Ex Parte York et al

Board of Patent Appeals and Interferences

Mar 20, 2012

10422342 (B.P.A.I. Mar. 20, 2012)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
10/422,342 04/24/2003 Peter York 0168.00 8280
21968 7590 03/20/2012
NEKTAR THERAPEUTICS
455 Mission Bay Blvd., South, Suite 100
San Francisco, CA 94158
EXAMINER
HAGHIGHATIAN, MINA
ART UNIT PAPER NUMBER
1616
MAIL DATE DELIVERY MODE
03/20/2012 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 PETER YORK, BORIS YU SHEKUNOV,
MAHBOOB UR REHMAN, and JANE CATHERINE FEELEY
__________

Appeal 2011-010194
Application 10/422,342
Technology Center 1600
__________

Before DONALD E. ADAMS, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an active
substance in particulate form. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

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Statement of the Case
Background
“The present invention provides particulate powders, such as might be
of use for delivery using a DPI [dry powder inhaler] or similar delivery
device, having properties which may be beneficial to the DPI delivery
process” (Spec. 2, ll. 22-24).
The Claims
Claims 1, 3-18, 23, 30-36, and 65-83 are on appeal. Claims 1 and 77
are representative and read as follows:
1. An active substance in particulate form suitable for
administration via a dry powder inhaler, the particulates
comprising:
a volume mean aerodynamic diameter of less than
7 microns;
a bulk powder density within a range from about
0.1 g/cm3 to about 0.5 g/cm3; and
a surface-to-volume ratio of at least 2.5 times that
of spherical particles of a corresponding volume
diameter, wherein the particulates are solid, non-hollow,
nonporous particles and the active substance is selected
from the group consisting of insulin, pro-insulin, mono-
acylated insulin, insulinotropin, and insulin-like growth
factor.

77. An active substance in particulate form suitable for
administration via a dry powder inhaler, the particulates
comprising:
a volume mean aerodynamic diameter of less than
7 microns;
a bulk powder density within a range from about
0.1 g/cm3 to about 0.5 g/cm3;and
a surface-to-volume ratio of at least 2.5 times that
of spherical particles of a corresponding volume
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diameter, wherein the particulates are solid, non-hollow,
nonporous particles and the active substance is selected
from the group consisting of salbutamol, terbutalene,
salmeterol, fenoterol, and bromocriptine.

The issues

A. The Examiner rejected claims 1, 3-18, 23, 30-36, and 65-83 under 35
U.S.C. § 103(a) as obvious over York,1 Kuo,2 and Bisrat3 (Ans. 5-9).
B. The Examiner rejected claims 1, 3-18, 23, 30-36, and 65-83 under 35
U.S.C. § 103(a) as obvious over Edwards,4 York, and Bisrat (Ans. 9-12).
A. 35 U.S.C. § 103(a) over York, Kuo, and Bisrat
The Examiner finds it obvious “to have modified the teachings of
York et al by preparing the particles with various active agents and the
desired properties of particles as taught by Kuo et al and Bisrat[] et al with a
reasonable expectation of successfully preparing flowable particles for
efficient pulmonary delivery of various active agents to the patients in need
thereof” (Ans. 8).
The Examiner finds that “the properties such as surface-to-volume
ratio, shape coefficient, surface area, etc, are expected to be the same as
those particles disclosed by the prior art or it would have been obvious to
one of ordinary skill in the [art] to obtain them through the methods known
in the art” (Ans. 8).

1 York et al, WO 95/01324 A1, published Jan. 12, 1995.
2 Kuo et al., US 6,518,239 B1, issued Feb. 11, 2003.
3 Bisrat et al., WO 98/52544 A1, published Nov. 26, 1998.
4 Edwards et al., US 6,977,087 B2, issued Dec. 20, 2005.
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The Examiner finds that “limitations such as shape factor, shape
coefficient, aerodynamic shape factor, etc. are physical properties of the
particles claimed by applicant. It would have been expected for the said
physical properties to be the same since the prior art teach the claimed
particle” (Ans. 8).
Appellants contend that “York, Kuo, and Bisrat, alone or in
combination, do not teach, show, or suggest ‘a surface-to-volume ratio of at
least 2.5 times that of spherical particles of a corresponding volume
diameter,’ as recited in all independent claims of the present application”
(App. Br. 9). Appellants contend that “claims 6-9, 74-76, and 81-83 of the
present application recite ‘specific surface area of at least 10 m2/g” (App. Br.
9).
Appellants contend that “Bisrat teaches against these claimed physical
properties. For example, Bisrat teaches particles which ‘are substantially
smooth and have a surface area BET gas absorption value of from 1,
preferably from 2.0, to 4.5, preferably to 3.6 m2/g’” (App. Br. 9-10).
Appellants “submits that the Examiner can not apply the principals of
In re Spada by relying on a combination of three references - namely - York,
Kuo, and Bisrat - as a single reference of prior art for teaching a particular
chemical structure” (App. Br. 11). Appellants also contend that the
“Examiner also provides no evidence of motivation for the skilled artisan to
choose particular chemical compositions or properties disclosed by York,
Kuo, and Bisrat - while ignoring other chemical compositions or properties
disclosed by York, Kuo, and Bisrat” (App. Br. 11).
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The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that York, Kuo, and Bisrat render the
claims obvious?
Findings of Fact
1. The Specification teaches that by “‘active substance’ is meant a
substance capable of performing some useful function in an end product,
whether pharmaceutical, pesticidal or whatever” (Spec. 19, ll. 16-17).
2. The Specification teaches that “particulate active substances
which exhibit the improved DPI performance and other advantageous
properties described above can be produced using the so-called SEDS™
(‘Solution Enhanced Dispersion by Supercritical fluid’) process” (Spec. 24,
ll. 25-17).
3. The Specification teaches that “[c]arrying out a SEDS™
process specifically involves using the anti-solvent fluid simultaneously both
to extract the vehicle from, and to disperse, the target solution/suspension”
(Spec. 24, ll. 27-28).
4. York teaches “the co-introduction into said vessel of a
supercritical fluid and a vehicle containing at least one substance in solution
or suspension, into said vessel, such that dispersion and extraction of the
vehicle occur substantially simultaneously by the action of the supercritical
fluid” (York 3, ll. 33-36).
5. York teaches “a pharmaceutical composition in the form of a
dry powder suitable for inhalation which comprises salmeterol xinafoate”
(York 12, ll. 30-32).

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6. Table 2 of York is reproduced below:

Table 2 shows dynamic bulk densities of salmeterol xinafoate ranging from
0.059 g/cm3 to 0.312 g/cm3, depending on the preparation (see York 21, ll.
25-30).
7. York teaches that “there is provided salmeterol xinafoate in a
form with a dynamic bulk density of less than 0.1g.cm-3. In a preferred
aspect of the present invention, there is provided salmeterol xinafoate in a
form with a dynamic bulk density in the range between 0.01 and 0.1g.cm-3”
(York 10, ll. 10-13).
8. Table 3 of York is reproduced below:

Table 3 shows particle sizes of 1-3 um to 18.84 um (see York 23, ll. 16-20).
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9. York teaches that the “flow rates of the supercritical fluid
and/or the vehicle may also be controlled so as to achieve a desired particle
size, shape and/or form” (York 9, ll. 17-18).
10. Kuo teaches “a method for delivery of a dry powder
composition to the lungs of a mammalian subject by administering by
inhalation the compositions of the invention” (Kuo, col. 3, ll. 12-15).
11. Kuo teaches that “[e]xamples of active agents suitable for use in
this invention include but are not limited to . . . human growth hormone . . .
factor IX insulin, pro-insulin, insulin analogues . . . insulintropin . . .
parathyroid hormone . . . fluoroquinolones such as ciprofloxacin . . .
aminoglycosides such as . . . tobramycin . . . albuterol sulfate” (Kuo, col. 6,
l. 52 to col. 7, l. 45).
12. Kuo teaches that “powders may be prepared by . . . super
critical fluid processing” (Kuo, col. 12, ll. 23-25).
13. Bisrat teaches that “[f]inely divided particles of budesonide are
used in therapy in administration by inhalation where it is desired that the
drug particles penetrate deep into the lung” (Bisrat 1, ll. 9-10).
14. Bisrat teaches “providing finely divided, substantially
crystalline particles of budesonide characterised in that they are substantially
smooth and have a surface area BET gas absorption value of from 1,
preferably from 2.0, to 4.5, preferably to 3.6 m2/g” (Bisrat 1, ll. 24-27).
15. Bisrat teaches that it “is preferred that the finely divided
particles according to the invention have a mass median diameter (MMD) of
less than 10 µm, preferably less than 5 µm, more preferably less than 3 µm”
(Bisrat 2, ll. 12-14).
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16. Bisrat teaches that “the particles of the invention have an
energy of recrystallisation of 20 less than 1.0 J/g, more preferably less than
0.5 J/g” (Bisrat 2, ll. 19-20).
17. Bisrat teaches that the “finely divided particles of the invention
may be prepared by the co-introduction of a solution of budesonide in a
solvent and of a supercritical fluid into an apparatus wherein the temperature
and pressure of the apparatus are controlled such that dispersion and
extraction of the solvent by the action of the supercritical fluid occur
substantially simultaneously” (Bisrat 2, ll. 25-29).
Principles of Law
“Inherency … may not be established by probabilities or possibilities.
The mere fact that a certain thing may result from a given set of
circumstances is not sufficient.” MEHL/Biophile Int’l. Corp. v. Milgraum,
192 F.3d 1362, 1365 (Fed. Cir. 1999) (quoting In re Oelrich, 666 F.2d 578,
581 (CCPA 1981)).
Analysis
York, Kuo, and Bisrat all teach active substances for administration
by dry powder inhalers (FF 5, 10, 13). Kuo teaches insulin as the active
substance (FF 11). York teaches diameters less than 7 microns (FF 8) and “a
dynamic bulk density in the range between 0.01 and 0.1g.cm-3” (York 10, ll.
12-13; FF 7) for an active agent, which overlaps the claimed density range.
Appellants contend that “York, Kuo, and Bisrat, alone or in
combination, do not teach, show, or suggest ‘a surface-to-volume ratio of at
least 2.5 times that of spherical particles of a corresponding volume
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diameter,’ as recited in all independent claims of the present application”
(App. Br. 9).
The Examiner responds that the “specific surface-to-volume ratio or
surface area are simply adjusted according to specific need and desire” (Ans.
13).
We find Appellants have the better position. While the Examiner
argues that the surface to volume ratio is a result optimizable variable, the
Examiner does not provide evidence supporting that point. That is, York’s
teaching that the particle size, shape and form may be controlled does not
provide any suggestion that the surface to volume ratio is a feature that
should be optimized, nor that a value of at least 2.5 times that of spherical
particles would be desirable. This case is similar to Antonie, where the
claim required a particular ratio and the Examiner found that optimizing the
value was mere mechanical experimentation. In re Antonie, 559 F.2d 618,
619 (CCPA 1977). However, the court concluded that where the parameter
optimized was not recognized to be a result-effective variable, routine
optimization would not have been obvious. Id. at 620. In the instant case,
there is no evidence that the surface to volume ratio is a results effective
variable.
We also do not find the inherency argument relying upon Spada
persuasive, since the underlying predicate of an inherency rejection is that
the products of the prior art are substantially similar or the same as the
product claimed. See, e.g., In re Spada, 911 F.2d 705, 708 (Fed.Cir.1990)
(“[W]hen the PTO shows sound basis for believing that the products of the
applicant and the prior art are the same, the applicant has the burden of
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showing that they are not”). Here, that predicate requirement is not met
since there is no evidence or teaching in the prior art to suggest that the
surface to volume ratio is at least 2.5 times that of spherical particles.
Indeed, Bisrat recognizes particles which are smooth and would expressly
not satisfy the requirements of the claims (FF 13).
Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that York, Kuo, and Bisrat render the claims obvious.
B. 35 U.S.C. § 103(a) over Edwards, York, and Bisrat
The Examiner finds that “Dixit discloses a finely divided binder in
powder form comprising hollow microspheres comprising
polyvinylpyrrolidone (a vinyllactam polymer)” (Ans. 4). The Examiner
finds it obvious to optimize since “Applicant’s average particle size range of
2 microns to 35 microns overlaps with 20 to 100 microns taught by Dixit
and Applicant’s apparent density of less than 0.2 g/ml overlaps with 0.01 to
0.5 g/cc taught by Dixit” (Ans. 5).
Appellants contend that the
Examiner has not provided the required evidence to explain
why the skilled artisan would be motivated to prepare
particles having an irregular or rough surface textures and
porous structures which reduces particle agglomeration and
provides highly flowable powders, as taught by Edwards,
while Bisrat teaches that substantially smooth particles
which have a low surface area and a lower tendency to stick
together than particles with a higher surface area such as the
irregular particles taught by Edwards. The skilled artisan
lacks motivation to combine Edwards and Bisrat, but also,
Edwards and Bisrat contradict each other and strongly teach
away from each other
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(App. Br. 19).
Appellants contend “that the Examiner can not apply the principals of
In re Spada by relying on a combination of three references - namely -
Edwards, York, and Bisrat - as a single reference of prior art for teaching a
particular chemical structure” (App. Br. 19).
Appellants contend that “[e]very pending claim of the present
application recites ‘solid, non-hollow, non-porous particles’ instead of the
porous particles as taught by Edwards; ‘a bulk powder density within a
range from about 0.1 g/cm3 to about 0.5 g/cm3,’ instead of the dynamic bulk
density of less than 0.1 g/cm3 as taught by York” (App. Br. 22). Appellants
contend that the claims require “‘a surface-to-volume ratio of at least 2.5
times that of spherical particles of a corresponding volume diameter’ instead
of the substantially smooth particle surfaces as taught by Bisrat” (App. Br.
22).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that the combination of Edwards, York,
and Bisrat renders the claim obvious?
Findings of Fact
17. Edwards teaches “biodegradable particles of low density and
large size for delivery to the pulmonary system” (Edwards, col. 1, ll. 18-20).
18. Edwards teaches that “the particles have a tap density less than
about 0.4 g/cm3. Features of the particle which can contribute to low tap
density include irregular surface texture and porous structure” (Edwards, col.
4, ll. 33-36).
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19. Edwards teaches that “[a]dministration of the low density
particles to the lung by aerosolization permits deep lung delivery of
relatively large diameter therapeutic aerosols, for example, greater than 5
µm in mean diameter” (Edwards, col. 4, ll. 36-39).
20. Edwards teaches that a “rough surface texture also can reduce
particle agglomeration and provide a highly flowable powder, which is ideal
for aerosolization via dry powder inhaler devices” (Edwards, col. 4, ll. 39-
42).
21. Edwards teaches that “[a]ny of a variety of therapeutic agents
can he incorporated within the particles, which can locally or systemically
deliver the incorporated agents following administration to the lungs of an
animal. Examples include . . . antibiotics, antivirals . . . insulin . . .
parathyroid hormone-related peptide . . . salmeterol” (Edwards, col. 9, ll. 20-
62).
22. Edwards teaches that the “particles may be fabricated or
separated, for example, by filtration, to provide a particle sample with a
preselected size distribution. For example, greater than 30%, 50%, 70%, or
80% of the particles” (Edwards, col. 4, ll. 54-57).
23. Edwards teaches that in “one preferred embodiment, at least a
portion of the particles have a diameter between about 9 and 11 µm.
Optionally, the particle sample also can be fabricated wherein at least 90%,
or optionally 95% or 99%, have a diameter within the selected range”
(Edwards, col. 4, ll. 61-66).

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Analysis
We again find Appellants have the better position for substantially the
same reasons. As discussed above, York’s teaching that the particle size,
shape and form may be controlled does not provide any suggestion that the
surface to volume ratio is a feature that should be optimized, nor that a value
of at least 2.5 times that of spherical particles would be desirable. In the
instant case, there is no evidence that the surface to volume ratio is a results
effective variable.
We appreciate the Examiner’s argument that Spada should apply to
claim 77 which “is drawn to the same chemical structure as taught by York
et al (i.e. salmeterol)” (Ans. 18). However, the salmeterol product of York
with the demonstrated bulk density in the claimed range, the conventionally
crystallized salmeterol xenafoate, either micronized or not, with a density of
0.137 if micronized and 0.312 if not micronized, was not prepared by the
SEDS technique and therefore would not necessarily have been expected to
share identical properties with salmeterol xinafoate prepared using a SEDS
type technique of the claimed invention (FF 6). “Inherency … may not be
established by probabilities or possibilities. The mere fact that a certain thing
may result from a given set of circumstances is not sufficient.”
MEHL/Biophile Int’l. Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir.
1999) (quoting In re Oelrich, 666 F.2d 578, 581 (CCPA 1981)).
Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that the combination of Edwards, York, and Bisrat renders the claim
obvious.
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SUMMARY
In summary, we reverse the rejection of claims 1, 3-18, 23, 30-36, and
65-83 under 35 U.S.C. § 103(a) as obvious over York, Kuo, and Bisrat.
We reverse the rejection of claims 1, 3-18, 23, 30-36, and 65-83 under
35 U.S.C. § 103(a) as obvious over Edwards, York, and Bisrat.

REVERSED

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