Ex Parte BRANDENBURG et al

Patent Trial and Appeal Board

Aug 2, 2018

14694155 (P.T.A.B. Aug. 2, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/694,155 04/23/2015 Joerg BRANDENBURG
28501 7590 08/06/2018
C/0 VP, IP, LEGAL
BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD
P. 0. BOX 368
RIDGEFIELD, CT 06877-0368
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
01-1902-US-5 3735
EXAMINER
DESAI, RITA J
ART UNIT PAPER NUMBER
1625
NOTIFICATION DATE DELIVERY MODE
08/06/2018 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):
USPTO.e-Office.rdg@boehringer-ingelheim.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOERG BRANDENBURG,
WALDEMAR PERENGLE 1
Appeal2017-009442
Application 14/ 694,155 2
Technology Center 1600
Before RICHARD M. LEBOVITZ, JEFFREY B. ROBERTSON,
DAVID COTTA, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to processes of preparing
tiotropium salts. The Examiner rejected the claims as obvious under 35
U.S.C. § 103(a) and under obvious-type double-patenting. Appellants
appeal the rejection pursuant to 35 U.S.C. § 134. We have jurisdiction under
35 U.S.C. § 6(b). The rejections are affirmed.
1 The Appeal Brief ("Appeal Br.") (entered Feb. 24, 2017) lists Boehringer
Ingelheim International GmbH & Co. KG as the real party in interest.
Appeal Br. 2.
2 Hereinafter, "the '155 Application".
Appeal2017-009442
Application 14/694, 155
STATEMENT OF THE CASE
Claims 1, 12, and 14 stand finally rejected by the Examiner as
follows:
1. Claims 1, 12, and 14 under 35 U.S.C. § I03(a) as obvious in view
of Brandenburg et al. (U.S. Pat. No. 6,747,154 B2, issued Jun. 8, 2004)
(English equivalent of WO 03/057694 Al, published July 17, 2003)
("Brandenburg '154"); three cited "Banholzer" patents, U.S. Pat. Nos.
7,321,039, 6,506,900, and 6,486,321; and Qureshi (Abstract in 228th ACS
National Meeting, Philadelphia, PA, United States, August 22-26, 2004).
Ans. 3. Although the Examiner cited three Banholzer patents, the only
patent relied upon in setting forth the rejection in the Answer is U.S. Pat.
No. 6,486,321 Bl (issued Nov. 26, 2002) ("Banholzer '321"). Id. 6.
Consequently, Banholzer '321 is the only Banholzer patent discussed in this
decision.
2. Claims 1, 12, and 14 on the ground of non-statutory obvious-type
double patenting as obvious over claims 1-25 of Brandenburg '154 in view
of "Banholzer" and Qureshi. Ans. 10. The Examiner did not identify which
Banholzer publication is intended, but Appellants refer to "Banholzer" as US
Published Pat. Appl. 2005/0124813 Al, published Jun. 9, 2005. See Appeal
Br. 1-2.
Claim 1, the only independent claim on appeal, is reproduced below.
1. A process for preparing tiotropium salts of formula !
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Application 14/694, 155
+ Me
Me-N~
0
wherein x- represents bromide,
compnsmg:
;
H
X
0
1 _,
reacting in one step a compound of formula J
wherein y- is hexafluorophosphate,
with a compound of formula J.
3
H
OH
y
2. _,
J,
Appeal2017-009442
Application 14/694, 155
wherein R is methoxy or ethoxy,
in a solvent selected from acetone, acetonitrile or pyridine with the
addition of a catalyst selected from zeolites to obtain a compound of
formula 4
wherein the group x- has the meaning given above, and
without being isolated, the compound of formula ~ is converted into the
compound of formula! by reacting formula~ with a salt cat+x-, wherein
cat+ denotes a cation selected from the group consisting of Li+, Na+, and
K+, and x- has the meaning given above.
CLAIMS
Claim 1 is directed to a process for making tiotropium bromide having
the structure of formula 1. Tiotropium bromide is a known anticholinergic
drug used to treat diseases, such as asthma and chronic obstructive
pulmonary disease ("COPD"). '155 Application 1:9--15. The process
recited in claim 1 comprises the following steps and limitations (numbered
for reference):
[ 1] Reacting, in one step, a compound of formula 2 (having counter
ion y-, which is hexafluorophosphate)
[2] with a compound of formula 3
[3] in a solvent selected from acetone, acetonitrile, or pyridine
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Application 14/694, 155
[ 4] with a zeolite catalyst
[5] to obtain a compound of formula 4, and
[ 6] without being isolated, reacting the compound of formula 4 with a
bromide salt cat+Br- to convert it into tiotropium bromide of formula 1.
OBVIOUSNESS REJECTION
The Examiner found that Brandenburg '154 describes a process of
making tiotropium similar to the process of rejected claim 1. Ans. 5-6. 3
However, the Examiner found that Brandenburg '154 does not describe the
formula 2 compound having the counter ion y- which is
hexafluorophosphate as required by the rejected claims. Id. 8. Otherwise,
the structure of the formula 2 compound of Brandenburg '154 is the same as
the structure of the formula 2 compound of the claims. The structure of the
formula 3 compound of Brandenburg ' 154 reacted with the formula 2
compound also has the structure of the corresponding formula 2 compound
of the claims.
To meet the deficiency in Brandenburg '154 of the formula 2
compound lacking counter ion y- as a hexafluorophosphate, the Examiner
further cited Banholzer '321 and Qureshi. Id.
Banholzer '321 also describes making tiotropium bromide. Banholzer
'321, col. 1, 11. 13--47. Banholzer '321 process starts with a formula (V)
compound ("tropenol") which can optionally be in the form of an acid
addition salt. Id. col. 5, 11. 19-35. Banholzer '321 lists hexafluorophosphate
as one of the choices for the acid addition salt. Id. col. 6, 11. 26-30. The
3 ("Ans.") refers to the Examiner's Answer, mailed Apr. 21, 2017.
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Application 14/694, 155
formula (V) compound ofBanholzer '321 has similar, but not identical,
structure to the compound of formula 2 used in claim 1. The formula (V) is
reacted with a compound of formula (VI) (id. col. 5, 11. 19-35). The
compound of formula (VI) has the same structure of the compound of
formula 3 used in claim 1 and described in Brandenburg '154. Thus,
Banholzer '321 makes the same compound as does Brandenburg '154 and
the claims, but using a different starting material ( formula V versus formula
2).
Qureshi is an abstract stating that "[ a ]lthough the hexafluorophosphate
anion has been available for over 50 [years] ... , it is only now beginning to
gain ... interest due to the stability of its organic quaternary salts and the
relative low reactivity of the anion."
The Examiner found that it would have been obvious to use the
formula 2 compound of Brandenburg ' 154 with hexafluorophosphate
counter ion because Banholzer '321 describes utilizing a structurally similar
compound (formula V) with a hexafluorophosphate counter ion as a starting
material in a process of making tiotropium bromide and Qureshi teaches that
hexafluorophosphate is stable. Ans. 8.
DISCUSSION
Coupling agent
Appellants attempt to distinguish the cited prior art, arguing that the
"Prior Brandenburg Process" utilizes a "coupling reagents including
carbonyldiimidazole (CDI) [which] results in a very dominant side
reaction." Appeal Br. 4--5. The "Prior Brandenburg Process" is the process
described in Brandenburg '154. Appellants describe the claimed process as
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Application 14/694, 155
the "Two-Step Brandenburg Process." Id. 3--4. Appellants argue that the
Two-Step Brandenburg Process does not utilize a coupling reagent, but uses
zeolite instead, and therefore does not give rise to the side reaction and has a
much higher and more robust yield. Id. 5---6.
This argument does not demonstrate an error in the Examiner's
rejection. It is true that Brandenburg '154 describes the use of coupling
agents when a formula 2 compound is reacted with a formula 3 compound as
claimed. Brandenburg '154, col. 5, 1. 67---col. 6, 1. 17. However, as
discussed by the Examiner, when the formula 3 compound has a hydroxy at
R 1 as it does in the claims, the use of a zeolite catalyst is explicitly disclosed
by Brandenburg '154. Ans. 5, 8, 12. Table 1 below compares the formula 3
compound recited in the rejected claims to the formula 3 compound of
Brandenburg '154.
Table 1
Claim Brandenburg '154
~R
R: ().-R
H {'A,
s i\f
J.
wherein R is methoxy or ethoxy R denotes a group selected from a
list that includes methoxy and
ethoxy (col. 3, 11., 62-63)
Ar is thienyl Ar may represent a group selected
from a list that includes thienyl ( col.
3, 11. 33-34)
R 1 is hydroxy R 1 may represent a group selected
from a list that includes hydroxyl
(col. 3, 11. 31-32)
zeolite "If the intention is to prepare
compounds of formula 1 wherein R 1
denotes hydroxy, instead of the
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Application 14/694, 155
abovementioned base-catalyzed
reaction, transesterification under
milder reaction conditions may also
appear advantageous. Zeolites may
be advantageously used as catalysts"
( col. 6, 11. 46-50)
Thus, Appellants' argument that "the Two-Step Brandenburg Process
does not give rise to the side reaction mentioned above" and "shows a much
higher yield due to less side reaction much more robust in practice" (Appeal
Br. 6) has no merit, because Brandenburg '154 describes utilizing a zeolite
catalyst when R 1 is hydroxy as recited in the rejected claims and not the
coupling agent described by Appellants.
Hexafluorophosphate
Appellants state that Banholzer teaches that "tropenol ester is first
epoxidized and then quatemized by addition of methyl bromide to yield
tiotropium bromide." Appeal Br. 6. Appellants further state that neither
Banholzer '321 nor Brandenburg '154 "uses a hexafluorophosphate salt as
an intermediate to form a bromide salt of tiotropium." Id.
First, Appellants' statement that a "tropenol ester is first epoxidized,"
ignores the teaching in Banholzer '321 that the ester (formula (VI))
compound is first reacted with a tropenol (V) in a reaction similar to the
reaction of formula 2 with formula 3 which is claimed and described in
Brandenburg '154. See Banholzer '321, col. 5, 11. 20-65 showing the
reaction of (V) and (VI) to form a tropenol ester of formula (VII), which is
then epoxidized and quatemized as described at col. 6, 11. 1-20.
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Application 14/694, 155
Second, Banholzer '321 does use "a hexafluorophosphate salt as an
intermediate to form a bromide salt of tiotropium," contrary to Appellants'
contention. Table 2 below illustrates the similarities between the processes
of Brandenburg '154 and that ofBanholzer '321:
TABLE2
Brandenburg '154 Banholzer '321
.M'=·,+ .. ~Mi~
~,,.:,~~.,,-\,?,.:,
N J
s~H
I"
(l n~,Jl ..
~ I I>,,
~l /
x· ,..-,:$- ~nu{)
r \ / \_I 'I,------. .. : \ ""--....
\ '
I 6: Id
.~!
Embodiments are disclosed where tiotropium bromide
the formula depicted above is
tiotropium bromide ( col. 10, 11. 10-
30, Example 2)
Tiotropium bromide is formed by a process comprising:
Reacting a compound of formula 2 Reacting a compound of formula
(col. 3, 11. 40-50) (V) ( col. 5, 11. 20-30)
Mc , 1\k )\fr
'-.N/ / N .
·~ y· ~H
on OH
y- may represent bromine, Optionally in the form of an
methanesulfonate, or addition salt, where the salt is
trifluoromethanesulfonate ( col. 5, 11. selected from a list that includes
34-35) hexafluorophosphate ( col. 5, 11.30-
35; col. 6, 11. 36-27)
With a compounds of formula 3 With an ester of formula (VI)
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Application 14/694, 155
where the substituents are the same
as those in the formula (VI)
compound ofBanholzer '321 as
shown in Table 1 above
wherein R is selected from a list
that includes methoxy and ethoxy
(col. 5, 11. 46-47)
Thus, as shown in the Table 2, Banholzer '321 describes a process
similar to Brandenburg '154, and explicitly teaches an embodiment in which
a compound in the form of a hexafluorophosphate is used to form a bromide
salt of tiotropium. The steps referred to by Appellants in which "a tropenol
ester is first epoxidized and then quatemized by addition of methyl bromide
to yield tiotropium bromide" (Appeal Br. 6) take place after the steps
depicted in Table 2. Banholzer '321, col. 5, 1. 55---col. 6, 1. 20.
Because of the structural similarity of the process steps, as found by
the Examiner and illustrated above in Table 2, one of ordinary skill in the art
would have had reason to use the formula 2 compound of Brandenburg '154
as a hexafluorophosphate salt as taught by Banholzer '321 and Qureshi.
Appellants state that there is no suggestion to have used the formula 2
compound of the claims as the hexafluorophosphate salt and that Qureshi
states hexafluorophosphate has "relatively low activity." Appeal Br. 6.
This argument is not persuasive. Appellants do not adequately
address the Examiner's finding that Banholzer '321 describes a synthetic
pathway that reacts a compound structurally similar to the compound of
Brandenburg '154 (formula V versus formula 2), but as a
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Application 14/694, 155
hexafluorophosphate addition salt, with the same compound (formula VI) as
in Brandenburg '154 (formula 3) and in the claims (formula 3). Moreover,
Appellants' argument that the hexafluorophosphate ion has "low activity" is
also not persuasive since it is not the counter ion which is being reacted, but
the formula 2 and formula V compounds of Brandenburg ' 154 and
Banholzer '321, respectively.
Appellants contend that "dramatic and many changes [are] necessary"
to "convert the Prior Brandenburg Process into the Two-Step Brandenburg
Process" (Appeal Br. 7), but as summarized by the Examiner the difference
is the use of a formula 2 compound as a hexafluorophosphate salt, rather
than as a bromine, methanesulfonate, or trifluoromethanesulfonate as
described by Brandenburg '154. Ans. 8. The Examiner provided a fact-
based reason for replacing the latter counter ions with hexafluorophosphate.
Id. 7-8.
Brandenburg Declaration
Appellants provided a declaration by Joerg Brandenburg, Ph.D.
("Brandenburg Deel."), who is a co-inventor of the '155 application, as well
as an inventor of Brandenburg '154. Dr. Brandenburg was an employee of
the Boehringer Ingelheim, the real-party-in-interest, when the declaration
was executed. Brandenburg Deel. ,r 2.
Dr. Brandenburg states that the "Prior Brandenburg [' 154] Process"
provides low yields and is not suitable for commercial pharmaceutical
production oftiotropium. Brandenburg Deel. ,r,r 5, 6. Dr. Brandenburg
states that the process disclosed in the '155 Application, however, is suitable
for commercial production. Id. ,r 7. Dr. Brandenburg describes the Two-
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Application 14/694, 155
Step Brandenburg Process as using a zeolite Linde-Type A, pore size 4A,
and acetone which "is crucial" to achieve a suitable yield of tiotropimn. Id.
,r,r 7, 10. Dr. Brandenburg acknowledges the Examiner's finding that
Brandenburg '154 describes using zeolites, but argues that "the Two-Step
Brandenburg Process demonstrates that only zeolite 4A is suitable for its
process and that using zeolite 4A enhances yields by more than 5-10% when
alcoholate is also added." Id. ,r 11.
We have considered these arguments, but they are not persuasive. As
discussed by the Examiner, the claims are not limited to zeolite 4A as argued
by Dr. Brandenburg. Ans. 13. Thus, Dr. Brandenburg's argument is based
on a limitation that does not appear in the claims.
The assertion by Dr. Brandenburg that "only zeolite 4A is suitable for
its process" is also inconsistent with the actual claimed process at issue in
this appeal which is not restricted to this specific zeolite. Likewise, Dr.
Brandenburg asserts that acetone is "crucial" to the Two-Step Brandenburg
Process (id. ,r 7), yet the rejected claims are not limited to this solvent, but
also can use acetonitrile or pyridine as a solvent. Thus, Dr. Brandenburg's
arguments are not commensurate with the full scope of the claim because the
claims are limited to a process using zeolite 4A or acetone. Dr.
Brandenburg's statement that "the reaction does not work unless both zeolite
4A and alcoholate are both present" (id. at ,r 11) also raises questions
concerning the operability of the claimed process because the claims do not
recite nor require both components to be used in the recited method of
preparing tiotropium.
Dr. Brandenburg also reasons that it would not have been obvious to
have utilized acetone as a solvent. Brandenburg Deel. ,r 10. This argument
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Application 14/694, 155
does not distinguish the cited prior art from the claimed process because the
claims do not require the reaction solvent to be acetone.
The statement in the Appeal Brief 4, 7 (and Reply Brief 6) that "the
Two-Step Brandenburg Process is surprisingly and unexpectedly superior
and different from the Prior Brandenburg Process in multiple ways" is based
on a process of using acetone as a solvent and the claims are not limited to
acetone. Brandenburg Deel. ,r 10 ("acetone is crucial"). Unexpected results
must be "commensurate in scope with the degree of protection sought by the
claimed subject matter." In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
In view of the foregoing, the rejection of claim 1 is affirmed.
Dependent claims 12 and 14 fall with claim 1 because separate reasons for
their patentability were not provided. 37 C.F.R. § 41.37( c )(1 )(iv).
OBVIOUSNESS TYPE DOUBLE PATENTING REJECTION
Appellants make the same argument as they do for the obviousness
rejection under§ 103(a). Appeal Br. 8. Because we did not find these
arguments persuasive, the obvious type double patenting rejection of claims
1, 12 and 14 is affirmed for the same reasons.
TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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