Ex Parte Brueck-Scheffler

Patent Trial and Appeal Board

Nov 3, 2014

10582499 (P.T.A.B. Nov. 3, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte ANTJE BRUECK-SCHEFFLER
__________

Appeal 2012-004773
Application 10/582,499
Technology Center 1600
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Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a method
for preparing a sterile aqueous suspension of ciclesonide suitable for
nebulization. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 Appellant identifies the Real Party in Interest as NYCOMED
GmbH (see App. Br. 3).
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Statement of the Case
Background
Ciclesonide “has undergone evaluation as an antiasthmatic and
pharmacokinetic studies show that it will be useful in an inhaler
formulation” (Spec. 1). While “water-soluble drugs aqueous solutions are
nebulized, this is not possible in case of water-insoluble drugs such as
ciclesonide . . . In order to allow deposition within the lungs the particle size
of the aerosol droplets after nebulization needs to be in the range of
approximately 1-7 µm” (Spec. 2). “Another requirement for suspension for
nebulization is that these suspensions have to be isoosmotic in order to avoid
irritation of the tissue” (Spec. 2). “In addition formulations for
administration by nebulization have to be sterile. . . . Sterilization by
filtration is no option when micronized drug substance with a mean particle
size of 2-6 µm is used, since the particles are not able to pass the filter”
(Spec. 2).
The Claims
Claims 1–10 and 12–20 are on appeal. Claim 1 is representative and
reads as follows:
1. A method for preparing a sterile aqueous suspension
of ciclesonide suitable for nebulization comprising the steps
of:
a. providing an aqueous suspension of ciclesonide,
containing at least one non-ionic agent for adjusting
osmolality, and one or more pharmaceutically acceptable
excipients, which one or more excipients are all non-ionic
excipients; and
b. autoclaving the aqueous suspension provided in (a).

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The issues
A. The Examiner rejected claims 1–4, 7–10, and 12–20 under 35 U.S.C.
§ 103(a) as obvious over Nishibe,2 Saidi,3 and Lintz4 (Ans. 3, 6–95).
B. The Examiner rejected claim 5 under 35 U.S.C. § 103(a) as obvious
over Nishibe, Saidi, Lintz, Allen,6 and ACS registry7 (Ans. 9–10).
C. The Examiner rejected claim 6 under 35 U.S.C. § 103(a) as obvious
over Nishibe, Saidi, Lintz, and Sambuco8 (Ans. 10–11).
A. 35 U.S.C. § 103(a) over Nishibe, Saidi, and Lintz
The Examiner finds that “Nishibe et al. teach a ciclesonide containing
sterile aqueous suspension sterilized by autoclaving . . . The suspension may
comprise suspending agents and wetting agents” (Ans. 6). The Examiner
finds that Saidi teaches a “cortiscosteroid that can be delivered through a
nebulizer (see abstract). The composition comprises an osmolality agent
such as glucose such that the osmolality of the composition is from about
280-300 mosmol/kg . . . The composition also comprises a surfactant such as
. . . Tween” (Ans. 7). The Examiner finds that Linz teaches “kits for the
preparation of liquid composition that are administered as aerosols through

2 Nishibe et al., US 2006/0166953 A1, published Jul. 27, 2006.
3 Saidi et al., US 6,241,969 B1, issued Jun. 5, 2001.
4 Lintz et al., US 2004/0247628 A1, published Dec. 9, 2004.
5 Although the Examiner’s statement of the rejection includes
claim 11 and does not include claim 10, the Examiner clarified that
this rejection is applied to claims 1–4, 7–10, and 12–20 (Ans. 3).
The Reply Brief notes the correct claims to which the rejection is
applied (Reply Br. 3).
6 Allen et al., Inhaled corticosteroids: Past lessons and future
issues, 112 J. ALLERGY CLINICAL IMMUNOL. S1-S40 (2003).
7 STN Registry database, RN 161115-59-9 (1995).
8 Sambuco et al., US 2005/0175546 A1, published Aug. 11, 2005.
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nebulization” (Ans. 7). The Examiner finds that Linz teaches
“ciclesonide . . . that can be administered with excipients such as citric and
tartaric acid to adjust the pH (see paragraph 25) and surfactants . . . to
improve the dissemination of the aerosol droplets in the lungs . . . Preferable
surfactants include Tween 60” (Ans. 7).
The Examiner finds it obvious to “combine the method of Nishibe et
al. and provid[e] the composition in a nebulizer because Saidi et al. teach
that compositions can be made with corticosteroids to be delivered through a
nebulizer to provide treatment for ailments and diseases of the respiratory
tract” (Ans. 7). The Examiner further finds it obvious to provide
“osmolality agents of claims 1, 2, 7 and 8 and at the osmolality range of
claim 20 because Saidi et al. teach nebulizer compositions comprising
corticosteroids that have an osmolality agent such as glucose such that the
osmolality of the composition is from about 280-300 mosmol/kg” (Ans. 8).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Nishibe, Saidi, and Lintz render the
claims obvious?
Findings of Fact
1. Nishibe teaches “a ciclesonide-containing sterile aqueous
suspension sterilized by autoclaving, wherein the concentration of
ciclesonide after autoclaving is 95% or more comparing to that before
autoclaving” (Nishibe 2 ¶ 30).
2. Nishibe teaches a “ciclesonide-containing sterile aqueous
suspension sterilized by autoclaving, wherein the suspension contains
hydroxypropylmethylcellulose” (Nishibe 2 ¶ 31).
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3. Nishibe states that the “objects of the present invention have
been achieved by discovering that the uniformity of ciclesonide content can
be maintained when hydroxypropylmethylcellulose is coexisted, even after
sterilization by autoclaving” (Nishibe 2 ¶ 21).
4. Nishibe teaches that the “ciclesonide-containing sterile aqueous
suspension of the present invention can be administered via any other routes
than nasal route such as ophthalmic, transdermal or oral route” (Nishibe 3
¶ 46).
5. Saidi teaches
compositions containing corticosteroid compounds as
active agents for the treatment of ailments and diseases of
the respiratory tract, particularly the lungs, by way of nasal
and pulmonary administration. The corticosteroid
compounds are present in a dissolved state in the
compositions. The compositions can be formulated in a
concentrated, essentially non-aqueous form for storage or in
a diluted, aqueous-based form for ready delivery. In a
preferred embodiment, the corticosteroid composition
contains an ethoxylated derivative of vitamin E and/or a
polyethylene glycol fatty acid ester as the high-HLB
surfactant present in the formulation. The compositions are
ideally suited for inhaled delivery with a nebulizer or for
nasal delivery.

(Saidi, abstract).
6. Saidi teaches that the
osmotic agent can be used in the compositions to
enhance the overall comfort to the patient upon delivery of
the corticosteroid composition. It is preferred to adjust the
osmolality of the composition to about 280–300 mOsm/kg.
Such agents include any low molecular weight water-soluble
species pharmaceutically approved for pulmonary and nasal
delivery such as sodium chloride and glucose.
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(Saidi, col. 7, ll. 3–9).
7. Saidi teaches that the “corticosteroid compositions can contain
other high HLB surfactants, such as . . . sorbitan esters such as the Tween
series” (Saidi, col. 8, ll. 54–57).
8. Lintz teaches that for
pulmonary administration, a liquid composition can
be inhaled either through the nose or, more preferably,
through the mouth. This is done, for instance, after
nebulizing the liquid to form an aerosol, which is a
dispersion of finely divided liquid droplets or solid particles
in a gaseous phase. Various nebulizers are known and
available for pharmaceutical applications.

(Lintz 2 ¶ 18).
9. Lintz teaches that “[e]xamples of drugs that may be
administered using the teachings of the invention include . . . ciclesonide”
(Lintz 2 ¶ 19).
10. Lintz teaches that “[c]ompounds useful as water-soluble
excipients which also affect the pH include e.g. citric acid, tartaric acid”
(Lintz 4 ¶ 25).
11. Lintz teaches a “surfactant to increase the wettability of the
active compound or to improve the dissemination of the aerosol droplets in
the lungs. A surfactant should also be pharmaceutically acceptable in the
amount that is incorporated in the formulation. Examples of surfactants that
may be used are . . . Tweens” (Lintz 4 ¶ 27).
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Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,416 (2007).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 6–9; FF 1–11) and agree that the
claims are obvious over Nishibe, Saidi, and Lintz. We address Appellant’s
arguments below.
Appellant contends that “Nishibe et al. discloses some of the problems
associated with autoclaving suspensions. In particular, Nishibe et al. address
the issue of ‘drug content uniformity’ in paragraph [0014]” (App. Br. 13).
Appellant contends that “starting with the Nishibe et al. reference, the person
of ordinary skill in the art is faced with the technical problem of providing a
sterile aqueous ciclesonide suspension that does not suffer from clogging
and a suspension that is suitable for nebulization, i.e. inhalative
administration” (App. Br. 13).
We are not persuaded. While Nishibe explains that drug content
uniformity was a problem in the prior art (Nishibe 1 ¶ 14), Nishibe states
that the “objects of the present invention have been achieved by discovering
that the uniformity of ciclesonide content can be maintained when
hydroxypropylmethylcellulose is coexisted, even after sterilization by
autoclaving” (Nishibe 2 ¶ 21; FF 3). Thus, the entire thrust of this argument
was already addressed by Nishibe, who teaches that addition of
hydroxypropylmethylcellulose maintains content uniformity after
autoclaving (FF 3).
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Appellant contends that
the presently pending claims are directed to preparing
suspensions of ciclesonide sterilized through autoclaving
suitable for nebulization. In contrast, the methods of Saidi
et al. are focused on solutions of corticosteroids sterilized
through filtration. One of ordinary skill would not look to a
reference teaching a solution of an active sterilized through
filtration to modify a method of preparing a suspension of
an active sterilized through autoclaving.

(App. Br. 14). Appellant also contends that Lintz is “focused on dissolving
the solid composition to form a liquid composition that is sterilized through
filtration. One of ordinary skill would not look to a reference teaching a
solution of an active sterilized through filtration to modify a method of
preparing a suspension of an active sterilized through autoclaving” (App. Br.
15). Appellant contends that the “Examiner is using improper hindsight to
allege her prima facie case” (App. Br. 16).
We are not persuaded because the obviousness question does not
relate to the mode of sterilization, but rather to whether the ordinary artisan
would have found it obvious to administer Nishibe’s autoclaved ciclesonide
in nebulizer form. In this regard, Lintz teaches pulmonary administration
steroids, including ciclesonide, using nebulizers (FF 8–9). Saidi further
teaches the addition of osmotic agents “to enhance the overall comfort to the
patient upon delivery of the corticosteroid composition . . . . Such agents
include . . . water-soluble species pharmaceutically approved for pulmonary
and nasal delivery such as sodium chloride and glucose” (Saidi, col. 7, ll. 3–
9; FF 6).
While we are fully aware that hindsight bias often plagues
determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36
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(1966), we are also mindful that the Supreme Court has clearly stated that
the “combination of familiar elements according to known methods is likely
to be obvious when it does no more than yield predictable results.” KSR,
550 U.S. at 416.
In this case, we conclude that the ordinary artisan, interested in sterile
pulmonary or nasal administration of the steroid ciclesonide by nebulization
as taught by Lintz (FF 8–9), would have reasonably included the osmotic
agents of Saidi to improve delivery comfort of steroids (FF 6), and would
have autoclaved the ciclesonide as taught by Nishibe, since Nishibe’s
method results in sterile and uniform ciclesonide content (FF 1–3). We
agree with the Examiner that the “motivation to provide a nebulizable form
of the Nishibe et al. composition is to provide treatment for respiratory tract
ailments and diseases” (Ans. 14).
Appellant contends that “Saidi et al. not only teaches the non-ionic
osmolality agent glucose, but also teaches the ionic osmolality agent sodium
chloride” (App. Br. 17). Appellant contends that, based on the
Specification, “ionic osmotic agents such as sodium chloride - indeed even
in the same concentration as that disclosed as acceptable in Saidi et al. - do
not successfully render the presently claimed ‘sterile aqueous suspension of
ciclesonide suitable for nebulization’” (App. Br. 17). Appellant contends
that in “view of the clear lack of teaching or suggestion contained in the
cited references regarding the selection of only non-ionic agents in the
presently claimed method, the presently pending claims are not obvious over
the cited references” (App. Br. 18).
We are not persuaded. While Appellant provides a single example
showing a ciclesonide suspension with sodium chloride results in large white
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aggregates (see Spec. 11, Example 7), the example lacks incorporation of the
hydroxypropylmethylcellulose required by Nishibe for maintaining
uniformity (FF 3). Appellant has not demonstrated that the use of non-ionic
compounds yields an unexpected result relative to the closest prior art.
Therefore, we agree with the Examiner that the example is not a comparison
with the teachings of the closest prior art (see Ans. 15). See In re Baxter
Travenol Labs., 952 F.2d 388, 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.”).
We also agree with the Examiner that the ordinary artisan would “test
for the best osmotic agent to render the best result for nebulization based on
the teachings” of the prior art (see Ans. 16). Thus, motivated by Saidi to
incorporate preferred osmotic agents such as NaCl or glucose (FF 6), the
ordinary artisan would have tested these compounds to identify amounts and
compounds which would successfully yield sterile nebulizable ciclesonide as
desired by Lintz (FF 8–9) when combined with the teachings of Nishibe and
Saidi (FF 1–7).
Appellant responds that the Examiner “ignored the requirements of
MPEP 2143.01 by casting aside appellant’s arguments and data contained
within their specification that shows that the ionic osmotic excipient sodium
chloride as taught by Saidi et al is unacceptable and would ‘render the prior
art [i.e. Nishibe et al] unsatisfactory for its intended purpose’” (App. Br. 20).
We are not persuaded because the Examiner specifically addresses
this argument, relying upon Saidi to evidence that “non-ionic and ionic
osmotic agents are known to be used in the art to adjust the osmolality of a
composition from about 280-300 mosmol/kg for cortiscosteroid
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formulations” (Final Rej. 10; cf. Ans. 15; FF 6). Even if we credit the
teaching in the Specification in Examples 5 and 7, which do not include the
hydroxypropylmethylcellulose component taught by Nishibe as necessary
for suspension uniformity, as indicating that ionic osmotic agents will not
function, the ordinary artisan when presented with two osmotic agents by
Saidi would reasonably test both for efficacy, and rely upon the functioning
osmotic agent. See Pfizer v. Apotex, 480 F.3d 1348, 1368–69 (Fed. Cir.
2007) (holding obvious a patent claim to amlodipine besylate over prior art
disclosing the small genus of pharmaceutically acceptable amlodipine salts,
where there was an insufficient showing that the properties of amlodipine
besylate, purportedly superior for the purpose of mass-manufacturing
tablets, were unexpectedly superior to other obvious-to-try salts).
Appellant contends that the “Examiner has seemingly ignored the
requirement that the proposed modification of the prior art must have had a
reasonable expectation of success, determined from the vantage point of the
skilled artisan at the time the invention was made” (Reply Br. 7).
We are not persuaded. We agree with the Examiner that there would
be a reasonable expectation of success in making the claimed composition
since Lintz teaches nebulized ciclesonide with non-ionic surfactants such as
tween (FF 8–11), Saidi suggests nebulization for steroids with osmotic
agents such as glucose and surfactants such as tween (FF 5–7) and Nishibe
evidences that ciclesonide is stable and remains uniform after autoclaving
with the proper excipient (FF 1–4). As O’Farrell notes “[o]bviousness does
not require absolute predictability of success ... all that is required is a
reasonable expectation of success.” In re O’Farrell, 853 F.2d 894, 903–904
(Fed. Cir. 1988); see also Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d
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1326, 1331 (Fed. Cir. 2014) (“Conclusive proof of efficacy is not necessary
to show obviousness.”).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
Nishibe, Saidi, and Lintz render the claims obvious.
B. 35 U.S.C. § 103(a) over Nishibe, Saidi, Lintz, Allen, and ACS Registry
Appellant does not identify any specific additional deficiencies in the
rejection further relying upon Allen and the ACS registry, instead
contending that “a person of ordinary skill in the art would not look to Allen
et al. and the ACS Registry to remedy the deficient teachings of Nishibe et
al., Saidi et al. and/or Lintz et al. to arrive at the presently pending claims”
(App. Br. 22).
Having affirmed the obviousness rejection over Nishibe, Saidi, and
Lintz for the reasons given above, we also find that the further obvious
combination with Allen and ACS registry renders claim 5 obvious for the
reasons given by the Examiner (see Ans. 9–10).
C. 35 U.S.C. § 103(a) over Nishibe, Saidi, Lintz, and Sambuco
Appellant contends that “a person of ordinary skill in the art would
not look to Sambuco et al. to remedy the deficient teachings of Nishibe et
al., Saidi et al. and/or Lintz et al. to arrive at the presently pending claims”
(App. Br. 24).
Having affirmed the obviousness rejection over Nishibe, Saidi, and
Lintz for the reasons given above, we also find that the further obvious
combination with Sambuco renders claim 6 obvious for the reasons given by
the Examiner (see Ans. 10–11).
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SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over Nishibe, Saidi, and Lintz. Pursuant to
37 C.F.R. § 41.37(c), we also affirm the rejection of claims 2–4, 7–10, and
12–20, as these claims were not argued separately.
We affirm the rejection of claim 5 under 35 U.S.C. § 103(a) as
obvious over Nishibe, Saidi, Lintz, Allen, and ACS registry.
We affirm the rejection of claim 6 under 35 U.S.C. § 103(a) as
obvious over Nishibe, Saidi, Lintz, and Sambuco.
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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