Ex Parte Weers et al

Board of Patent Appeals and Interferences

Apr 24, 2007

10141032 (B.P.A.I. Apr. 24, 2007)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte JEFFRY WEERS, THOMAS E. TARARA,
and ANDREW CLARK
__________

Appeal 2007-0526
Application 10/141,032
Technology Center 1600
__________

Decided: April 24, 2007
__________

Before TONI R. SCHEINER, DONALD E. ADAMS, and ERIC GRIMES,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of administering tobramycin. The Examiner has rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
BACKGROUND
Pulmonary drug delivery techniques “rely on the inhalation of a
pharmaceutical formulation by the patient so that the active drug within the
dispersion can reach the distal (alveolar) regions of the lung” (Specification 1).
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Application 10/141,032

While some drug formulations use propellants or compressed gas to deliver
the drug to the patient’s lungs, passively inhaled powders rely on the
patient’s own inhalation to provide the energy needed to aerosolize the drug
formulation (id. at 1-2). However, “inspiration flow rate can drastically vary
between individuals. . . . Variability in inspiratory effort may affect the
ability of the formulation to be dispersed within a gas stream, the ability to
deagglomerate a powdered formulation, and/or the ability of the aerosolized
formulation to adequately reach the deep lung” (id. at 2).
“Due to its spreading characteristics on lung epithelia, surfactant has
been proposed as the ideal carrier for delivery of drugs to the lung, and via
the lung to the systemic circulation” (id. at 3). However, the Specification
discloses that using surfactants such as phospholipids to deliver drugs to the
lungs can be problematic because fine powders containing them may have
poor dispersibility, resulting in difficulties “when attempting to deliver,
aerosolize, and/or package the powders” (id.).
The Specification discloses “dry powder compositions of
phospholipids . . . [that] are efficiently delivered to the deep lung. The
phospholipid[s] may be delivered alone . . . or in combination another active
agent and/or excipient” (id.). “[A]ctive agents useful in this invention
include . . . tobramycin . . .” (id. at 5).
DISCUSSION
1. CLAIMS
Claims 20-31, 33-39, 42, and 51-59 are pending and on appeal.
Appellants separate the claims into two groups for argument, with
Group I containing claims 20-31, 33-39, and 42, and Group II containing
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claims 51-59 (Br. 7).1 Claims 20 and 51 are representative, and read as
follows:
20. A method for administering tobramycin to the
lungs of a patient, the method comprising:
providing a dry powder composition comprising a
phospholipid and tobramycin, said composition comprising
particles having a particle size ranging from 1 to 30 microns, a
mass median aerodynamic diameter of less than 5 microns, and
a bulk density of less than 0.5 g/cm3,
loading the composition into a passive dry powder
inhaler; and
delivering the composition from the inhaler to the
lungs of the patient during the patient’s inhalation,
wherein the composition is formulated so that
when the composition is delivered to a group of individuals at
60 LPM the relative standard deviation of interpatient
variability in lung deposition is less than 40 percent.

51. A method for administering tobramycin to the
lungs of a patient, the method comprising:
providing a dry powder composition comprising a
phospholipid and tobramycin, said composition comprising
particles, wherein the particles have a mass median diameter of
0.5 to 5 microns, a mass median aerodynamic diameter of less
than 5 microns, and a bulk density of less than 0.5 g/cm3,
loading the composition into a passive dry powder
inhaler; and

1 Pages 10 and 17 of the Brief contain the heading “Claims of Group[] I,
namely claims 51-59.” However, the argument in those sections is directed
to the requirement of interpatient variability of less than 40 percent (Br. 10,
11, 17, 18), which appears in claim 20, but not claim 51. The recitation
“claims 51-59” in the headings therefore appears to be an inadvertent error.
We understand the argument in those sections to be directed to Group I,
claims 20-31, 33-39 and 42.
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delivering the composition from the inhaler to the
lungs of the patient during the patient’s inhalation.

Thus, claims 20 and 51 are both directed to methods of using a
passive dry powder inhaler to deliver tobramycin to a patient’s lungs. Both
claims require a dry powder composition containing tobramycin and a
phospholipid. Both claims also require the powder composition to contain
particles having a mass median aerodynamic diameter of less than 5
microns, and a bulk density of less than 0.5 g/cm3.
Claim 20 additionally requires the powder composition to contain
particles having a particle size range from 1 to 30 microns, and requires the
composition to be formulated so that administration of the composition to a
group of individuals at 60 LPM2 results in a “relative standard deviation of
interpatient variability in lung deposition [of] less than 40 percent.” We
interpret this recitation to mean that in a group of individuals receiving the
composition, the amount of lung deposition in each individual does not vary
from the mean deposition amount by more than 40 percent.

2 We understand “60 LPM” to mean an inspiratory flow of 60 liters per
minute. The Specification uses the abbreviations “L/min” and “LPM”
interchangeably (Specification 21 (“peak inspiratory flows” of “29 L/min”
and “44 L/min”), 22 (Table 3 refers to the same rates as “LPM”).
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2. PRIOR ART
The Examiner relies on the following references:
Edwards WO 98/31346 Jul. 23, 1998
Vaghefi US 5,875,776 Mar. 2, 1999
Unger US 6,143,276 Nov. 7, 2000
(filed Mar. 21, 1997)

3. OBVIOUSNESS
Claims 20-31, 33-39, 42, and 51-59 stand rejected under 35 U.S.C.
§ 103 as obvious in view of Edwards, Vaghefi, and Unger (Answer 3).
The Examiner cites Edwards as disclosing, for use in a passive dry
powder inhaler, a drug delivery composition having a mass mean diameter
between 5 and 30 microns and a bulk density of 0.4 g/cm3, “which together
yield an aerodynamic diameter of the particles between 1 and 5 microns”
(id.). As advantages of Edwards’ composition, the Examiner points out that
over 35 percent of the composition’s particles are considered respirable, and
that the composition yields enhanced drug delivery (id.).
As relevant to claims 20 and 51, the Examiner points out that Edwards
teaches that antibiotics can be delivered using Edwards’ drug delivery
system, but concedes that Edwards does not teach tobramycin as an active
ingredient (id.). To meet this deficiency, the Examiner relies on Vaghefi:
“Vaghefi teaches that it [tobramycin] is deliverable by dry powder inhaler
(column 12 line 34). Thus, one of ordinary skill would deliver tobramycin
with the inhalation method of Edwards in view of its deliverability as an
inhaled powder as taught by Vaghefi” (id. at 4).
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We agree with the Examiner that one of ordinary skill in the art would
have considered claims 20 and 51 prima facie obvious in view of these
teachings.
Vaghefi describes methods of dispensing dry powdered
pharmaceuticals to the lung by inhalation (Vaghefi, col. 1, ll. 4-8). As
indicated by the Examiner, Vaghefi discloses that tobramycin is suitably
administered to the lungs in a dry powdered formulation. (See id. at col. 10,
l. 63, through col. 12, l. 34: “A wide variety of pharmaceuticals are
contemplated for delivery employing the invention inhalation device and
methods described herein. Examples include: . . . antibacterial agents (e.g., .
. . tobramycin sulfate).”)
Edwards discloses particles containing a phospholipid surfactant, as
recited in claims 20 and 51, for delivering therapeutic agents via inhalation
(Edwards, abstract). Edwards discloses that the particles have a tap density
of less than 0.4 g/cm3, a mass mean diameter between 5 and 30 microns, and
an aerodynamic diameter of between approximately one and three microns,
properties encompassed by claims 20 and 51 (id.). Appellants do not dispute
the Examiner’s position (Answer 3) that the “tap density” and “mass mean
diameter” ranges disclosed by Edwards overlap the “bulk density” and
“particle size” or “mass median diameter” ranges recited in claims 20 and 51.
Edwards states that the compositions “are effective carriers for
delivery of therapeutic agents to the deep lung[,] . . . avoid phagocytosis in
the deep lung,” and have “improved aerosolization properties and optimized
particle-particle interactions” (Edwards 5). Edwards discloses that “[a]ny of
a variety of therapeutic or prophylactic agents can be incorporated within the
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particles, or used to prepare particles consisting solely of the agent and
surfactant. . . . The agents to be incorporated can have a variety of
biological activities, such as . . . antibiotics . . .” (id. at 20).
Thus, one of ordinary skill administering tobramycin by inhalation, as
taught by Vaghefi, would have been motivated to use Edwards’ delivery
methods, because Edwards teaches that those methods effectively deliver
therapeutic agents such as antibiotics to the deep lung, avoid phagocytosis
within the lung, improve aerosolization of the drug composition, and
optimize particle-particle interactions. Because Vaghefi describes the
inhaled tobramycin as an “antibacterial” (Vaghefi, col. 12, l. 28), one of
ordinary skill would have reasonably expected tobramycin to be amenable to
Edwards’ methods, which are disclosed as being suitable for administering
“antibiotics” (Edwards 20).
We therefore agree with the Examiner that one of ordinary skill would
have considered it obvious to administer tobramycin via inhalation using
powders having the physical properties recited in claims 20 and 51.
The Examiner also concluded that Edwards’ delivery system provides
a formulation that meets claim 20’s requirement of less than 40 percent
relative standard deviation of interpatient variability when the composition is
administered to a group of individuals at 60 LPM. We agree. The instant
Specification describes tobramycin-containing particles meeting the
interpatient variability limitation of claim 20 that “were prepared using the
same general procedure as set forth in Example 1”; i.e., spray-drying an
emulsion containing the drug and a phospholipid (Specification 23, 19).
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As discussed above, Edwards teaches particles having the physical
properties recited in claims 20 and 51. Edwards teaches that the particles
can be prepared by spray-drying solutions containing the phospholipid and
drug (see, e.g., Edwards 41-42 (Example 9), 42-43 (Example 10)). Thus,
Edwards describes formulations having the same physical properties as
recited in the claims, prepared by the same technique. We therefore find that
the Examiner was reasonable in concluding that Edwards’ formulations meet
the interpatient variability limitation in claim 20. Because Edwards teaches
that specific drug delivery advantages come from inhaling the described
formulations, one of ordinary skill would have considered it obvious to have
used Edwards’ formulations to deliver inhaled drugs such as tobramycin.
Appellants argue that the obviousness rejection does not consider the
claimed invention as a whole (Br. 8-10). Appellants argue that “Edwards et
al. does not mention tobramycin and does not teach the claimed method of
administering tobramycin to the lungs of a patient using the claimed
particles. Instead, Edwards generally teaches methods of preparing particles
for inhalation” (id. at 8). Appellants urge that a general teaching regarding
particle formation for use in preparing inhaled powders “is not a teaching to
a particular method of administering tobramycin to a patient’s lungs with
specific particles as claimed,” nor does it “suggest the particular particle size
limitations and tobramycin composition of the claimed method, which
achieve high dosage levels while reduced interpatient inspiration variability”
(id.).
Appellants argue that Vaghefi does not compensate for Edwards’
deficiencies “because Vaghefi teaches the generalized structure of a dry
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powder inhaler but not the claimed drug delivery method and composition”
(id. at 9). Appellants urge that when Vaghefi is considered as a whole, the
disclosure of tobramycin among hundreds of other inhaled drugs of varying
properties “clearly does not suggest the desirability, and thus the
obviousness, of the claimed method of delivery of particular types of
particles comprising tobramycin which achieve reduced interpatient
respiratory dosage variability” (id.).
We do not find Appellants’ argument persuasive. We agree that
“obviousness requires a suggestion of all limitations in a claim.” CFMT,
Inc. v. Yieldup Int’l. Corp., 349 F.3d 1333, 1342, 68 USPQ2d 1940, 1947
(Fed. Cir. 2003). However, it is well settled that “[n]on-obviousness cannot
be established by attacking references individually where the rejection is
based upon the teachings of a combination of references. . . . [The
reference] must be read, not in isolation, but for what it fairly teaches in
combination with the prior art as a whole.” In re Merck & Co., 800 F.2d
1091, 1097, 231 USPQ 375, 380 (Fed. Cir. 1986).
Thus, Appellants analyze each reference in isolation, rather than in the
combination presented in the appealed rejection, as Merck requires. The fact
that Edwards and Vaghefi do not, in isolation, teach or suggest all the
limitations in claims 20 and 51 does not demonstrate that the claims are
nonobvious.
Rather, Edwards must be viewed alongside Vaghefi. When the
advantages of Edwards’ inhaled drug delivery formulation are viewed
alongside Vaghefi’s disclosure of the desirability of inhaling tobramycin, we
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agree with the Examiner that one of ordinary skill would have considered
claims 20 and 51 obvious, for the reasons discussed supra.
Appellants further argue that Unger does not make up for Edwards’ or
Vaghefi’s deficiencies, and that “[w]hen the Unger reference is considered
as a whole, the Unger invention has little to do with the claimed method . . .”
(Br. 9). However, the Examiner cites Unger only to meet the limitations in
claims 33 and 59 requiring distearoylphosphatidylcholine (DSPC) in the
administered powder (Answer 3-4), not to meet the limitations of claims 20
and 51. Appellants’ arguments regarding Unger are therefore not relevant to
representative claims 20 and 51.
Appellants further argue that when the Group I claims are considered
as a whole, Edwards, Vaghefi, and Unger “do not suggest the advantages of
an inspiration delivery method [in which] the composition is formulated so
that delivery of the composition to a group of individuals at 60 LPM,
provides a relative standard deviation of interpatient variability in lung
deposition that is less than 40 percent” (Br. 10-11). Appellants urge that
“[t]here is no reasonable expectation of achieving this success from the
teachings or suggestions of the cited references,” and that only hindsight
viewing of Appellants’ experimental data “suggests the desirability of this
combination of type of particles, pharmaceutical, and delivery method” (id.
at 11).
We do not agree. Edwards’ compositions have the physical properties
recited in claim 20 and are prepared by spray-drying (see, e.g., Edwards 41-
42 (Example 9), 42-43 (Example 10)), the same method Appellants use to
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prepare a composition meeting claim 20’s interpatient variability limitation
(see Specification 23).
Thus, by following the suggestions in Edwards for improving inhaled
tobramycin formulations such as Vaghefi’s, one of ordinary skill would not
only have made particles with the physical properties recited in claim 20, but
would also have used preparative methods that result in a composition
meeting the interpatient variability limitation in claim 20. We therefore
agree with the Examiner that, taken together, Edwards and Vaghefi suggest
all the limitations in claim 20.
Appellants argue that the “amount of experimentation that would be
required for one of ordinary skill in the art to fabricate formulations
comprising particles containing any selected one of the hundreds of
pharmaceutical agents listed in Vaghefi, using the selected particle
fabrication methods taught by Edwards et al., would be undue
experimentation” (Br. 13). Appellants urge that the rejection relies on
impermissible hindsight to reconstruct the claimed invention (id. at 14).
We do not find this argument persuasive. The obviousness of
including tobramycin in Edwards’ inhaled powder formulation is not
undermined by the fact that Vaghefi includes tobramycin in a large list of
other therapeutic agents suitably administered by inhalation. For example,
in Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 806-07, 10 USPQ2d
1843, 1845 (Fed. Cir. 1989), the court held a composition obvious despite
the fact that the two ingredients in the composition were one of 1200
possible combinations suggested in the prior art. Id. at 807, 10 USPQ2d at
1846 (“That the [reference] discloses a multitude of effective combinations
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does not render any particular formulation less obvious. This is especially
true because the claimed composition is used for the identical purpose taught
by the prior art.”).
Thus, because Vaghefi lists tobramycin among therapeutic agents
suitable for inclusion in inhaled powder formulations, one of ordinary skill
would have been motivated to include it in such formulations. Because of
the advantages disclosed for Edwards’ formulations, one of ordinary skill
would have been further motivated to include tobramycin in Edwards’
inhaled powder compositions. Moreover, Appellants do not point to, and we
do not see, any evidence supporting the assertion of undue experimentation.
Therefore, because Vaghefi lists tobramycin as an antibacterial agent
suitable for inhaled administration in powder form, we agree with the
Examiner that one of ordinary skill would not have had to engage in undue
experimentation to put tobramycin to that use. Moreover, because the
rationale for including tobramycin in Edwards’ formulations is derived only
from the references, we do not agree that one of ordinary skill would have
arrived at the claimed invention only through hindsight.
Appellants argue that the unexpected results of the claimed invention
“negate a finding of obviousness with respect to the present claims” (Br. 15-
17). Appellants urge that Example 5 of the Specification (pages 23-24)
demonstrates that tobramycin administered via the claimed formulations had
unexpected improvements in certain properties when compared to nebulized
tobramycin (Br. 16). Appellants argue that because claim 20 contains a
specific limitation regarding interpatient variability with respect to lung
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deposition, these results are particularly relevant to whether the claims of
group I are obvious (id. at 17-18).
We do not find Appellants’ argument persuasive. We note that
Example 5 shows a mean whole lung deposition of the claimed formulation
of 34 ± 5%, versus 5 ± 2% for nebulized formulation. However, we also
note that Edwards discloses that “[o]verall, greater than 35% (37 ± 2.1) of
aerosolized particles made with [the phospholipid] DPPC are considered
respirable . . .” (Edwards 34). Thus, it does not appear that the lung
deposition rate demonstrated in Example 5 is unexpected.
Moreover, “when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.” In re Baxter-Travenol Labs., 952 F.2d 388, 392,
21 USPQ2d 1281, 1285 (Fed. Cir. 1991).
In our view, Appellants have not compared the claimed invention to
the closest prior art. Specifically, because the claims recite the use of
compositions having all of the physical properties of Edwards’ formulations,
Edwards is the closest prior art, not a nebulized composition. We therefore
agree with the Examiner that the asserted showing of unexpected results is
not sufficient to overcome the Examiner’s prima facie case of obviousness
with respect to claims 20 and 51.
We therefore affirm the rejection of claims 20 and 51. Claims 22-31,
33-39, 42, and 52-59 fall with claims 20 and 51.
SUMMARY
Because Edwards suggests that it would have been advantageous to
administer orally inhaled antibacterial agents such as tobramycin using a
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passively inhaled powder having the claimed properties, we affirm the
rejection of claims 20-31, 33-39, 42, and 51-59 as being obvious over
Edwards, Vaghefi, and Unger.

AFFIRMED

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