Ex Parte Pairet et al

Board of Patent Appeals and Interferences

Jan 30, 2012

10776757 (B.P.A.I. Jan. 30, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MICHEL PAIRET, MICHAEL P. PIEPER,
CHRISTOPHER JOHN MONTAGUE MEADE, RICHARD REICHL,
and CHRISTEL SCHMELZER
__________

Appeal 2011-007772
Application 10/776,757
Technology Center 1600
__________

Before ERIC GRIMES, LORA M. GREEN, and STEPHEN WALSH,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims relating to
inhalable powder pharmaceuticals. The Examiner has rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The Specification discloses that “an unexpectedly beneficial
therapeutic effect, particularly a synergistic effect can be observed in the
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treatment of inflammatory or obstructive diseases of the respiratory tract”
(Spec. 1: 16-19) if an anticholinergic, such as a tiotropium salt (id. at
2: 11-13), is used together with a corticosteroid, such as ciclesonide (id. at
2: 28-31).
Claims 1, 3, 4, 9, 10, 15-17, 19-21, 23, 25, 26, 31-37, 39, and 63-66
are on appeal. Claim 1 is representative and reads as follows:
1. An inhalable powder pharmaceutical composition comprising:
(a) a tiotropium salt or a hydrate thereof;
(b) a steroid which is ciclesonide, and
(c) a pharmaceutically acceptable excipient selected from the group
consisting of glucose, arabinose, lactose, saccharose, and maltose,
wherein the tiotropium salt and the steroid are optionally in the form
of their enantiomers, mixtures of their enantiomers, or their racemates.
I.
Issue
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 103(a) as being obvious in view of Nishimura,1 Banholzer,2 and Keller.3
The claims have not been argued separately4 and therefore stand or fall
together. 37 C.F.R. § 41.37(c)(1)(vii).

1 Koichi Nishimura et al., Additive effect of oxitropium bromide in
combination with inhaled corticosteroids in the treatment of elderly patients
with chronic asthma, 48 ALLERGOLOGY INTERNATIONAL 85-88 (1999)
2 Banholzer et al., US 5,610,163, Mar. 11, 1997
3 Keller et al., WO 00/28979, May 25, 2000. Our citations are to the English
equivalent of record, US Pat. No 6,645,466 B1, Nov. 11, 2003.
4 Although the Appeal Brief presents claim 39 under a separate heading, in
the form of a separate argument, it incorporates by reference only the same
arguments presented for the other claims, and adds no freestanding separate
argument. (Appeal Brief 14.)
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The Examiner finds that Nishimura discloses “an inhalation
composition comprising anticholinergic agents, such as, oxitropium bromide
and ipratropium bromide and corticosteroids such as beclomethasone
dipropionate for treating asthma” (Answer 3). The Examiner finds that
Nishimura discloses that “the addition of oxitropium bromide to
beclomethasone dipropionate shows beneficial effects” (id. at 3-4).
The Examiner finds that Banholzer discloses “thienyl carboxylic acids
such as tiotropium and its salts as strong anticholinergic agents having
prolonged action for use in treating asthma” (id. at 4). The Examiner finds
that Banholzer discloses that “the compounds show similar toxicity to
ipratropium bromide while at the same time the therapeutic effect is stronger
and prolonged” (id.).
The Examiner finds that Keller discloses “dry powder formulations
for inhalation … containing a β-mimetic and/or an anticholinergic and/or a
corticosteroid” (id. at 5). The Examiner also finds that Keller discloses
“carriers for … dry powder formulations such as glucose, lactose, sucrose,
etc.,” tiotropium bromide as an anticholinergic agent, and ciclesonide as a
corticosteroid (id.).
The Examiner concludes that “a dry powder inhalation formulation
comprising an anticholinergic agent, such as a tiotropium salt and a
corticosteroid, such as ciclesonide would have been obvious to the skilled
artisan” in view of the cited references (id. at 6). The Examiner finds that a
skilled artisan would have been motivated to combine an anticholinergic
agent with a corticosteroid based on “(a) the knowledge in the art of the
utilization of each in treating … asthma and (b) the teaching by Nishimura
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of the beneficial effect of a combination of an anticholinergic agent and a
corticosteroid” (id.). The Examiner also finds “motivation to utilize
tiotropium as the anticholinergic agent … based on the teaching of
Banholzer of [its] stronger and prolonged therapeutic action” (id.).
Appellants contend that claim 1 would not have been prima facie
obvious in view of the cited references because none of the cited references
suggests the specific combination of tiotropium and ciclesonide (Appeal Br.
12-13). Appellants also contend that they have presented evidence of
unexpected results that overcomes any prima facie case of obviousness (id.
at 9-12).
The issues presented are: Does the evidence of record support the
Examiner’s conclusion that claim 1 would have been prima facie obvious in
view of the cited references?
If so, have Appellants provided evidence of unexpected results that
outweighs the evidence supporting the prima facie case of obviousness?
Findings of Fact
1. Nishimura discloses that “inhaled corticosteroids are the
established treatment of choice in cases of chronic asthma.… The addition
of other bronchodilators including … inhaled anticholinergic agents has
been recommended in … patients whose asthma is not well controlled.”
(Nishimura 85, right col.)
2. Nishimura discloses a study to evaluate the “efficacy of the
addition of inhaled oxitropium bromide in combination with inhaled
corticosteroids in the treatment of elderly asthmatic patients” (id., abstract).
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3. Nishimura discloses that the “efficacy of treatment with and
without regular inhalation of oxitropium bromide in addition to inhaled BDP
[beclomethasone dipropionate] was compared” (id. at 86, left col.).
4. Nishimura discloses that “[f]orced expiratory volume in 1 second
(FEV1) was significantly improved after treatment with regular inhalation of
oxitropium bromide…. Both morning and evening peak expiratory flow
rates were significantly greater during the treatment period with regular
inhalation of oxitropium bromide. The score for dyspnea/chest tightness
was also significantly improved during the oxitropium bromide period.”
(Id., abstract.)
5. Banholzer discloses anticholinergic agents that are “useful for the
treatment of chronic obstructive bronchitis or slight to moderately severe
asthma” (Banholzer, abstract).
6. Banholzer discloses that the anticholinergic agents “have
prolonged action. Action lasting at least 24 hours is achieved at inhaled
dosages in the μg range.… [T]he toxicity is in the same range as the
commercial product Ipratropium bromide while at the same time the
therapeutic effect is stronger.” (Id. at col. 3, ll. 27-32.)
7. The Examiner finds that compound A in column 5 of Banholzer is
tiotropium (Answer 4). Appellants do not dispute this finding (see Appeal
Br. 7).
8. Keller discloses dry powder formulations for inhalation (Keller,
col. 4, ll. 44-47) that “comprise a pharmaceutically inactive carrier…, [and]
a finely divided pharmaceutically active compound of inhalable particle
size” (id. at col. 4, ll. 57-63).
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9. Keller discloses that the carrier can be, for example, glucose or
lactose (id. at col. 8, ll. 1-4).
10. Keller discloses that the active compound can be “a beta-
mimetic…, an anticholinergic, such as tiotropium, ipratropium, oxitropium
or glycopyrronium, [or] a corticosteroid, such as butoxicart, rofleponide,
budesonide, ciclesonide…, [or] beclomethasone” (id. at col. 6, ll. 13-21).
11. Keller discloses that “the formulations according to the invention
can contain two or more pharmaceutically active compounds” (id. at col. 6,
ll. 36-37).
12. Keller discloses that “dry powder formulations which contain a
beta-mimetic and/or an anticholinergic and/or a corticosteroid” (id. at col. 6,
ll. 52-54).
13. Appellants have provided a declaration under 37 C.F.R. § 1.132
(Declaration of Thierry Bouyssou, filed Nov. 4, 2009).
14. Dr. Bouyssou declares that the “inhibitory effect of tiotropium
bromide in combination with ciclesonide on acetylcholine-induced
bronchoconstriction over 24 hours after single administration was
investigated in comparison to the respective mono-therapies” (Bouyssou
Declaration, 3).
15. Dr. Bouyssou declares that “[c]iclesonide applied at 0.1 mg/kg
only induced slight bronchoprotection of 5 ± 10 %, 3 hours after drug
inhalation which remained constant over 24 hours” (id. at 4).
16. Dr. Bouyssou declares that bronchoprotection with tiotropium
bromide “reached 35 ± 25 % at 0.06 μg/kg … 3 hours after inhalation. The
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compound maintined [sic] at the end of the 24 hour study period a
bronchoprotection of 12 ± 7 %” (id.).
17. Dr. Bouyssou declares that “[c]ompared to the efficacy of each
mono-therapy, the combination of submaximal doses of ciclesonide (0.1
mg/kg) and tiotropium bromide (0.06 μg/kg) resulted in an unexpected
super-additive bronchoprotection of 49 ± 7 % at 3 hours and of 41 ± 14 %
after 24 hours” (id.).
18. Dr. Bouyssou declares that “the synergistic bronchoprotection
properties of the combined administration of tiotropium bromide and
ciclesonide would not have been expected by those of ordinary skill in the
art from the consideration of the Nishimura …; Banholzer …; and Keller
references” (id.).
Analysis
Claim 1 is directed to an inhalable powder composition comprising a
tiotropium salt, ciclesonide, and one of glucose, arabinose, lactose,
saccharose, or maltose. Nishimura discloses that treatment with inhaled
corticosteroids and inhaled anticholinergic agents has been recommended
for patients whose asthma is not well controlled. Nishimura discloses that
significant improvement was achieved by adding treatment with oxitropium
bromide, an anticholinergic agent, to standard treatment with the
corticosteroid beclomethasone dipropionate.
Banholzer discloses that tiotropium is an anticholinergic agent that
shows prolonged action, with similar toxicity to the commercial product
ipratropium bromide, but with a stronger therapeutic effect. Keller discloses
inhalable dry powder formulations which contain a beta-mimetic and/or an
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anticholinergic (such as tiotropium) and/or a corticosteroid (such as
ciclesonide), and a carrier component that can be glucose or lactose.
In view of these disclosures, it would have been obvious to one of
ordinary skill in the art to formulate an inhalable powder pharmaceutical
composition comprising tiotropium and ciclesonide in order to take
advantage of the combined therapeutic effects of an anticholinergic agent
and a corticosteroid as suggested by Nishimura. It would also have been
obvious to include glucose or lactose because Keller discloses that they can
be used as carrier compounds with inhalable powder formulations, including
formulations containing an anticholinergic and a corticosteroid.
Appellants argue that none of the cited references “provide any reason
for one of ordinary skill in the art to make the particular combination as
claimed” (Appeal Br. 13). Appellants argue that Nishimura discloses a
different combination of anticholinergic and steroid than is recited in claim 1
and that Nishimura “is very specific on this particular combination” (id.).
Appellants further argue that Keller does not discuss the specific
combination of claim 1 (id.).
This argument is not persuasive. Although Nishimura specifically
evaluates the combination of oxitropium bromide and beclomethasone
dipropionate, it does not suggest that this specific combination is the only
one suitable for treating asthma. Instead, Nishimura discloses that “inhaled
corticosteroids,” generically, are the established treatment for chronic
asthma, and that the addition of “inhaled anticholinergic agents,”
generically, is recommended for patients whose asthma is not well
controlled by corticosteroids alone. Thus, it would have been obvious to use
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other corticosteroids and anticholinergic agents in Nishimura’s combination
treatment method.
Appellants also argue that they have provided evidence of unexpected
results that overcomes the asserted case of prima facie obviousness.
Appellants argue that the Bouyssou Declaration provides evidence that
unexpected synergistic bronchoprotective effects were achieved by the
combination of tiotropium and ciclesonide (Appeal Br. 9-12). The
Bouyssou Declaration describes a study in dogs with acetylcholine-induced
bronchoconstriction in which the bronchoprotective effects of tiotropium
combined with ciclesonide was compared with the bronchoprotective effects
of the therapeutic agents individually (see FFs 14-18).
The Examiner responds that “the combination of an anticholinergic
agent and a corticosteroid is taught by the art as evidenced by Nishimura and
there is no evidence on record that said results would be unobvious and/or
unexpected when compared with the combination taught by Nishimura
under similar conditions” (Answer 10).
We agree with the Examiner that Appellants have not provided
evidence of unexpected results sufficient to overcome the prima facie case of
obviousness. The burden of demonstrating unexpected results rests on the
party asserting them. In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972).
That burden has not been carried here because Appellants have not
established that the results shown for the combination of tiotropium and
ciclesonide were unexpectedly superior compared to closest prior art, which
is the combination of oxitropium bromide and beclomethasone dipropionate
disclosed by Nishimura. See In re Baxter-Travenol Labs., 952 F.2d 388,
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392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.”).
Nishimura discloses that the combination of corticosteroids and
anticholinergic agents, generically, is used to treat asthma, and that the
combination of oxitropium and beclomethasone, specifically, shows
improved benefit compared to beclomethasone alone. Thus, one of skill in
the art would have expected that the combination would also be superior to a
corticosteroid alone in the acetylcholine-induced bronchoconstriction model
cited in the Bouyssou Declaration.
Although the Bouyssou Declaration states that synergistic effect
resulted from combining, tiotropium and ciclesonide, a showing of
unexpectedly superior results for the claimed combination requires a
comparison to the prior art combination of oxitropium bromide and
beclomethasone in the same experimental system, or at least a showing that
those skilled in the art would recognize that the declaratory evidence can be
validly compared to the results shown in the prior art.
Here, the Bouyssou Declaration provides no persuasive basis for
concluding that Nishimura’s results in human asthma patients can validly be
compared to the results found in the Bouyssou Declaration for acetylcholine-
induced bronchoconstriction in dogs. Thus, the statement in Bouyssou
Declaration that the synergistic bronchoprotection properties of the
tiotropium/ciclesonide combination “would not have been expected by those
of ordinary skill in the art from the consideration of” Nishimura, Banholzer
and Keller (FF 18) is not adequately supported by the evidence of record.
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Since Appellants have not provided a valid comparison of the claimed
combination to the closest prior art, they have not carried the burden of
demonstrating unexpected results.
Appellants argue that providing a direct comparison to the closest
prior art is not required because “a showing of a synergistic effect of a
combination alone can be sufficient proof of nonobviousness” (Reply Br. 1-
2; Appeal Br. 4, citing MPEP § 716.02(a)(I)). This argument is not
persuasive. The cited portion of the MPEP indicates that unexpected results
may be shown by demonstrating a greater than expected result, but goes on
to say, consistent with the case law cited above, that “Applicants must
further show that the results were greater than those which would have been
expected from the prior art to an unobvious extent” (MPEP § 716.02(a)(I),
emphasis added).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that claim
1 would have been prima facie obvious in view of the cited references.
Appellants have not provided evidence of unexpected results that outweighs
the evidence supporting the prima facie case of obviousness.
II.
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 103(a) as being obvious in view of Nishimura and Banholzer. We agree
with Appellants, however, that “[n]either of Nishimura or Banholzer provide
any suggestion to combine the particular steroid ciclesonide” (Appeal Br. 7-
8). In articulating this rejection, the Examiner asserted that ciclesonide is a
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well-known corticosteroid, but did not cite any evidence to support this
assertion. Thus, the Examiner has not met the initial burden of presenting a
prima facie case of obviousness based solely on Nishimura and Banholzer.
SUMMARY
We reverse the rejection based on Nishimura and Banholzer. We
affirm the rejection of claims 1, 3, 4, 9, 10, 15-17, 19-21, 23, 25, 26, 31-37,
39 and 63-66 under 35 U.S.C. § 103(a) in view of Nishimura, Banholzer and
Keller.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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