyl, l-pyrrolidinylacetyl, 2-pyrrolidinylacetyl, 3-pyrrolidinylacetyl, 3-(2-pyrrolidinyl)-
propionyl, piperidinoacetyl, 2-piperidinylacetyl, 4-piperidinylacetyl, morpholinoacetyl, l-aziridine-
carbonyl, 1-azetidinecarbonyl, 3-azetidinecarbonyl, 1-pyrrolidinecarbonyl, 2-pyrrolidinecarbonyl, 3-
pyrrolidinecarbonyl, 1-piperidinecarbonyl 2-piperidinecarbonyl, 4-piperidinecarbonyl, 4-
morpholinecarbonyl, phenacyl group, sulpho group, C -C alkoxysulphonyl groups, C -C1 6 1 6
alkylsulphonyl groups, C -C alkenylsulphonyl groups, C -C alkynylsulphonyl groups, cyclo-2 6 2 6
propylsulphonyl, cyclobutylsulphonyl, cyclopentylsulphonyl, cyclohexylsulphonyl, cyclopropyl-
methylsulphonyl, cyclobutylmethylsulphonyl, cyclopentylmethylsulphonyl, cyclohexylmethyl-
sulphonyl, 2-cyclopentylethylsulphonyl, 2-cyclohexylethylsulphonyl, 3-cyclopentylpropyl-sulphonyl,
2-cyclopentylpropylsulphonyl, phenylsulphonyl, l-naphthylsulphonyl, 2-naphthyl-sulphonyl,
benzylsulphonyl, phenethylsulphonyl, 3-phenylpropylsulphonyl, 2-phenylpropyl-sulphonyl, 2-
thienylsulphonyl, 4-thiazolylsulphonyl, 2-pyridylsulphonyl, 4-pyridyl-sulphonyl, 2-
thienylmethylsulphonyl, 3-(2-thienyl)propylsulphonyl, 4-thiazolylmethylsulphonyl, 2-pyridyl-
methylsulphonyl, 4-pyridylmethylsulphonyl group, groups of the formula
Appeal No. 94-4265
Application 08/035,915
-14-
wherein R represents a hydrogen atom or a C -C alkyl group and R represents a10 111 4
hydrogen atom, allyloxycarbonyl, 2-methylallyloxycarbonyl, 2-chloroallyloxy-
carbonyl, 2,2,2-trichloroethoxy-carbonyl, 2,2,2-tribromoethoxycarbonyl, p-nitro-
benzyloxycarbonyl or o-nitrobenzyloxycarbonyl,
groups of the formula
wherein R and R are the same or different and each represents a hydrogen atom12 13
or a C -C alkyl group and Y represents an oxygen atom, a sulphur atom or an imino1 4
group which may be optionally substituted with a C -C alkyl group,1 4
C -C alkoxycarbonyl groups, benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl2 7
and o-nitrobenzyloxy carbonyl group; and
the substituents attached to the nitrogen atoms of the non-aromatic heterocyclic
groups may be substituted with one or more groups selected from the group
consisting of C -C alkyl groups, C -C alkoxy groups hydroxy, amino, halogen, C -1 4 1 4 , 1
C aliphatic acyloxy groups, C -C aliphatic acylarnino groups, cyano, azido, carboxy,5 1 5
C -C alkoxycarbonyl groups, the carbamoyl group, C -C alkylthio group, C -C2 5 1 4 l 4
alkylsulphinyl groups, C -C alkylsulphonyl groups, nitro group, and groups of1 4
formula
wherein R and R are the same or different and each represents a hydrogen atom14 15
or a C -C alkyl group;1 4
a substituted alkyl group, said substituted alkyl groups being selected from the group consist-
ing of a hydroxyalkyl group, a protected hydroxy alkyl group, an aminoalkyl group, and a protected
Appeal No. 94-4265
Application 08/035,915
-15-
aminoalkyl group;
a group represented by the formula
wherein R , R , and R are the same or different and each represents hydrogen, methyl, ethyl, an7 8 9
amino-protecting group, or R and R or R and R , together with the atom or atoms to which they7 8 8 9
are attached, form a ring and when R and R form a ring, they together represent ethylene, tri-8 9
methylene, tetramethylene, when R and R form a ring, R and R together represent ethylene or7 8 7 8
trimethylene;
an aryl-substituted alkyl group, selected from the group consisting of benzyl, p-methoxy-
benzyl, m-nitrobenzyl, o-methylbenzyl, p-bromobenzyl and p-aminobenzyl; furfuryl;
an alkyl group having a non-aromatic heterocyclic substituent, the alkyl group of which is a
C -C alkyl, and the non-aromatic heterocyclic substituent is selected from the substituted or1 4
unsubstituted non-aromatic heterocyclic groups within the definition hereinbefore of R ;4
an alkenyl group or a substituted alkenyl group, selected from the group consisting of vinyl,
allyl, 1-propenyl and 2-butenyl;
an alkynyl group or a substituted alkynyl group selected from the group consisting of ethynyl,
2-propynyl and 1-propynyl;
and when R represents a substituted alkenyl or alkynyl group as defined above, the4
substituents are selected from the group consisting of the formula ) NR R wherein16 17
R and R are the same or different and each represents hydrogen, methyl, ethyl,16 17
propyl, isopropyl group, ormyl, acetyl, propionyl, isobutyryl, chloroacetyl, trifluoro-
acetyl, benzoyl group or an amino-protecting group; groups of the formula
) CONHR , wherein R represents a hydrogen, methyl, ethyl, propyl, or an amino-18 18
protecting group; groups of the formula ) NHCONHR ; groups of the formula18
) COOR ; wherein R represents hydrogen, methyl, ethyl, propyl or a carboxy-19 19
protecting group; groups of the formula ) SR , wherein R represents hydrogen,20 20
methyl, ethyl, propyl, allyl, vinyl, 1-methylvinyl, 1-propenyl, ethynyl, 2-propynyl, 1-
propynyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentyl-
methyl, 2-cyclohexylethyl, 2-cyclopentylethyl, benzyl, phenethyl, p-methoxybenzyl,
p-bromobenzyl phenyl, p-tolyl, p-methoxyphenyl, thienyl, furyl, imidazolyl, pyridyl,,
thienylmethyl, 2-thienylethyl, pyridylmethyl, imidazolylmethyl and thiazolymethyl;
groups of the formula ) S(:0)R ; groups of the formula ) SO R wherein R20 21 212
Appeal No. 94-4265
Application 08/035,915
-16-
represents any of the groups defined for R or methoxy, ethoxy or propoxy; groups20
of formula ) OSO R ; cyano; nitro; and azido groups;2 20
R represents hydrogen, or a carboxy-protecting group;5
R represents an alkoxy group having from 1 to 6 carbon atoms, or a phenoxy group selected6
from the group consisting of phenoxy, p-methylphenoxy, p-methoxyphenoxy groups, and a dialkyl-
amino group wherein each alkyl group has from 1 to 6 carbon atoms, or two R groups together6
represent an o-phenylenedioxy group, and the other R represents any other R group, or the three6 6
R groups together represent a group of the formula CH ) (CH ) 0) ) .6 3 2 3