Ex parte SINGH et al.

Board of Patent Appeals and Interferences

Aug 7, 1998

08007950 - (D) (B.P.A.I. Aug. 7, 1998)

Application for patent filed January 25, 1993. According to1
applicants, the application on appeal is a continuation-in-part of application
07/912,384, filed July 13, 1992. The real party in interest appears to be
Bristol-Myers Squibb Company.
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journal and (2) is not binding precedent of the Board.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. 10
UNITED STATES PATENT AND TRADEMARK OFFICE
_____________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
_____________
Ex parte JANAK SINGH, GREGORY S. BISACCHI,
JOLLIE D. GODFREY, Jr., TOOMAS MITT, RICHARD H. MUELLER,
ROBERT ZAHLER and THOMAS P. KISSICK

_____________
Appeal No. 95-0865
Application 08/007,9501
______________
ON BRIEF
_______________
Before: WINTERS and WILLIAM F. SMITH, Administrative Patent
Judges, and McKELVEY, Senior Administrative Patent Judge.
McKELVEY, Senior Administrative Patent Judge.
Decision on appeal under 35 U.S.C. § 134
The appeal is from a decision of the Primary Examiner
rejecting claims 6-22 and 25 (Paper 6, page 1, item 4 under
Appeal No. 95-0865
Application 08/08/007,950
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Part II "Summary of Action"), which are all of the claims in the
application on appeal. We reverse, but enter new grounds of
rejection pursuant to 37 CFR § 1.196(b) as to Claims 6-9, 11-17,
19-22 and 25. We do not enter new grounds of rejection as to
Claims 10 and 18.
A. Findings of fact
The record supports the following findings by a
preponderance of the evidence.
The invention
1. The invention relates to a process for making
2-amino-6-halo-9-[2,3-disubstituted-cyclobutyl]-purines.
2. The invention also relates to converting the
purines to known antiviral agents, e.g., [1R-(1",2$,3")]-2-amino-
9-[2,3-bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one.
3. A 9-cyclobutane purine ring has the following
structure and
numbering system:
Appeal No. 95-0865
Application 08/08/007,950
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4. Claim 6 reads as follows (paragraph numbering
added):
A process for preparing the cyclobutyl purine of the formula
which comprises reacting a purine salt of the formula
Appeal No. 95-0865
Application 08/08/007,950
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with the bis(2,3-protected hydroxymethyl)cyclobutane of the
formula
wherein:
a. Prot is a hydroxy protecting group selected from
the group consisting of
(1) t-butyldimethylsilyl,
(2) t-butyldiphenylsilyl,
(3) (tri-phenylmethyl)dimethylsilyl,
(4) methyldiisopropylsilyl,
(5) triisopropylsilyl,
(6) benzyl,
(7) p-methoxybenzyl, and
(8) acyl groups of the formula
O
5
))))) C)) R5
wherein R is5
(a) straight or branched chain
alkyl of 1 to 6 carbon atoms
or
(b) phenyl;
b. X is
(1) a perfluoroalkane sulfonyloxy group,
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(2) a nitro-substituted benzene sulfonyloxy
group, or
(3) a fluorosylfonyloxy;
c. Y is chloro, bromo, or iodo;1
d. R , R , R and R are independently selected from1 2 3 4
the group consisting of
(a) straight or branched chain alkyl of
1 to 10 carbons and
(b) substituted straight or branched
chain alkyl of 1 to 10 carbons;
(1) [where] substituted straight or branched
chain alkyl of 1 to 10 carbons refers to
such alkyl groups having one, two, or
three substituents selected from the
group consisting of
(a) alkoxy of 1 to 6 carbons and
(b) aryl; and
(2) [where] aryl refers to phenyl and phenyl
having one, two, or three substituents
selected from the group consisting of
(a) alkyl of 1 to 6 carbons,
(b) alkoxy of 1 yo 6 carbons, [and]
(c) chloro, bromo, iodo and fluoro.
5. Insofar as we have been able to determine,
applicants' specification does not describe any particular
advantage of the claimed process vis-à-vis prior art processes
described in the specification (e.g., those at page 2, line 1
through page 3, line 14).
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The examiner's rejections
6. The examiner made the following four rejections in
the final rejection (Paper 6).
7. Claims 6-19 and 22 were finally rejected (Paper 6,
page 2) as being unpatentable under 35 U.S.C. § 103 over:
a. Bisacchi, U.S. Patent 5,064,961 (1991) or
Slusarchyk, European Patent Application
0 352 013 (published Jan. 24, 1990)
b. in view of Searcey, IMPROVED SYNTHESES OF
N-SUBSTITUTED NITROIMIDAZOLES, Synthetic
Communications, Vol. 19, pages 1309-15
(1989).
8. Claims 6-13 and 25 were finally rejected (Paper 6,
page 5) as being unpatentable under 35 U.S.C. § 103 over
Hagberg I, European Patent Application 0 055 239 (published
June 30, 1982). In the Examiner's Answer (Paper 9, page 6), the
examiner refers to claims 6-13 and 23-24 and does not mention
claim 25. Claims 23-24 were cancelled (Paper 5, page 2). Hence,
we will assume that the examiner intended in the Examiner's
Answer to maintain a rejection claims 6-13 and 25.
9. Claims 20-21 were finally rejected (Paper 6,
page 6) as being unpatentable under 35 U.S.C. § 103 over:
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Application 08/08/007,950
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a. Bisacchi or Slusarchyk
b. in view of Searcey
c. further in view of Hagberg II, U.S. Patent
4,495,190 (1985).
10. Claims 14-22 were finally rejected (Paper 6,
page 6) as being unpatentable under 35 U.S.C. § 103 over:
a. Hagberg I
b. in view of Bisacchi, Slusarchyk and
Hagberg II.
Bisacchi
11. Bisacchi, U.S. Patent 5,064,961 (1991) describes a
method for making compounds, including a compound having the
formula:
Appeal No. 95-0865
Application 08/08/007,950
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The method involves the reaction of Bisacchi cyclobutane
Compound 13 (col. 3)
with 2-amino-6-chloropurine (col. 7, last line through col. 8,
first line) to produce Bisacchi Compound 14 (col. 3)
where W can be 2-amino-6-chloropurine-9-yl (col. 7, lines 32-33):
Appeal No. 95-0865
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The reaction takes place in the presence of "a base such as
potassium carbonate [K CO ], sodium hydride [NaH], and the like,2 3
preferably potassium carbonate" (col. 8, lines 5-7).
12. X of Bisacchi Compound 13 is a "leaving group"
(col. 3, line 64) such as trifluoromethanesulfonyloxy (triflyl;
CF ) SO) O) ) (col. 3, lines 66-67), corresponding to applicants'3
claimed X which can be, inter alia, a perfluoroalkane sulfonyloxy
group. The Bisacchi X can also be methanesulfonyloxy (mesyl;
CH ) SO) O) ) (col. 3, line 65) or p-nitrobenzenesulfonyloxy (nosyl;3
O N ) C H ) SO ) O) ) (col. 4, lines 30-31).2 6 4
13. The R of Bisacchi's Compounds 13 and 14 is 4
a protecting group such as an acyl group (e.g., acetyl), a benzyl
group, t-butyldiphenylsilyl or t-triisopropylsilyl (col. 3,
lines 59-63), which corresponds to applicants' "Prot" group when
"Prot" is t-butyldiphenylsilyl, t-triisopropylsilyl or an acyl
group and applicants' R acetyl, i.e., is alkyl of 1 carbon.5
Appeal No. 95-0865
Application 08/08/007,950
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14. Bisacchi lists four possibilities for W (col. 4,
lines 31-37 and col. 7, last line through col. 8, first line).
15. The process described by Bisacchi differs from
applicants' claim 6 in that Bisacchi describes the use of purines
in potassium or sodium salt form whereas applicants claim the use
of a purine in its tetraalkylammonium salt form.
Searcey
16. Searcey describes the reaction of a nitroimidazole
with an "appropriate halo compound" (page 1309, first paragraph)
to make substituted nitroimidazole compounds. In order to
overcome certain yield problems said to occur using then known
methods (page 1309, beginning with second full paragraph through
page 1310, line 13), Searcey describes an investigation of the
reaction of a nitroimidazole compound in the form of a
tetraalkylammonium salt with the halo compound (page 1310, lines
13-17).
17. Table 1 (page 1311) of Searcey describes, better
yields when the halo compound is reacted with the nitroimidazole
compound in the form of a tetraalkylammonium salt vis-à-vis the
same nitroimidazole compound in the form of an alkali salt, e.g.,
a sodium salt.
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18. A nitroimidazole in its tetrabutylammonium salt
form is described at page 1312.
19. A reaction of nitroimidazole in its
tetrabutylammonium salt form with a benzyl halide (e.g., benzyl
chloride; first example in Table 1) proceeds generally along the
following lines (chemical reaction equation is not balanced):
Slusarchyk European Patent Application 0 352 013
20. Slusarchyk is similar to Bisacchi. As will become
apparent, however, there are some differences.
21. Slusarchyk describes the preparation of
Compound 15, which is a 2-amino-6-chloro-9-[3-monosubstituted]
purine having the formula (page 7, line 47 through page 8,
line 10):
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22. Slusarchyk Compound 15 is made by reacting
2-amino-6-chloro-purine (Slusarchyk Compound 14 (page 7)):
with Slusarchyk's cyclobutane Compound 2 (page 5, line 10) having
the formula:
Appeal No. 95-0865
Application 08/08/007,950
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where:
P is a protecting group, e.g., acyl (page 5, line 20) and
X is a leaving group, e.g., chloro, bromo, iodo or an aryl
group (e.g., p-toluenesulfonyloxy) or an alkyl group (e.g.,
methanesulfonyloxy) (page 5, lines 20-21).
23. The reaction of Slusarchyk Compound 2 with
Slusarchyk Compound 14 is carried out in the presence of a base,
such as potassium carbonate, sodium hydride or potassium hydride
(page 5, line 43).
24. Significant disclosure found in Slusarchyk, but
not found in Bisacchi, is that the leaving group X of Slusarchyk
Compound 2 is described as including halo groups (chloro, bromo,
iodo) whereas the corresponding X group of Bisacchi Compound 13
is not described as including halo groups (col. 3, lines 64
through col. 4, line 31; col. 7, lines 44-48).
Hagberg I European Patent Application 0 055 239
25. Hagberg I describes various organic synthesis
techniques. One technique of interest is Method of Preparation L
which begins on the last line of page 15 and continues to line 17
on page 16.
26. Method L is described as involving a reaction of a
Compound XII, which is said to have the formula:
Appeal No. 95-0865
Application 08/08/007,950
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with a Compound XIII (the one on the left side), which has the
formula:
27. A person having ordinary skill in the art would
immediately recognize that the formula of Compound XII, as set
out on page 16 of Hagberg I is erroneous in that a double bond is
missing between the 7- and 8-positions in the ring and a hydrogen
(H) is missing from the nitrogen (N) at the 9-position. See,
e.g., page 56, formula XII which shows the necessary double bond
between the 7- and 8-positions and an NH at the 9-position. See
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Application 08/08/007,950
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also the formula in Example 10 (page 33). The correct formula
would have been understood to be:
28. The reaction of Hagberg I Compound XII with
Hagberg I Compound XIII is said to be carried out by "methods
known per se" (page 16, line 14).
29. The R of Hagberg I Compound XII may be halo,7
including chloro, and benzyloxy [page 16, lines 10-11, referring
to Method E; page 12, lines 1-3, Y group and referring to Method
C1; page 10, line 1, X group and referring to Method B; page 9,1
lines 19-24 where X is defined inter alia as chlorine (sic--1
chloro) and ) OR where R can be benzyl].2 2
30. The R of Hagberg I Compound XII can be hydrogen11
[page 16, lines 10-11, referring to Method E; page 12, lines 6-7,
Appeal No. 95-0865
Application 08/08/007,950
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referring R in Method C; and page 10, lines 2-3 where R is6 6
defined inter alia as hydrogen].
31. The X of Hagberg I Compound XIII is defined as2
(page 13, lines 16-19):
a leaving group such as chlorine (sic-chloro), bromine
(sic-bromo), iodine (sic-iodo) or a group ) SO R where R is2 2 2
defined in Method B ***.
According to Method B (page 9, lines 21-24):
R is alkyl containing 1-8 carbon atoms, fluorinated alkyl2
containing 1-8 carbon atoms such as trifluoromethyl,
alkylaryl such as benzyl, or aryl such as unsubstituted or
substituted phenyl.
32. When X of Hagberg I Compound XIII is ) SO R and R2 2 22
is trifluoromethyl, the Compound XIII leaving group is the same
as one of the leaving groups described by Bisacchi (X is triflyl)
(col. 3, lines 66-67).
33. When X of Hagberg I Compound XIII is ) SO R and R2 2 22
is methyl (an alkyl having 1-8 carbon atoms), the Hagberg I
Compound XIII leaving group is the same as one of the leaving
groups described by Bisacchi (X is mesyl) (col. 3, lines 64-65).
34. R and R of Hagberg I Compound XIII may be alkyl1 12
(e.g., methyl) [page 16, lines 9-10, referring to Method A and
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page 8, line 36 where R is described as being inter alia alkyl1
containing 1-8 carbon atoms, with methyl being 1 carbon].
35. Pertinent to the issues involved in this appeal is
the method described by Hagberg I in Example 10 (pages 33-34).
Example 10 describes a reaction of
a. 2-amino-6-benzyloxypurine in the form of a
tetrabutylammonium salt [Hagberg I Compound
XII where R is benzyloxy () OCH C H ) and R7 112 6 5
is hydrogen () H)]
b. with (S)-4-O-methanesulfonyl-1,2-O-
isopropylidenebutane-1,2,4-triol [Hagberg I
Compound XIII (left side) where X is2
methanesulfonyloxy [i.e., mesyl] and R and1
R are methyl].12
The significant teaching of Example 10 is that a purine in its
tetraalkylammonium salt form may be reacted with a compound
having a mesyl leaving group. Searcey, on the other hand,
describes only the use of halo leaving groups on the compounds
reacted with the imidazole in its tetraalkylammonium salt form.
36. Findings with respect to other prior art, e.g.,
Ichikawa and Zahler, can be found in the Discussion portion of
this opinion.
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Application 08/08/007,950
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Level of ordinary skill in the art
37. The art involved in this case is the purine art,
and more particularly, the reaction of purines with other
compounds in such a manner that the other compound attaches to
the 9-position of the purine. The prior art (Bisacchi,
Slusarchyk, Hagberg I, Ichikawa and Zahler), with the exception
of Searcey, is within the field of applicants' endeavor.
38. Searcey, while not dealing with purines, is
relevant because it addresses a problem applicants sought and the
prior art seeks to solve, viz., attaching moieties to the NH of
an imidazole ring, it being noted that a purine includes an
imidazole ring.
39. The hypothetical person having ordinary skill in
the art would have been aware of the teachings of the prior art
mentioned above.
B. Discussion
1. The examiner's rejection based on
Bisacchi, Slusarchyk and Searcey
The examiner rejected claims 6-19 and 22 under 35 U.S.C.
§ 103 over Bisacchi, Slusarchyk and Searcey. All of these claims
require the use of a protected disubstituted cyclobutane having a
leaving group X which is one of:
Appeal No. 95-0865
Application 08/08/007,950
As will become apparent, infra, we found that "something more" in the2
teachings of Hagberg I, Ichikawa and Zahler.
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(1) a perfluoroalkane sulfonyloxy group,
(2) a nitro-substituted benzene sulfonyloxy group, or
(3) a fluorosylfonyloxy.
Bisacchi and Slusarchyk describe reaction of a purine in its
alkali salt form and a cyclobutane. Neither describes the use of
a purine in its tetraalkylammonium salt form.
Searcey describes the reaction of an imidazole in its
tetraalkylammonium salt form with compounds having leaving groups
which are halo groups.
The difficulty with the examiner's position is that there is
nothing in Searcey which would suggest that the imidazole in its
tetraalkylammonium salt form would also react with compounds
having leaving groups X called for by the claims. There is no
teaching in the combination of Bisacchi, Slusarchyk, and Searcey
which would show any interchangeability between the use of
purines in their alkali salt forms with purines in their
tetraalkylammonium salt forms. Thus, without something more, we2
regard the examiner's rejection to have been based on
impermissible hindsight. Compare In re McLaughlin, 443 F.2d
1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
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Application 08/08/007,950
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The decision of the examiner rejecting claims 6-19 and 22
based on Bisacchi, Slusarchyk and Searcey is reversed.
2. The examiner's rejection based on Hagberg I
The examiner rejected claims 6-13 and 25 as being
unpatentable under 35 U.S.C. § 103 over Hagberg I.
With reference to Method of Preparation L and Example 10,
Hagberg I differs from the subject matter of claim 6 in that
Hagberg I does not describe the reaction of a cyclobutane with a
purine.
Thus, it can be said that Hagberg I does not describe at
least one of applicants' starting materials, i.e., the
cyclobutane. According to the examiner, the failure of Hagberg I
to describe the cyclobutane starting materials is of no moment.
In support of his position, the examiner cites and relies on In
re Durden, 763 F.2d 1406, 226 USPQ 359 (Fed. Cir. 1985). More to
the point, in our opinion, is In re Ochiai, 71 F.3d 1565, 37
USPQ2d 1127 (Fed. Cir. 1995). The mere fact that a compound with
a mesyl group has been reacted with a purine does not per se
establish that it would have been obvious to react a cyclobutane
with a mesyl group with a purine. Based on Hagberg I alone, we
discern no reason, motivation or suggestion to use a cyclobutane
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in place of Hagberg I Compound XIII in the Method of Preparation
L or Example 10.
The decision of the examiner rejecting claims 6-13 and 25
over Hagberg I alone is reversed.
3. The examiner's rejection based on Bisacchi,
Slusarchyk, Searcey and Hagberg II
The examiner rejected claims 20-21 as being unpatentable
under 35 U.S.C. § 103 over Bisacchi, Slusarchyk, Searcey and
Hagberg II. This rejection is reversed for the same reason that
the rejection of claims 6-19 and 22 over Bisacchi, Slusarchyk and
Searcey was reversed. The information contained in Hagberg II
does not overcome the deficiencies of the combination of
Bisacchi, Slusarchyk and Searcey.
4. The examiner's rejection based on Hagberg I,
Bisacchi, Slusarchyk and Hagberg II
The examiner rejected claims 14-22 as being unpatentable
under 35 U.S.C. § 103 over Hagberg I, Bisacchi, Slusarchyk and
Hagberg II. This rejection is reversed for the same reason that
the rejection of claims 6-13 and 25 over Hagberg I alone was
reversed.
5. New grounds of rejection
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Application 08/08/007,950
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Pursuant to 37 CFR § 1.196(b), we enter the following new
grounds of rejection.
a. General observations concerning new grounds
of rejection based on the prior art
In making the following prior art rejections, we note that
applicants' use known starting materials to obtain a known
product having a known utility. The claims are directed to a
process, not products. Each of the process steps claimed by
applicants involves the use of known organic synthesis
techniques.
We have not overlooked arguments made in applicants' Appeal
Brief. Applicants maintain that there is an issue of whether a
person having ordinary skill in the art would have selected a
6-halopurine from the various purines described by Bisacchi
(Appeal Brief, page 15). There are at least two answers to
applicants' argument. First, Bisacchi describes only four
specific 6-substituted purines, one of which is 2-amino-6-
chloropurine (col. 7, last line to col. 8, first line). Second,
applicants' process is one for making a known compound from known
starting materials and Bisacchi describes the known starting
materials and the known final product. We believe that a person
having ordinary skill in the art, seeking to make the compound
applicants make, would have found it obvious to start with
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2-amino-6-chloropurine, among other compounds, to make the
compound applicants make.
Applicants further argue (Appeal Brief, pages 15 and 16)
that there would have been no motivation to select the
tetraalkylammonium salt described by Searcey in place of the
known alkali salts. On this record, we disagree for the reasons
given in connection with our explanation of the rejection of
claim 25, infra.
Applicants still further argue (Appeal Brief, pages 15 and
16-17) that one would not expect an increase in yield (as
described by Searcey) in the process of Bisacchi or Slusarchyk.
Again, there are at least two answers to applicants' argument.
First, applicants' claims do not require an increased yield. In
fact, applicants' specification does not set out a prior art
problem which is solved by the claimed process. Second, we
disagree that there is no expectation of success when a purine
in its tetraalkylammonium salt form is used. Example 10 of
Hagberg I demonstrates quite the contrary. Moreover, given the
rather compelling improved yield results described by Searcey, we
believe that a person having ordinary skill in the art would have
reasonably expected improved yields when a purine in its
tetraalkylammonium form is reacted with a halo-containing
compound to attach the compound to the purine at the 9-position.
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b. Claim 25
Claim 25 is rejected under 35 U.S.C. § 103 over Slusarchyk
and Searcey. Claim 25 is not a model of clarity due to its use
of Z and Z . Nevertheless, we believe claim 25 calls for1
reacting 6-halo-purine in its tetraalkylammonium salt form with a
compound having the formula Z )) X, including, inter alia,1
cyclobutanes having the formulae:
and
where:
(1) X is a leaving group selected from the group
consisting of:
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(a) chloro, bromo, iodo,
(b) an aryl sulfonyloxy group,
(c) a substituted alkyl sulfonyloxy group,
(d) a nitro-substituted benzene sulfonyloxy group, and
(e) fluorosulfonyloxy, and
(2) "P" or "Prot" is a protecting group (Z ) selected from1
the group consisting of:
(a) t-butyldimethylsilyl,
(b) t-butyldiphenylsilyl,
(c) (tri-phenylmethyl)dimethylsilyl,
(d) methyldiisopropylsilyl,
(e) triisopropylsilyl,
(f) benzyl,
(g) p-methoxybenzyl,
(h) trityl,
(i) 4-monomethoxytrityl,
(j) 4,4'-dimethoxytrityl and
(k) acyl groups of the formula
O
5
))))) C)) R5
wherein R is5
i) straight or branched chain alkyl
of 1 to 6 carbon atoms or
ii) phenyl.
Slusarchyk differs from the invention defined by claim 25 in
that Slusarchyk does not describe the use of the purine in its
tetraalkylammonium salt form. Rather, Slusarchyk describes the
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use of purines in their alkali salt forms. We also note that
Slusarchyk describes the use of only the 3-monosubstituted
cyclobutanes. See Compound 2 (page 5). The Slusarchyk leaving
group X is described as being selected from the group consisting
of chloro, bromo, iodo, an aryl sulfonate (e.g.,
p-toluenesulfonyloxy) or an alkyl sulfonate (e.g.,
methanesulfonyloxy (mesyl)) (page 5, lines 20-21).
Searcey describes the reaction of nitro-imidazoles with halo
containing compounds and indicates that better yields are
obtained when the nitro-imidazole is reacted in its
tetraalkylammonium salt form than when reacted in its alkali salt
form. To be sure, an imidazole is not the same as a purine.
However, the similarities between Searcey's imidazole and
Slusarchyk's purines are apparent upon review of their respective
structures:
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The imidazole is shown on the left and the purine on the right.
Both Slusarchyk and Searcey react halo-containing compounds with
their respective imidazoles or purines at the N)) H position.
What Searcey tells us is that if the tetraalkylammonium salt
form of the imidazole is used when reacting with a halo-
containing compound, better yields are obtained vis-à-vis an
alkali salt form of the imidazole. The use of an alkali salt for
of a purine is known as shown by Slusarchyk. Based on the
teachings of Searcey, we are of the opinion that one skilled in
the art would have recognized that the principles of Searcey
would be applicable to purines as well as imidazoles.
We have not overlooked applicants' argument that there is
"no indication [in Searcey] that the use of tetraalkylammonium
salts will be of benefit in reactions beyond those disclosed"
(Appeal Brief, page 16). It is true that there is no explicit
recognition of any benefit beyond nitro-imidazoles. However,
Searcey and Slusarchyk are attempting to add a moiety at the same
point, i.e., the N )) H in the diagram set out above. We believe
one skilled in the art would recognize that the technique of
Searcey would be expected to have applicability beyond mere
nitro-imidazoles. Moreover, we need not bottom our obviousness
rationale on improved yields. While improved yields may well be
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Application 08/08/007,950
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expected in light of Searcey when the tetraalkylammonium salt
form of a purine is used, it would not make any difference to our
decision if no improved yield were obtained. The fact is
applicants do not describe any advantage vis-à-vis the prior art
for the claimed process in their specification. While an
advantage need not be described in order to establish
patentability, the absence of a stated problem and solution mean
that any cogent reason for combining the teachings of Searcey and
Slusarchyk suffices to establish obviousness. The improved
yields described by Searcey provide a cogent reason--it simply
cannot be argued in this day and age, consistent with common
sense, that organic chemists do not seek improved yields. Hence,
we believe that a person having ordinary skill in the art would
have found it obvious to use Searcey's process in the purine art
and reasonably would have expected success in using Searcey's
process to add a moiety at the 9-position of the purine.
c. Claim 6
Claim 6 is rejected as being unpatentable under 35 U.S.C.
§ 103 over Bisacchi, Slusarchyk, Searcey, Hagberg I, Ichikawa,
European Patent Application 0 358 154 (published March 14, 1990)
and Zahler, European Patent Application 0 458 363 (published
November 27, 1991).
Appeal No. 95-0865
Application 08/08/007,950
- 29 -
The reason we reversed the examiner's rejection of claim 6
based on Bisacchi, Slusarchyk and Searcey was the absence of any
teaching in Searcey that the use of the tetraalkylammonium salt
form would serve in reactions with compounds beyond those
containing a halo group. The deficiency we found in the
examiner's rejection, however, is cured by a reference already in
the record, namely, Hagberg I, Ichikawa and Zahler. Whereas
Searcey reacts an imidazole in the tetraalkylammonium salt form
with a compound containing a halo group, Hagberg I teaches
reaction of a purine in the tetraalkylammonium salt form with a
compound containing mesyl group. See Example 10 of Hagberg I
(page 33). Furthermore, Hagberg I teaches that the "leaving"
group X (see Compound XIII, page 16) can be chloro, bromo, iodo2
or ) SO R (page 13, lines 18-19) where R can be (page 9,2 2 2
lines 21-24):
(1) alkyl containing 1-8 carbon atoms (e.g.,
mesyl);
(2) fluorinated alkyl containing 1-8 carbon
atoms, such as trifluoromethyl (triflyl);
(3) alkylaryl such as benzyl, or
(4) aryl such as unsubstituted for substituted
phenyl.
Appeal No. 95-0865
Application 08/08/007,950
- 30 -
Given that Hagberg I treats his various X groups as2
interchangeable and describes the use of the alkyl group mesyl as
working with the tetraalkylammonium salt form of a purine, we are
of the opinion that a person having ordinary skill in the art
would have recognized that compounds containing any of the X2
groups listed by Hagberg I, including halo, mesyl and triflyl,
would react with purines in the tetraalkylammonium salt form.
Also teaching the interchangeability of halogen, mesyl and
triflyl leaving groups in an analogous reaction is Ichikawa.
Specifically, Ichikawa describes the reaction of (1) a
cyclobutane (Compound V--page 5) having an X leaving group which
can be, inter alia, halogen, triflyl or mesyl (page 5, lines 43-
45) with (2) a purine (e.g., Compound XIV--page 6) to make
Compound IV (page 3) where B can be 2-amino-(Y is amino)-3
6-chloro-(Y is halogen)-purine (page 4, line 15, left formula).2
In light of the organic synthesis techniques described
collectively by Searcey and Hagberg I, we believe that one
skilled in the art would recognize that a tetraalkylammonium salt
form of either an imidazole or a purine could be reacted with a
compound containing either a halo group (Searcey) or a mesyl
group (Hagberg I).
Our conclusion that the subject matter of claim 6 (as well
as other claims) would have been obvious is reinforced by Zahler.
Appeal No. 95-0865
Application 08/08/007,950
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Zahler describes the reaction of purines with cyclobutanes.
Zahler specifically describes the reaction of (1) a cyclobutane
Compound 2 (page 9) having a leaving group which may be, inter
alia, mesyl, triflyl or nosyl (page 9, lines 24-25) with (2) a
purine Compound 3 (also page 9) to make (3) a 9-disubstituted-
purine (Compound 4) using either potassium carbonate, sodium
hydride or potassium hydride (page 9, line 43) or Compound 3 in
its tetraalkylammonium salt form (page 10, lines 19-21). Zahler
also describes making a 9-disubstituted cyclobutane-6-chloro-2-
amino-purine (Compound 6--page 11) "under conditions analogous to
those used in making the preparation of compound 4" (page 11,
lines 12-13).
In light of our discussion above, a person having ordinary
skill in the art would have found it obvious to react applicants'
purine in its tetraalkylammonium salt form with a bis
(2,3-protected hydroxymethyl) cyclobutane having an X group which
is a perfluoroalkane sulfonyloxy group, such as triflyl. It
follows that the subject matter of claim 6 includes subject
matter which would have been obvious within the meaning of
35 U.S.C. § 103.
d. Claim 7
Appeal No. 95-0865
Application 08/08/007,950
- 32 -
Claim 7 is rejected as being unpatentable under 35 U.S.C.
§ 103 over Bisacchi, Slusarchyk, Searcey, Hagberg I, Ichikawa and
Zahler.
Claim 7 is believed to be unpatentable for the same reasons
that Claim 6 is unpatentable. Bisacchi describes R "protecting"4
groups which are the same as applicants' claimed Prot groups
(col. 3, lines 59-63). The use of a cyclobutane wherein X is
trifluoromethanesulfonyloxy has already been discussed. Bisacchi
(col. 7, last line), Slusarchyk (page 7, Compound 14) and Hagberg
I (page 16, line 10 where R is chloro) describe the use of7
compounds corresponding to applicants' compound wherein X is1
chloro. Both Searcey (page 1312) and Hagberg I (Example 10)
describe the use of tetrabutylammonium salt forms.
e. Claim 8
Claim 8 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler.
Claim 8 is believed to be unpatentable for the same reasons
that Claims 6 and 7 are unpatentable, it being further noted that
Bisacchi describes an R protecting group which is acetyl (col.4
3, line 61) or benzoyl (col. 3, line 62).
f. Claim 9
Appeal No. 95-0865
Application 08/08/007,950
- 33 -
Claim 9 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler.
Claim 9 is believed to be unpatentable for the same reasons
that Claims 6-8 are unpatentable, it being further noted that
Hagberg I describes the use of R groups, corresponding to7
applicants' Y group, which may be iodo (page 16, line 10; page1
12, lines 1-3 referring to Y; page 10, line 1 referring to X ;1
and page 9, lines 19-20 wherein X can be "iodine (sic--iodo)").1
g. Claim 10
We do not reject claim 10 because we have not been able to
find anything in the combination of Bisacchi, Slusarchyk,
Searcey, Hagberg I, Ichikawa and Zahler which suggests the use of
an ammonium salt wherein R is benzyl. Our decision not to4
reject claim 10 under 37 CFR § 1.196(b) is without prejudice to
the examiner citing and applying additional prior art which
describes the use of an ammonium salt within the scope of claim
10.
h. Claim 11
Claim 11 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler.
Claim 11 is believed to be unpatentable for the same
reasons that Claims 6-9 are unpatentable. Bisacchi describes (1)
Appeal No. 95-0865
Application 08/08/007,950
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the use of an R protecting group which is benzoyl (col. 3, line4
62, corresponding to applicants' Prot group; (2) the leaving
group triflyl (col. 3, line 67), corresponding to applicants' X;
and (3) 2-amino-6-chloropurine (col. 7, last line), which
corresponds to applicants' Y being chloro. As previously noted,1
both Searcey and Hagberg I describe the use of tetrabutylammonium
salt forms corresponding to applicants' R through R being n-1 4
butyl.
i. Claim 12
Claim 12 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler.
Claim 12 is believed to be unpatentable for the same
reasons that Claims 6-9 and 11 are unpatentable, it being noted
that Bisacchi describes the use of a leaving group X which can be
p-nitrobenzenesulfonyloxy (nosyl) (col. 4, lines 30-31).
j. Claim 13
Claim 13 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler. Claim 13
requires two additional steps.
Step (b) involves treatment to remove the "Prot" protecting
groups and replacement of those groups with hydrogen () H) groups.
The reaction is shown schematically below:
Appeal No. 95-0865
Application 08/08/007,950
- 35 -
Bisacchi contains an extensive discussion of the manner in which
protective groups are removed (col. 8, line 17 through col. 10,
line 14).
Step (c) involves treatment of the deprotected compound to
convert the Y group from a chloro () Cl) to an oxo group to1
produce the compound [1R-(1",2$,3")]-2-amino-9-[2,3-
bis(hydroxymethyl)-cyclobutyl]-1,9-dihydro-6H-purin-6-one
according to the following reaction scheme:
Slusarchyk describes the conversion of a chloro-compound to an
oxo-compound (page 8, lines 28-48).
Appeal No. 95-0865
Application 08/08/007,950
- 36 -
The addition of steps (b) and (c) to what is otherwise
basically the process of Claim 6 does not render Claim 13, as a
whole, patentable over the prior art. A person having ordinary
skill in the art would have wanted the oxo compound because it is
a known active and useful compound (specification, page 1;
Bisacchi, col. 1, lines 7-20). Steps (b) and (c), as shown by
the prior art, are conventional organic synthesis techniques.
k. Claim 14
Claim 14 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler.
Claim 14 is believed to be unpatentable for the same
reasons that Claim 13 is unpatentable.
Claim 14 requires that step (b) take place in the presence
of a fluoride ion. Bisacchi describes the use of compounds which
produce fluoride ions to accomplish deprotection (col. 8,
lines 29-31 and 53-54; col. 9, line 47).
Step (c) of Claim 14 further requires acid hydrolysis.
Slusarchyk describes the use of aqueous hydrochloric acid to
accomplish conversion of the chloro group to an oxo group (page
8, line 28).
Appeal No. 95-0865
Application 08/08/007,950
- 37 -
Applicants' claimed steps (b) and (c) would appear to
involve use of well known organic synthesis techniques for their
intended purpose.
l. Claim 15
Claim 15 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler. Claim 15
is believed to be unpatentable for the same reasons that Claims
13-14 are unpatentable. Claim 15 requires a "Prot" group which
is benzyl and use of boron trichloride to accomplish
deprotection. Bisacchi describes the use of R protection groups4
which are benzyl and their deprotection using, inter alia, boron
trichloride (col. 8, lines 35-44).
m. Claim 16
Claim 16 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler.
Claim 16 is believed to be unpatentable for the same
reasons that Claims 13-15 are unpatentable. Claim 16 requires a
"Prot" group which is acetyl and use of sodium methoxide in
methanol to accomplish deprotection. Bisacchi describes the use
of R protection groups which are acetyl and their deprotection4
using, inter alia, sodium methoxide in methanol (col. 8, lines
44-50).
Appeal No. 95-0865
Application 08/08/007,950
- 38 -
n. Claim 17
Claim 17 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler. Claim 17
requires the same two additional steps as Claim 13, but in
reverse order. The order in which deprotection and conversion of
the chloro group to the oxo group at the 6-position take place
would not seem to be significant. In this respect, we call
attention to Bisacchi (col. 8, lines 20-26) which teaches that
(1) deprotection then chloro to oxo conversion or (2) chloro to
oxo conversion followed by deprotection are optional orders for
accomplishing both deprotection and chloro to oxo conversion.
o. Claim 18
We do not reject claim 18 because we have not been able to
find anything in the combination of Bisacchi, Slusarchyk,
Searcey, Hagberg I, Ichikawa and Zahler which describes the use
of hot aqueous acetic acid for conducting step (b). Our decision
not to reject claim 10 under 37 CFR § 1.196(b) is without
prejudice to the examiner citing and applying additional prior
art which describes the use of hot aqueous acetic acid for
accomplishing conversion of a chloro group to an oxo group at the
6-position of a purine.
Appeal No. 95-0865
Application 08/08/007,950
- 39 -
p. Claim 19
Claim 19 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler. Claim 19
requires the same two additional steps as Claim 13, but in
reverse order. The order in which deprotection and conversion of
the chloro group to the oxo group at the 6-position take place
would not seem to be significant. In this respect, we call
attention to Bisacchi (col. 8, lines 20-26) which teaches that
(1) deprotection then chloro to oxo conversion or (2) chloro to
oxo conversion followed by deprotection are optional orders for
accomplishing both deprotection and chloro to oxo conversion.
The use of "hydrogenolysis" to deprotect R groups is described4
by Bisacchi (col. 8, lines 36-44), particularly when the P
protecting group is benzyl as required by Claim 19.
q. Claims 20-21
Claims 20-21 are rejected as being unpatentable over
Bisacchi, Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler.
Claim 20 is similar to Claim 13, but calls for a step (b) in
which the "Prot" protecting groups are removed and the Y group1
(e.g., a chloro) at the 6-position is converted to a 6-methoxy
( ) O) CH ) group. As is apparent from Claim 21, step (b) may be3
accomplished by treatment with sodium methoxide in methanol.
Appeal No. 95-0865
Application 08/08/007,950
- 40 -
Bisacchi describes deprotection by treatment with sodium
methoxide in methanol (col. 8, lines 44-50), particularly when
the "Prot" group is benzoyl, as required by Claim 21. Slusarchyk
reveals that conversion of a chloro group at the 6-position to an
alkoxy group ( ) O) R in Slusarchyk) can be accomplished by known4
methods (page 9, last line through page 10, line 22).
Hagberg I describes hydrolysis of Compound III (page 9)
containing an X group which can be, inter alia, ) OR , where R ,1 2 2
inter alia, may be alkyl (e.g., methyl), in the presence of
sodium hydroxide (page 9, line 27) to produce a "compound of the
[Hagberg I invention" which, of course, is a purine compound with
an oxo ( 4 O) at the 6-position (page 7, Compound I).
r. Claim 22--prior art rejection
Claim 22 is rejected as being unpatentable over Bisacchi,
Slusarchyk, Searcey, Hagberg I, Ichikawa and Zahler. Claim 22 is
narrower than Claim 6 in that it limits the "Prot" group to acyl.
Claim 22 also requires a step (b) and a step (c).
Step (b) calls for (indentation and paragraph numbers
added):
(1) treating the product from part (sic--step) (a)
with hot aqueous sodium or potassium hydroxide or
Appeal No. 95-0865
Application 08/08/007,950
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(2) treating the product of part (a) with an acid such
as hydrochloric acid followed by sodium or
potassium hydroxide and heat (sic--heating)
to remove the protecting groups and convert the Y1
substituent to a 6-oxo ***.
Slusarchyk describes treatment of a product similar to that
obtained in applicants' step (a) with hot aqueous hydrochloric
acid to convert a chloro group in the 6-position to a 6-oxo group
(page 8, lines 28-48).
Bisacchi describes treatment of a compound like the compound
obtained in applicants' step (a) with potassium hydroxide to
remove the R protecting groups, particularly when the R group4 4
is an acyl group (col. 8, lines 44-50).
Step (c) requires separating the desired product from the
reaction mixture. Bisacchi describes obtaining a purified
product through chromatography (col. 9, lines 21-22).
Applicants' steps (b) and (c) would appear to involve
conventional techniques for removing protecting groups and
converting a chloro group in the 6-position to a 6-oxo group and
separating to obtain a desired product.
s. Claim 22--indefiniteness rejection
Appeal No. 95-0865
Application 08/08/007,950
- 42 -
Claim 22 is rejected under the second paragraph of 35 U.S.C.
§ 112 as being indefinite. The limitation which is indefinite is
"an acid such as hydrochloric acid ***." The language "such as
hydrochloric acid" does not limit Claim 22 because the claim
otherwise reads on the use of any "acid." Moreover, it is
unclear as to whether applicants claim an "acid" or only
"hydrochloric acid." As a general proposition, we believe that
every word in a claim should be capable of having some limiting
significance. The words "such as hydrochloric acid" would not
appear to limit Claim 22. If an applicant can use the language
"such as hydrochloric acid," it follows that the applicant could
also recite "such as hydrochloric acid" followed by an extensive
list of other acids, all of which would serve to make claims
difficult to understand and/or interpret. Consistent with all of
the paragraphs of 35 U.S.C. § 112, the proper manner to claim
both "acid" and "hydrochloric acid" is to present one claim to
"acid" and another (perhaps dependent) to "hydrochloric acid."
C. Decision
The examiner's prior art rejections are reversed.
Claims 6-9, 11-17, 19-22 and 25 have been rejected pursuant
to 37 CFR § 1.196(b) as being unpatentable under 35 U.S.C. § 103
over the prior art.
Appeal No. 95-0865
Application 08/08/007,950
- 43 -
Claim 22 has been rejected pursuant to 37 CFR § 1.196(b) as
being indefinite within the meaning of the second paragraph of
35 U.S.C. § 112.
D. Further observation
We have expressly indicated why Claims 10 and 18 have not
been rejected. If applicants are aware of any prior art which
would overcome our stated reasons for not rejecting either Claim
10 or Claim 18, applicants (or their attorneys) should make the
examiner aware of that prior art. 37 CFR § 1.56. Apart from any
obligation of applicants to inform the examiner of any prior art
mentioned in the preceding sentence, should the examiner be aware
of any such prior art, the examiner should feel free to make a
rejection of Claims 10 and/or 18. In short, nothing in this
opinion should be treated as precluding the examiner from making
a rejection of Claims 10 and/or 18 (or any other claim) based on
additional prior art not mentioned in this opinion.
E. Time for taking action
This opinion contains a new ground of rejection pursuant
to Rule 196(b) (37 CFR § 1.196(b), amended effective Dec. 1,
1997). See Notice of Final Rule, 62 Fed. Reg. 53131, 53197
Appeal No. 95-0865
Application 08/08/007,950
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(Oct. 10, 1997), reprinted in 1203 Off. Gaz. Pat. & Trademark
Office 63, 122 (Oct. 21, 1997)).
Rule 196(b) provides that, "A new ground of rejection shall
not be considered final for purposes of judicial review."
Rule 196(b) also provides that the applicant, WITHIN TWO
MONTHS FROM THE DATE OF ENTRY OF THIS DECISION, must exercise one
of the following two options with respect to the new ground of
rejection to avoid termination of proceedings (§ 1.197(c)) as to
the rejected claims:
(1) Submit an appropriate amendment of
the claims so rejected or a showing of facts
relating to the claims so rejected, or both,
and have the matter reconsidered by the
examiner, in which event the application will
be remanded to the examiner. . . .
(2) Request that the application be
reheard under § 1.197(b) by the Board of
Patent Appeals and Interferences upon the
same record. . . .
No time period for taking any subsequent action in
connection with this appeal may be extended under 37 CFR
§ 1.136(a).
Appeal No. 95-0865
Application 08/08/007,950
- 45 -
REVERSED
(37 CFR § 1.196(b))
______________________________
SHERMAN D. WINTERS, )
Administrative Patent Judge )
)
)
______________________________)
WILLIAM F. SMITH, ) BOARD OF PATENT
Administrative Patent Judge ) APPEALS AND
) INTERFERENCES
)
______________________________)
FRED E. McKELVEY, Senior )
Administrative Patent Judge )
Appeal No. 95-0865
Application 08/08/007,950
- 46 -
cc (via First Class mail)
Burton Rodney, Esq.
BRISTOL-MYERS SQUIBB COMPANY
P.O. Box 4000
Princeton, NJ 08543-4000