Ex Parte Bettoni et al

Patent Trial and Appeal Board

Feb 17, 2017

13852234 (P.T.A.B. Feb. 17, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/852,234 03/28/2013 Piergiorgio BETTONI SS122-1097 2225
122515 7590
Silvia Salvadori, P.C.
Silvia Salvadori
270 Madison Avenue, 8th Floor
New York, NY 10016
EXAMINER
O DELL, DAVID K
ART UNIT PAPER NUMBER
1625
NOTIFICATION DATE DELIVERY MODE
02/22/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
silvia@salvadorilaw.com
silvia30121 @ me. com
eofficeaction @ appcoll.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PIERGIORGIO BETTONI, JACOPO ROLETTE,
and PAOLO PAISSONI
Appeal 2016-001379
Application 13/852,234
Technology Center 1600
Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.
MILLS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
Appeal 2016-001379
Application 13/852,234
STATEMENT OF CASE
According to the Specification, the present invention relates to an
advantageous process for the preparation of iloperidone, wherein the
intermediate l-[ 4-(3-chloropropoxy)- 3-methoxyphenyl]-ethanone is not
isolated but used in the next step with no need to conduct any work-up,
isolation or purification step. Spec 1.
The following claim is representative.
1. A process for the preparation of iloperidone comprising the
following steps:
i. alkylating acetovanillone with l-bromo-3-chloropropane to obtain
intermediate l-[ 4-(3-chloropropoxy)-3-methoxyphenyl]ethanone in the
presence of an inorganic base;
ii. alkylating 6-fluoro-3-( 4-piperidinyl)-l,2-benzisoxazole
hydrochloride with the intermediate l-[ 4-(3-chloropropoxy)-3-
methoxyphenyljethanone obtained in the first step, in the presence of an
inorganic base, to obtain a reaction mixture containing iloperidone;
iii. isolating iloperidone from the reaction mixture obtained in the
second step;
wherein in the first step 0.9-1.2 molar equivalents of l-bromo-3-
chloropropane with respect to acetovanillone are used; and wherein the
intermediate l-[ 4-(3-chloropropoxy)-3- methoxyphenyljethanone is not
isolated.
Grounds of Rejection
Claims 1-9 are rejected under 35 U.S.C. § 103(a) as being
unpatentable over Reguri in view of Anderson.
FINDINGS OF FACT
The Examiner’s findings of fact are set forth in the Non-final Action
(dated Dec. 16, 2014) at pages 2-7.
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Application 13/852,234
PRINCIPLES OF LAW
In making our determination, we apply the preponderance of the
evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427
(Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings
before the Office).
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
To show criticality of the claimed range, ‘“it is not inventive to
discover the optimum or workable ranges by routine experimentation. ’ In re
Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Only if the
‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be
obtained for the claimed critical range. In re Antonie, 559 F.2d 618, 620
(CCPA 1977).” In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997).
“[Discovery of an optimum value of a result effective variable in a
known process is ordinarily within the skill of the art.” In re Boesch, 617
F.2d 272,276 (CCPA 1980).
Obviousness Rejection
The Examiner finds that Reguri discloses a process of synthesizing
iloperidone which includes the isolation of intermediate, l-[4-(3-
chloropropoxy)-3-methoxyphenyl]ethanone and the instant invention does
not. Final Act. 3.
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Appeal 2016-001379
Application 13/852,234
However, the Examiner finds that
Not isolating the l-[4-(3-chloropropoxy)-3-
methoxyphenyljethanone intermediate (II) and carrying out the
reaction in order to produce the desired product, iloperidone, is
considered obvious to one of ordinary skill in the art. It is well in the
purview of the skilled artisan to reduce steps in order to achieve the
desired product faster, more efficiently and in higher yields.
The term the inventors have applied to the claimed process is named
“telescoping”. Anderson clearly discloses that the isolation of
intermediates have many disadvantages. Additional handling via
isolation increases the potential for contamination and increases
operating costs for the company. Furthermore, the use of telescoping
a reaction typically leads to overall dramatic increases in yields. A
skilled artisan, in this case a medicinal or synthetic chemist, would be
highly motivated to reduce the number of steps without isolating said
intermediate which would result in higher yields, less risk of
contamination and serve as a cost effective route for a company.
Final Act. 3-4.
Appellants contend that
Reguri is completely silent with regard to not isolating the
intermediate l-[ 4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and
with regard to using a significant low amount of l-bromo-3-
chloropropane in the synthesis of said intermediate, as presently
claimed (e.g., present specification, page 1 lines 3-6).
Nothing in the literature would help the skilled artisan to
provide for Reguri's missing link to arrive at the presently claimed
subject matter.
App. Br. 9. Appellants argue that they
have unexpectedly and surprisingly found that by using a
stoichiometric ratio close to 1.0 between l-bromo-3-chloropropane
and acetovanillone it is possible to convert the intermediate l-[ 4-(3-
chloropropoxy)-3-methoxyphenyl]ethanone in a one pot process to
iloperidone with no need to conduct any work-up, isolation or
purification step, (e.g., page 9 lines 11 -to the end of the page). The
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Appeal 2016-001379
Application 13/852,234
use in the first step of the present process of a stoichiometric ratio
close to 1.0 between l-bromo-3-chloropropane and acetovanillone, the
reversal of the order of addition of acetovanillone and l-bromo-3-
chloropropane to the reaction mixture and the replacement of acetone
with acetonitrile or acetonitrile/N,N,-dimethylformamide mixtures,
results in a significant improvement of the conversion of
acetovanillone to l-[ 4-(3-chloropropoxy)-3-methoxyphenyl]ethanone
which can be converted in an one-pot process to iloperidone
characterized by an excellent purity profile.
App. Br. 10.
ANALYSIS
We agree with the Examiner’s fact finding, statement of the rejection
and responses to Appellants’ arguments as set forth in the Answer. We find
that the Examiner has provided evidence to support a prima facie case of
obviousness. We provide the following additional comment to the
Examiner’s argument set forth in the Final Rejection and Answer.
Reguri teaches the claimed process but teaches isolation of a l-[4-(3-
chloropropoxy)-3-methoxyphenyl]ethanone intermediate. The Examiner
finds that Anderson provides a motivation not to isolate intermediates in
chemical reactions. In particular,
Anderson clearly discloses that the isolation of intermediates
(the prior art) has many disadvantages. Additional handling via
isolation increases the potential for contamination and increases
operating costs for the company. As stated by Anderson, the use of
telescoping a reaction is a way to “greatly increase overall yields.” A
skilled artisan, in this case a medicinal or synthetic chemist, would be
highly motivated to reduce the number of steps without isolating said
intermediate which would result in higher yields, less risk of
contamination and serve as a cost effective route for a company.
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Appeal 2016-001379
Application 13/852,234
Ans. 6. Thus, Anderson provides one of ordinary skill in the art at the time
of the invention motivation to omit isolation of intermediates step, for
example, in the process of preparing iloperidone of Reguri. When a prima
facie case is made, the burden shifts to the applicant to come forward with
evidence and/or argument supporting patentability. In re Glaug, 283 F.3d
1335, 1338 (Fed. Cir. 2002). Rebuttal evidence is “merely a showing of
facts supporting the opposite conclusion.” In re Piasecki, 745 F.2d 1468,
1472 (Fed. Cir. 1984).
While Appellants allege that they have unexpectedly and surprisingly
found that by using a stoichiometric ratio close to 1.0 between l-bromo-3-
chloropropane and acetovanillone it is possible to convert the intermediate
l-[ 4-(3-chloropropoxy)-3-methoxyphenyl]ethanone in a one pot process to
iloperidone with no need to conduct any work-up, isolation or purification
step (App. Br. 10), Appellants provide no evidence of unexpected results. In
fact, Anderson suggests that removal of intermediate isolation steps from a
chemical process can result in higher yields. Anderson, p. 34. Expected
beneficial results are not evidence of nonobviousness. See In re Skoner, 517
F.2d 947, 950 (CCPA 1975). “Mere improvement in properties does not
always suffice to show unexpected results. In our view, however, when an
applicant demonstrates substantially improved results . . . and states that the
results were unexpected, this should suffice to establish unexpected results
in the absence of evidence to the contrary.” In re Soni, 54 F.3d 746, 751
(Fed. Cir. 1995) (emphasis in original). Appellants have failed to provide
evidence of substantially improved results in view of the disclosure and
suggestions of Reguri in combination with Anderson.
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Appeal 2016-001379
Application 13/852,234
The Examiner finds regarding the amount of l-chloro-3-bromopropane
that,
the prior art uses 1.32 eq, while that of the instant claims is 0.9 - 1.2.
At least Reguri is silent to the amounts (Examples 1 and 2 on pages 18
and 19), which on the face suggests they were equimolar. According
to the argument, the reaction is very old and described in U.S.
4,366,162 which uses 1.32 equivalents of the dihalide. Optimization
of molar quantities is within the scope of what one skilled in the art
would be capable of and is insufficient to establish patentable
unobviousness.
Ans. 7. With respect to criticality of a claimed range of molar equivalents of
l-bromo-3-chloropropane with respect to acetovanillone, ‘“it is not inventive
to discover the optimum or workable ranges by routine experimentation.’” In
re Aller, 220 F.2d 454, 456 (CCPA 1955). Appellants provide no
convincing evidence of unexpected results when compared to the closest
prior art.
Having found no persuasive evidence of unexpected results or other
rebuttal evidence, we affirm the obviousness rejection.
CONCLUSION OF LAW
The cited references support the Examiner’s obviousness rejections,
which are affirmed for the reasons of record. All pending, rejected claims
fall.
No time period for taking any subsequent action in connection with
appeal may be extended under 37 C.F.R. § 1.136(a)(1).
AFFIRMED
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