Ex Parte Edwards et al

Board of Patent Appeals and Interferences

Feb 24, 2009

09822716 (B.P.A.I. Feb. 24, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte
DAVID A. EDWARDS and JEFFREY S. HRKACH
__________

Appeal 2007-11371
Application 09/822,716
Technology Center 1600
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Decided: February 24, 2009 2
__________

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

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL

1 The real party in interest is Advanced Inhalation Research, Inc.
2 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).

Appeal 2007-1137
Application 09/822,716

This is an appeal under 35 U.S.C. § 134 involving claims 1-8, 10, 13-
29, and 49-52. We have jurisdiction under 35 U.S.C. § 6(b).
STATEMENT OF THE CASE
“[M]any illnesses or conditions require administration of a constant or
sustained level[ ] of a bioactive agent to provide an effective therapy” (Spec.
2: 3-4). “However, delivery of bioactive agents to the pulmonary system
typically results in rapid release of the agent following administration” (id.
at 2: 7-8). “[A] need exists for formulations suitable for inhalation . . .
wherein the bioactive agent of the formulation is released in a sustained
fashion into the systemic and/or local circulation” (id. at 2: 15-17).
The present invention “is based upon the unexpected discovery that
complexation of a multivalent metal cation with a therapeutic, prophylactic
or diagnostic agent carrying a negative, and therefore opposite charge to that
of the cation, results in a sustained release profile of the agent upon
pulmonary delivery” (id. at 2: 19-22).
Claim 1 is representative of the claimed subject matter:
1. A method of delivery to the pulmonary system comprising:
administering to the respiratory tract of a patient in need of treatment,
prophylaxis or diagnosis an effective amount of a dry powder comprising:
a) a multivalent metal cation which is complexed with a therapeutic,
prophylactic or diagnostic agent;
b) a pharmaceutically acceptable carrier; and
c) optionally, a multivalent metal cation-containing component
wherein, the dry powder is spray-dried and has a total amount of multivalent
metal cation which is more than about 1% w/w of the total weight of the
agent, a tap density of less than about 0.4 g/cm3, a median geometric
diameter of between about 5 micrometers and about 30 micrometers and an
aerodynamic diameter of from about 1 to about 5 microns.

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Application 09/822,716

Claims 1-8, 10, 13-29, and 49-52 are pending and on appeal.3 The
Examiner rejected the claims as follows:
Claims 1-8, 10, 13-17, 21-26, 28, 49, 51, and 52 under 35 U.S.C. §
103(a) as unpatentable over Jensen (U.S. Patent 6,043,214, issued March 28,
2000) in view of Maa (U.S. Patent 6,284,282 B1, issued September 4, 2001);

Claims 1-8, 10, 13-17, 21-28, and 49-52 under 35 U.S.C. § 103(a) as
unpatentable over Jensen in view of Weers (U.S. Patent 6,309,623 B1,
issued October 30, 2001); and

Claims 18-20 and 29 under 35 U.S.C. § 103(a) as unpatentable over
Jensen in view of the International Cosmetic Ingredient Dictionary and
Handbook, Volume 2, 7th Edition (Ed. John A. Wenninger, The Cosmetic,
Toiletry, and Fragrance Assn., Washington, D.C.) (1997) (the “Cosmetic
Handbook”).

We reverse.
THE ISSUE
The issue raised by this appeal is whether the Examiner has
established that the prior art relied on discloses or suggests a dry powder,
obtainable by spray drying, comprising a multivalent metal cation
complexed with a therapeutic agent, wherein the powder has a tap density of
less than about 0.4 g/cm3, a median geometric diameter of between about 5
μm and about 30 μm and an aerodynamic diameter of from about 1 μm to
about 5 μm.

3 The Examiner included claims 9, 11, 12, and 30-48 in one or more of the
rejections in the Answer, but these claims were canceled by amendments
filed May 24, 2004 and September 20, 2004.
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Application 09/822,716

FINDINGS OF FACT
FF1 According to the Specification, “complexation of a multivalent
metal cation with a therapeutic, prophylactic or diagnostic agent carrying a
negative, and therefore opposite charge to that of the cation, results in a
sustained release profile of the agent upon pulmonary delivery” (Spec. 2: 19-
22).
FF2 The Specification teaches that “the agent can be insulin and the
multivalent metal cation can be zinc” (Spec. 7: 3-6).
FF3 In order to form a complex between insulin and the cation, the
insulin is “mixed with the desired metal cation component in an aqueous
buffer system (e.g. citrate, phosphate, acetate, etc.), the pH of the resultant
solution then can be adjusted to . . . about pH 6.7. At this pH insulin
molecules have a net negative charge . . . and complexation of the metal
cation component to the insulin achieves a precipitate of the metal cation
complexed insulin” (Spec. 8: 15-21). “[T]he solution containing the
precipitated metal cation complexed biologically active agent is mixed with
a solution of the pharmaceutically acceptable [phospholipid] carrier . . .
[and] solvent is then removed from the resulting mixture . . . for example,
[by] lyophilization, evaporation and spray drying. Spray drying . . . is a
preferred method” (id. at 8: 23-29; 10: 5-6).
FF4 The Specification teaches that
Particles which have a tap density of less than about 0.4
g/cm3, median diameters of at least about 5 μm, and an
aerodynamic diameter of between about 1 μm and about 5 μm
. . . are more capable of escaping inertial and gravitational
deposition in the oropharyngeal region, and are targeted to the
airways or the deep lung. The use of larger, more porous
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particles is advantageous since they are able to aerosolize more
efficiently than smaller, denser aerosol particles . . .

(Spec. 19: 13-18).
FF5 Appellants claim a method of delivering a therapeutic,
prophylactic, or diagnostic agent to the pulmonary system of a patient by
administering a dry powder comprising (a) the agent complexed with a
multivalent metal cation, wherein the multivalent metal cation is more than
about 1% w/w of the total weight of the agent and (b) a pharmaceutically
acceptable carrier. Claim 1 requires that the powder
• is spray-dried;

• has a tap density of less than about 0.4 g/cm3;

• has a median geometric diameter of between about 5
micrometers and about 30 micrometers;

• and has an aerodynamic diameter of from about 1 to about 5
microns.

(Claim 1.)
Jensen
FF6 Jensen discloses a process for preparing “a therapeutic powder
formulation comprising particles composed of insulin” (Jensen, col. 2: 42-
43), starting with a) an acidic aqueous solution of insulin, a penetration
enhancer (e.g., surfactants including phospholipids and bile salts), and zinc
(zinc chloride solution); b) adjusting the pH to 4.5 to 7.4; c) precipitating a
product comprising insulin, enhancer and zinc; and d) removing the water in
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a vacuumdryer after allowing the preparation to stand at rest for 16 hours
(id. at col. 2, ll. 46-54; col. 3, ll. 1-3; Examples I-IV).
FF7 According to Jensen, the precipitates formed in step c) of the
method are initially amorphous, but become crystalline upon standing in
water, and “[t]he size of the individual crystals was determined to [be] 1µ-
5µ” in all of the working examples (Jensen, Examples I-IV).
FF8 Jensen’s process “results in a [crystalline] powder formulation
of insulin and enhancer which elucidates a better stability profile [and better
flow properties] than powders of essentially the same composition prepared
by spray drying, freeze-drying, vacuum drying and open drying” (Jensen,
col. 2, ll. 55-59, 66), which “have been described as mainly amorphous” (id.
at. col. 1, ll. 59-60).
FF9 Jensen does not disclose the aerodynamic diameter or tap
density of the particles in his dry powder formulation.
Maa
FF10 Maa teaches that “[t]he success of a dry powder inhalation
product is based on the ease of powder dispersibility . . . Many physical
characteristics affect the dispersibility of the powder, including . . . particle
size/distribution, particle shape/morphology, and moisture content” (Maa,
col. 4, ll. 1-7). In general, “diminishing the density of the particle may
permit delivery of larger particle sizes into the deep lungs” (id. at col. 4, ll.
53-55). In other words, “a light (low density) particle having the same
physical size . . . as a heavy (high density) particle . . . will have a smaller
aerodynamic size than the heavy particle; therefore, light particles are [more]
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likely to travel with air streamlines and reach in the deep lung” (id. at col. 4,
ll. 42-47).
FF11 Maa discloses “spray freeze-dried formulations of therapeutic
proteins [including insulin], that show good dispersibility and respirable
properties, as well as good stability” (Maa, col. 3, ll. 54-56; col. 6, ll. 46).
FF12 Unlike Jensen’s formulations, Maa’s formulations are
“substantially free of ‘penetration enhancers’”, i.e., surfactants) (Maa, col. 9,
ll. 47-49).
FF13 According to Maa,
Spray freeze drying is a process conceptually similar to spray
drying, in that a homogeneous aqueous mixture of a therapeutic
protein, termed herein the “pre-spray freeze dry formulation”, is
introduced via a nozzle . . . , spinning disk or an equivalent
device into a cold fluid to atomize the solution to form fine
droplets. . . . [but] [t]he cold fluid, either a liquid or a gas, is at a
temperature below the freezing point of the aqueous solvent of
the pre-spray freeze dry formulation. Spraying the formulation
into the cold fluid results in the rapid freezing of the atomized
droplets to form particles. The particles are collected, and then
the solvent is removed, generally through sublimation
(lyophilization) in a vacuum. . . . This produces a fine dry
powder having particles of a specified size and characteristics . . .

(Maa, col. 5, ll. 8-28).
FF14 Maa’s spray freeze dried powders are “characterized on the
basis of a number of parameters, including, . . . the average particle size, the
range of particle sizes, . . . the average particle density, and the mass median
aerodynamic diameter (MMAD)” (Maa, col. 5, ll. 43-47). The particles
preferably have “tap densities of less than about 0.4 g/cm3” (id. at col. 6, ll.
8-9), an “average particle size rang[ing] from about 5 μm to about 30 μm”
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(id. at col. 5, ll. 50-51), and “an aerodynamic mass median diameter of less
than 6.8 μm” (id. at 5, ll. 61-62).
FF15 Maa compared the physical properties of spray dried (SD) and
spray freeze dried (SFD) powders of rhDNAse and anti-IgE antibody, and
found “a significant difference between SD and SFD” (Maa, col. 18, l. 46).
Essentially, during spray drying, atomized particles shrink upon water
removal, and the resultant dried particles have different shapes depending
upon formulation and drying conditions. During spray freeze drying, the
atomized particles maintain their shape and size upon water removal, and
simply become more porous (id. at col. 18, ll. 46-55). Maa teaches that
“[s]pray freeze-dried powders consistently outperformed spray-dried
powders” (id. at col. 19, 21-22), and suggests that “the superior aerosol
performance by the spray freeze-dried powder might be simply due to its
smaller aerodynamic particle size despite its larger physical size” (id. at col.
19, ll. 53-56).
Weers
FF16 Weers describes “perforated microstructures” comprising “a
powder of dry, hollow, porous microspherical shells” with a mean geometric
particle size “preferably about 0.5-50 µm , more preferably 1-30 µm . . . less
than 20 µm or less than 10 µm”, especially approximately “1 to 10 µm in
diameter, with shell thicknesses of approximately 0.1 µm to approximately
0.5 µm” (Weers, col. 13, ll. 35-50). The microstructures typically have a
density of less than 0.5 g/cm3, and a mean aerodynamic diameter of less
than about 5 µm, or roughly three times smaller than their median geometric
diameter (id. at col. 14, ll. 28-41).
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FF17 The perforated microstructures are designed for administration
by metered dose inhaler (MDI), which delivers an active agent in the form of
a solution or dispersion (Weers, col. 1, ll. 39-42). The perforated
microstructures are stabilized by suspending them in a fluid medium with
approximately the same apparent density as the microstructures. In Weers’
“homodispersion,” the suspension medium infiltrates the microstructures,
“substantially eliminating the attractive van der Waals forces” (Weers, col.
9, l. 41; col. 11, ll. 25-28), and allowing the suspension to be free-flowing
even when the microstructures are closely packed (id. at col. 11, ll. 43-49).
FF18 “[T]he components of the microparticle matrix” are highly
variable, and “are preferably selected, as much as possible given other
considerations, to approximate the density of the suspension medium” (id. at
col. 11, ll. 29-32). The perforated microstructures may comprise essentially
100% active agent, or may comprise “relatively high levels of surfactants
(i.e., phospholipids)”, i.e., anywhere between 1% and “essentially 100%”
(Weers, col. 17, ll. 45-65). In addition, “the structural matrix defining the
perforated microstructure optionally comprises synthetic or natural polymers
. . . [e.g.] polylactides, polylactide-glycolides, cyclodextrins, . . . polyvinyl
pyrrolidones, polysaccharides (dextrans, starches, chitin, chitosan, etc.),
hyaluronic acid, proteins, (albumin, collagen, gelatin, etc.)” (id. at col. 18, ll.
10-19).
FF19 Weers’ perforated microstructures may be formed by spray
drying an emulsion formed from whatever components are to be included in
the microstructures, additional surfactants, and an inflating or blowing agent
(e.g., perfluorohexane, Freon, or carbon dioxide) which vaporizes during the
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spray drying process, leaving behind hollow, porous microstructures (Weers,
col. 21, l. 55 to col. 22, l. 11). Examples I-XVIII show that the physical and
aerodynamic properties of Weers’ perforated microstructures are highly
variable depending on the base composition of the particles, the amount and
type of surfactants incorporated, and the type of inflating agent used, etc.
PRINCIPLES OF LAW
“[R]ejections on obviousness grounds cannot be sustained by mere
conclusory statements; instead, there must be some articulated reasoning
with some rational underpinning to support the legal conclusion of
obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). “[T]his
analysis should be made explicit” and it “can be important to identify a
reason that would have prompted a person of ordinary skill in the relevant
field to combine the elements in the way the claimed new invention does.”
KSR International Co., v. Teleflex Inc., 550 U.S. 398, ___, 127 S. Ct. 1727,
1741 (2007).
ANALYSIS
The present claims require a dry powder comprising a therapeutic
agent-multivalent metal cation complex (an insulin-zinc complex, for
example), obtained (or obtainable) by spray drying, with a specified tap
density, geometric diameter, and aerodynamic diameter. The powder is
delivered to the pulmonary system of a patient in need of treatment.
Jensen and Maa
The Examiner concluded that the invention of claims 1-8, 10, 13-17, 21-
26, 28, 49, 51, and 52 is unpatentable over Jensen and Maa because one of skill
in the art, “given the general teachings of a powder formulation of insulin of
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Jensen” (Ans. 4), would have looked to other prior art references, such as Maa,
“for specific particle characteristics” of “effective formulations for pulmonary
delivery” (id.). Moreover, the Examiner asserts that “the instant claims are
drawn to a method of delivery and not a method of making particles, thus the
specific steps of preparation are not examined here and not given patentable
weight” (id. at 7).
Appellants contend that the requirement that the product be spray
dried cannot be ignored, “[w]here, as here, the evidence suggests that the
process has a substantive impact on the product” (App. Br. 5). Appellants
contend that there is no evidence that Jensen’s crystalline powders have the
tap density, geometric diameter, and aerodynamic diameter required by the
claims, nor is there any reason one of skill in the art would expect to obtain a
powder with the required physical properties by “mix[ing] and match[ing]
components of the[ ] two very different processes” disclosed by Jensen and
Maa (id. at 5).
As discussed above, Jensen describes a dry powder for delivery to the
pulmonary system comprising insulin, penetration-enhancing surfactants,
and zinc (FF6). However, Jensen’s powder is not made by spray drying, and
is not disclosed to have the various physical properties required by the
claims (FF6, 7). Jensen mentions prior art spray dried powders “of
essentially the same composition” (FF8), but the Examiner has not
established that any of those spray dried powders have the various physical
properties required by the claims. Moreover, Jensen’s powders are
crystalline, while the prior art spray dried powders are described as
amorphous (FF7, 8). In addition, Jensen teaches that his crystalline powders
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differ from spray dried powders in terms of stability and flow properties
(FF8).
Maa, on the other hand, describes a dry powder comprising a protein
(insulin, for example), which is not complexed with a multivalent metal
cation, but which does meet the limitations of the claims with respect to tap
density, median geometric diameter, and aerodynamic diameter (FF11, 14).
However, Maa’s powders are made by spray freeze drying, rather than spray
drying, and Maa attributes the physical properties and “superior”
performance of his powders to the spray freeze drying process (FF13, 15).
Given these facts, we agree with Appellants that the Examiner has not
established that any of the powders disclosed by Jensen have the physical
properties required by the claims. Moreover, even if one skilled in the art
would have had a reason to use Maa’s spray freeze dry process to prepare a
powder from Jensen’s starting composition, the Examiner has not
established that the physical properties required by the claims would have
been obtained, given the differences between Jensen’s starting composition
and Maa’s starting composition (e.g., the presence of surfactants in Jensen’s
composition, versus the lack of surfactants in Maa’s (FF6, 12)). Finally,
both references disclose that protein-containing powders for inhalation
therapy made by spray drying were known in the art, but both references
indicate that such powders differ from powders made by Jensen’s method or
Maa’s method, and the Examiner has not provided any rational basis for
concluding that spray dried powders would have been expected to have the
physical properties required by the claims.

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Jensen and Weers
The Examiner concluded that the invention of claims 1-8, 10, 13-17, 21-
28, and 49-52 is unpatentable over Jensen and Weers because one of skill in
the art, “given the general teachings of a powder formulation of insulin of
Jensen” (Ans. 5), would have looked to other prior art references, such as
Weers, “for specific particle characteristics” of “effective formulations for
pulmonary delivery” (id.). Again, the Examiner asserts that “the instant claims
are drawn to a method of delivery and not a method of making particles, thus
the specific steps of preparation are not examined here and not given patentable
weight” (id. at 7).
As discussed above, Jensen is directed to making and administering dry,
crystalline powders, while Weers is directed to a method of making and
administering a “homodispersion” of perforated microstructures suspended in a
fluid of approximately the same apparent density (FF17). The composition and
physical properties of the microstructures are highly variable, but their
composition complements, and is dependent on the composition and density of
the suspension medium (FF18, 19).
We agree with Appellants that it would not have been obvious for one
skilled in the art to have prepared Jensen’s dry powders using Weers’
method, given the differences in their objectives. Moreover, even if one
skilled in the art would have had a reason to use Weers’ process to prepare a
powder from Jensen’s starting composition, the Examiner has not
established that the physical properties required by the claims would have
been obtained, given the highly variable physical properties obtained with
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Weers’ method depending on the starting composition of the microstructures
(FF19).
Jensen and the Cosmetic Handbook
The Examiner concluded that the invention of claims 18-20 and 29 is
unpatentable over Jensen and the Cosmetic Handbook because the Cosmetic
Handbook discloses that carboxylic acids “are well known pH adjusters in
pharmaceutical and cosmetic formulations” and it would have been obvious
to substitute a carboxylic acid for Jensen’s hydrochloric acid “to perform a
pH adjusting function” (Ans. 6).
Nevertheless, we agree with Appellants that the Cosmetic Handbook
“does not provide what the Jensen and Weers [and Maa] references lack”
(App. Br. 9-10).
CONCLUSIONS OF LAW
The Examiner has not established that the prior art relied on discloses
or suggests a dry powder, obtainable by spray drying, comprising a
multivalent metal cation complexed with a therapeutic agent, wherein the
powder has a tap density of less than about 0.4 g/cm3, a median geometric
diameter of between about 5 μm and about 30 μm and an aerodynamic
diameter of from about 1 μm to about 5 μm.
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SUMMARY
The rejection of claims 1-8, 10, 13-17, 21-26, 28, 49, 51, and 52 under
35 U.S.C. § 103(a) as unpatentable over Jensen and Maa is reversed.
The rejection of claims 1-8, 10, 13-17, 21-28, and 49-52 under 35
U.S.C. § 103(a) as unpatentable over Jensen in view of Weers is reversed.
The rejection of claims 18-20, and 29 under 35 U.S.C. § 103(a) as
unpatentable over Jensen in view of the Cosmetic Handbook is reversed.

REVERSED

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