Ex Parte Bosch et al

Board of Patent Appeals and Interferences

Sep 28, 2010

10035324 (B.P.A.I. Sep. 28, 2010)

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.
10/035,324 01/04/2002 H. William Bosch 029318-0107 2223
31049 7590 09/28/2010
Elan Drug Delivery, Inc. c/o Foley & Lardner
3000 K Street, N.W.
Suite 500
Washington, DC 20007-5109
EXAMINER
HAGHIGHATIAN, MINA
ART UNIT PAPER NUMBER
1616
MAIL DATE DELIVERY MODE
09/28/2010 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte WILLIAM H. BOSCH, DONNA M. MARCERA,
KEVIN D. OSTRANDER, NIELS P. RYDE and DOUGLAS A. WHITE
____________

Appeal 2010-005029
Application 10/035,324
Technology Center 1600
____________

Before RICHARD E. SCHAFER, MICHAEL P. TIERNEY, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL1

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
Appeal 2010-005029
Application 10/035,324

2
This is a decision on the appeal under 35 U.S.C. § 134 by the Patent
Applicant from the Patent Examiner’s rejections of claims 1-7, 9-11, 13, 14,
and 35-37. The Board’s jurisdiction for this appeal is under 35 U.S.C.
§ 6(b). We affirm.

STATEMENT OF THE CASE
The claims are directed to a sterile nanoparticulate dispersion
comprising tyloxapol and beclomethasone or budesonide particles. The
dispersion is recited to be free from biological contaminants. Tyloxapol is a
surface stabilizer which is “adsorbed onto the surface of the nanoparticulate
beclomethasone and/or nanoparticulate budesonide particles.” (Claim 1).
The dispersion can be used as an oral inhalant to treat asthma (Spec. 7-9).
According to the Specification, the “present invention is directed to the
unexpected discovery that nanoparticulate compositions of beclomethasone
or budesonide having tyloxapol as a surface stabilizer can be readily
sterilized by sterile filtration.” (Id. at 9).
Claims 1-7, 9-11, 13, 14, and 35-37 stand rejected by the Examiner
under 35 U.S.C. § 103(a) as obvious in view of:
1) Wiedmann,2 Desai,3 and Verrecchia4 (Ans. 4); and
2) Wood, 5 Desai, and Verrecchia (id. at 7).
Because Appellants relied on the same arguments for both rejections
(App. Br. 19), we consider the rejections together.

2 U.S. Patent 5,747,001 issued May 5, 1998.
3 U.S. Patent Application Publication 2007/0117862 A1 published May 24,
2007.
4 U.S. Patent 6,139,870 issued Oct. 31, 2000.
5 WO 96/25918 published Aug. 29, 1996.
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Claim 1 is representative and reads as follows:
1. A sterile, stable nanoparticulate dispersion comprising:
(a) a liquid dispersion medium;
(b) nanoparticulate beclomethasone particles,
nanoparticulate budesonide particles or a combination thereof
dispersed in the dispersion medium, the nanoparticulate
beclomethasone and nanoparticulate budesonide particles
having an effective average particle size of less than
150 nm;
(c) tyloxapol as a surface stabilizer adsorbed onto the
surface of the nanoparticulate beclomethasone and/or the
nanoparticulate budesonide particles in an amount effective to
prevent the aggregation of the nanoparticulate beclomethasone
and/or budesonide particles; and
(d) optionally, at least one secondary surface stabilizer
adsorbed onto the surface of the nanoparticulate
beclomethasone and/or the nanoparticulate budesonide
particles,
wherein the nanoparticulate dispersion is free from biological
contaminants by sterile filtration with a filter having a pore size
of 0.2 µm or less.

ISSUES
Whether it would have been obvious to persons of ordinary skill in the
art to have sterile-filtered the Wiedmann and Wood preparations as taught
by Desai and Verrecchia.
Whether Appellants provided sufficient evidence to rebut the
Examiner’s obviousness determination.

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LEGAL PRINCIPLES

“An obviousness determination requires that a skilled artisan would
have perceived a reasonable expectation of success in making the invention
in light of the prior art.” Amgen, Inc. v. F. Hoffmann-La Roche Ltd., 580
F.3d 1340, 1362 (Fed. Cir. 2009).
“One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of ‘unexpected results,’ i.e., to show that
the claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or
unexpected. The basic principle behind this rule is straightforward – that
which would have been surprising to a person of ordinary skill in a particular
art would not have been obvious.” In re Soni, 54 F.3d 746, 750 (Fed. Cir.
1995).
“For objective evidence to be accorded substantial weight, its
proponent must establish a nexus between the evidence and the merits of the
claimed invention.” In re GPAC, Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995).
Unexpected results must also 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).

FACTUAL FINDINGS (“FF”)
Desai
1. Desai describes particles for delivery of pharmacologically active
agents. (Desai, ¶ [0001].)
2. Desai discloses that its nanoparticle formulations can be sterile-
filtered.
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The invention further provides a method for the reproducible
formation of unusually small nanoparticles (less than 200 nm
diameter), which can be sterile-filtered through a 0.22 micron
filter. This is achieved by addition of a water soluble solvent
(e.g. ethanol) to the organic phase and by carefully selecting the
type of organic phase, the phase fraction and the drug
concentration in the organic phase. The ability to form
nanoparticles of a size that is filterable by 0.22 micron filters is
of great importance and significance, since formulations which
contain a significant amount of any protein (e.g., albumin),
cannot be sterilized by conventional methods such as
autoclaving, due to the heat coagulation of the protein.
(Desai, ¶ [0051].)
3. The method described by Desai involves combining an organic
solvent having a dissolved active agent, water or an aqueous solution
surfactant, and cosurfactant to form an emulsion, and then removing the
organic solvent to produce a suspension of nanoparticles of the active agent
(id. at ¶¶ [0094] – [0100]).
4. In a further embodiment, Desai teaches that the drug particles are
coated with protein (id. at ¶¶ [0101] – [0104]).
5. Desai discloses that its compositions can be prepared without
conventional surfactants, but instead employing protein as a stabilizing agent
(Desai, ¶¶ [0047] & [0050]).
6. In describing its process of making nanoparticles with a protein
employed as stabilizing agent, Desai states that “[u]nlike conventional
methods for nanoparticle formation, no surfactant . . . is added to the
mixture.” (Id. at ¶ [0163].)
7. Beclomethasone and budesonide are among a list of exemplary
pharmacologically active agents (id. at ¶¶ [0115] & [0112] – [0156]).
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8. Desai describes various solvents (id. at ¶¶ [0161] & [0169]) and
proteins (id. at ¶ [0175]) that can be employed in its methods.
9. Desai also describes different surfactants and cosurfactants that can
be employed to form spontaneous microemulsions (id. at ¶¶ [0271], [0272],
& [0274] – [0280]).
10. In the nanoparticles that comprise surfactants and cosurfactants,
Desai states that matrix-forming polymers (such as PVP) may be added to
the solvent and the “stabilization and solid-form properties may be altered
by the addition of water soluble polymer other than the protein (CMC, gums,
and the like)” (id. at ¶¶ [0283] – [0284]).

Verrecchia
11. Verrecchia describes a method of making particles of less than
100 nm which can be filtered through a 0.22 µm filter.

It has now been found, and this forms the subject of the present
invention, that particles can be prepared, 95% of which have an
average diameter of less than 100 nm . . . which can thus be
subjected to a sterile filtration on 0.22 µm filters without a loss
in yield. These particles are moreover more stable than those
which could be obtained according to the prior art and can be
lyophilized without leading to any phenomenon of particle
agglomeration.
According to the invention, the nanoparticles comprise at least
one hydrophobic, water-insoluble and water-indispersible
polymer or copolymer emulsified in a solution or aqueous
dispersion of phospholipids and of an oleic acid salt, in
particular sodium oleate.
According to the invention, an active principle may be
introduced with the polymer or the copolymer into the
nanoparticles.
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(Verrecchia, col. 1, ll. 25-43.)

Wiedmann
12. Wiedmann describes tyloxapol as a polymer and preferred surface
stabilizer for beclomethasone nanoparticles (Wiedmann, col. 4, ll. 52-67;
col. 2, ll. 20-37).

Answer
13. We adopt the factual findings of the Examiner on pages 3-9 of the
Answer with respect to the Wiedmann, Woods, Desai, and Verrecchia
publications.
ANALYSIS
Claim 1 is directed to a “sterile, stable nanoparticulate dispersion”
comprising “(b) nanoparticulate beclomethasone particles” or
“nanoparticulate budesonide particles” having an average particle size of
less than 150 nm and “(c) tyloxapol as a surface stabilizer.” The
“nanoparticulate dispersion is free from biological contaminants by sterile
filtration with a filter having a pore size of 0.2 µm or less.”
The Examiner found that Wiedmann and Wood described the claimed
dispersion with nanoparticulate particles coated with tyloxapol as a surface
stabilizer, but did not disclose that the dispersion “is free from biological
contaminants by sterile filtration with a filter having a pore size of 0.2 µm or
less,” as recited in claim 1. (Ans. 4 & 7-8.) However, the Examiner found
that each of Desai and Verrecchia taught that filtration of nanoparticle
dispersions through filters was conventional and determined it obvious to
have applied these teachings to Wiedmann or Wood “because sterilized
formulations are safer and beneficial to recipients” (Id. at 7 & 9).
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Appellants do not challenge the Examiner’s findings regarding the
Wiedmann and Wood publications nor the difference between Wiedmann
and Wood and the subject matter of claim 1. Rather, Appellants contend:
the primary disagreement between Appellants and the Examiner
is whether sterile filtration of a nanoparticulate dispersion is a
known technique (as evidenced by Desai and Verrecchia)
and/or whether Appellants provided sufficient evidence of
unpredictability in the art of sterile filtration of nanoparticles to
rebut the Examiner’s broad interpretation of the cited
references.
(App. Br. 10.)

Sterile Filtration
Appellants contend that the Examiner did not establish, based on
Desai and Verrecchia, that it would have been obvious to apply sterile
filtration to the Wiedmann and Wood dispersions. (App. Br. 10-11.)
With regard to Desai, Appellants contend that the “type of dispersion
which can be sterilized by filtration as taught by Desai is limited to
an albumin-bound isoreserpine particle dispersion. This is the only type of
dispersion taught in the examples of Desai that is shown to be capable of
sterile filtration.” (App. Br. 12.) Appellants argue that the Examiner has
improperly expanded Desai’s teachings beyond what is enabled. (Id.)
Appellants’ narrow reading of Desai is not supported by the evidence.
In paragraph [0051], Desai describes methods to produce particles of a size
which can be sterile-filtered through a 0.22 micron filter (FF2). There is no
evidence that this disclosed method was intended to be restricted to the
specific working examples. To the contrary, the broad disclosure in Desai of
different types of active agents, solvents, and formulations (FF3 & FF7-10)
would have led the skilled worker to reasonably expect that Desai’s method
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could be successfully employed to produce nanoparticles of a suitable size
for sterile filtration, including those based on protein or those with
surfactants and cosurfactants. The instant claims do not exclude dispersions
comprising protein and/or surfactants.
In sum, Appellants have not provided a persuasive reason as to why
the skilled worker would have restricted Desai’s teachings to its working
examples, when Desai expressly characterized its invention broadly as
providing “for the reproducible formation of unusually small nanoparticles
(less than 200 nm diameter), which can be sterile-filtered through a 0.22
micron filter” (FF2).
Appellants also disputed whether tyloxapol would have been
recognized as a component which could be substituted in Desai’s
nanoparticle formulations (App. Br. 12-13). Appellants’ argument appears
much the same as that above, i.e., that it would not have been reasonably
predicted that formulations other than those explicitly described in Desai
could be sterile-filtered.
Desai expressly described nanoparticle formulations comprising
surfactants and cosurfactants (FF3 & FF9). In describing this embodiment,
Desai stated that the nanoparticles can include other components, including
polymers “other than proteins” to alter the stabilization properties (FF10).
Thus, Desai did not exclude the addition of other components to its
nanoparticle formulations. Since tyloxapol is described by Wiedmann as a
polymer that can serve as a stabilizer (FF12), Desai’s polymer disclosure
(FF10) reasonably suggests tyloxapol’s addition to the nanoparticle
formulation. As sterile filtration was Desai’s stated objective (FF2), persons
of ordinary skill in the art would also have reasonably expected that the
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addition of tyloxapol to Desai’s formulations would not have impeded the
latter’s ability to be sterile-filtered.
Appellants also contend that Desai “teaches away” from the claimed
invention because it stated that its formulation is prepared in the absence of
conventional surfactants (Reply Br. 8). While it is correct that Desai makes
such a statement (FF5), Desai also describes alternative embodiments in
which surfactants are employed (FF9 & FF10).
Appellants contend that Verrecchia does not support the Examiner’s
position because it “does not teach a nanoparticulate dispersion having solid
particles in a dispersion medium.” (App. Br. 10.)
The dispersion of claim 1 comprises “nanoparticulate . . . particles.”
Appellants have not identified claim language or specification disclosure
that would distinguish this particle type from the particles disclosed in
Verrecchia.

Unpredictable Results
Appellants contend that it was not predictable that any combination of
active agent and stabilizer in the form of a nanoparticulate dispersion could
be sterile-filtered (App. Br. 10). To support this position, they rely on 18
examples disclosed in the Specification on pages 20-29.
To show obviousness, it must be established that the ordinary skilled
worker in the art recognized “a reasonable expectation of success in making
the invention in light of the prior art.” Amgen, 580 F.3d at 1362. In this
case, Appellants cited evidence from the Specification that was said to show
when surface stabilizers other than tyloxapol were utilized to make
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nanoparticulates, they did not produce preparations that could be sterile-
filtered (App. Br. 15).
Claim 1 is a product claim which is not restricted to a particular
process of preparing sterile nanoparticles. Both Desai and Verrecchia
describe methods of making nanoparticles capable of sterile filtration (FF2
& FF11). Thus, persons of ordinary skill in the art would have known of
methods for producing particles of a sterile filterable size. Based on these
teachings, persons of ordinary skill in the art would therefore have
reasonably expected that nanoparticles filterable through a sterile filter, such
as the beclomethasone/tyloxapol nanoparticles suggested by Wiedmann
(F12), could have been made by following the methods described in Desai or
Verrecchia.

Unexpected Results
In addition to arguing that there was a lack of predictability,
Appellants also contend that the claimed invention is based on the following
unexpected findings:
(i) that nanoparticulate active agents stabilized by surface
stabilizers other than tyloxapol were unable to be sterile
filtered; and (ii) that steroids other than budesonide and
beclomethasone stabilized by tyloxapol were unable to be
sterile filtered.
(Reply Br. 8.)
Examples 1-14 described on pages 20-27 of the Specification involve
the use of tyloxapol and other surface stabilizers to prepare nanoparticulate
compositions.
There must be a nexus between the evidence of unexpected results
and the merits of the claimed invention. See In re GPAC, 57 F.3d at 1580.
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Thus, it must be shown that the unexpected results arise from a limitation or
feature of the claimed invention. In this case, the claims are drawn to a
combination of tyloxapol with beclomethasone or budesonide. Appellants
contend that it was unexpected that tyloxapol would produce sterile-
filterable particles, while other surface stabilizers would not. “[A]ppellants
have the burden of explaining the data in any declaration they proffer as
evidence of non-obviousness.” Ex parte Ishizaka, 24 U.S.P.Q.2d 1621,
1624 (Bd. Pat. App. & Inter. 1992). Thus, it was Appellants’ burden to
show that tyloxapol, but not other surface stabilizers, would produce
particles of the claimed size – and that it was tyloxapol, but not other factors
or conditions, responsible for this result.
On pages 15-16 of the Appeal Brief, Appellants summarized
Examples 1-18 described in the Specification, stating the “inventors of the
present invention unexpectedly discovered that nanoparticulate active agents
stabilized by surface stabilizers other than tyloxapol and having a particle
size of less than 200 nm were unable to be sterile filtered (see Examples 5-9
and 12-14).” The only examples Appellants specifically referred to were
Examples 5 and 8, which use HPMC and polysorbate 80, respectively,
instead of tyloxapol. Appellants did not state whether the examples with
HPMC and polysorbate 80 were performed under the same process
conditions as the example dispersions prepared with tyloxapol – using the
same ratio of active agent, surface stabilizer, and water solvent. Thus,
Appellant has not met their burden of showing that it was the tyloxapol
responsible for the result, rather than the process conditions or some other
factor.
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It was also not established that the tyloxapol alone was responsible for
the result, or, for instance, whether it was the specific concentration of
tyloxapol, the ratio between tyloxapol and the drug, or the water, that
accounted for the result. Claim 1 is not restricted to a specific concentration
of tyloxapol, a ratio between tyloxapol and the drug, or water as the
dispersive medium.
Consequently, we conclude that Appellants have not established a
nexus between the claimed subject matter and the results, nor that the results
are commensurate with the scope of the claims. Harris, 409 F.3d at 1344.
Appellants also did not state that such results would have been unexpected
or surprisingly to a person of ordinary skill in the art. ” In re Soni, 54 F.3d
at 750.
Examples 15-18, described on pages 27-29 of the Specification,
involve the use of tyloxapol with active agents other than beclomethasone
and budesonide. Again, Appellants did not establish that these examples
were performed under the same conditions as the comparative examples
with beclomethasone and budesonide. For the same reasons stated above,
we do not consider these results sufficient to rebut the Examiner’s case.

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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14

bim

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