Ex Parte Chaudry

Patent Trial and Appeal Board

Dec 18, 2012

10657550 (P.T.A.B. Dec. 18, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte IMTIAZ CHAUDRY
__________

Appeal 2012-001043
Application 10/657,550
Technology Center 1600
__________

Before MELANIE L. McCOLLUM, JEFFREY N. FREDMAN, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
treatment of fungus-induced rhinosinusitis. The Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

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Statement of the Case
Background
The Specification teaches “treating the patient with an antifungal
agent will sufficiently reduce the level of fungal organisms in the patient’s
mucus such that the one ore [sic] more of the symptoms of rhinosinusitis are
prevented from developing, or are lessened, or are prevented from
worsening” (Spec. 3).
The Claims
Claims 1, 4-6, 10-12, 22-25, 27-30, 35, and 71-77 are on appeal.
Claim 1 is representative and reads as follows:
1. A formulation for the treatment of fungus-induced
rhinosinusitis in a mammal, said formulation comprising an
aqueous suspension comprising:
(a) 0.04% to 0.06% by weight of suspended solid
steroidal anti-inflammatory particles, wherein the steroidal anti-
inflammatory is fluticasone or a pharmaceutically acceptable
salt, ester, enol ether, enol ester, acid, or base thereof, said
suspended solid steroidal anti-inflammatory having the
following particle size distribution profile:
i. about 10% of the steroidal anti-inflammatory
particles have a particle size of less than 0.4 microns;
ii. about 25% of the steroidal anti-inflammatory
particles have a particle size of less than 0.8 microns;
iii. about 50% of the steroidal anti-inflammatory
particles have a particle size of less than 1.5 microns;
iv. about 75% of the steroidal anti-inflammatory
particles have a particle size of less than 3.0 microns; and
v. about 90% of the steroidal anti-inflammatory
particles have a particle size of less than 5.3 microns; and
(b) an antifungal agent; wherein said formulation is
suitable for administration to the nasal-paranasal mucosa.

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The issues
A. The Examiner rejected claims 1, 4-6, 10-13, 22-25, 27-30, 35, and 77
under 35 U.S.C. § 103(a) as obvious over Physician’s Desk Reference
(PDR®),
1
Lacy,
2
Bernini,
3
Harris,
4
and Osbakken
5
(Ans. 5-16).
B. The Examiner rejected claims 71-74 under 35 U.S.C. § 103(a) as
obvious over Physician’s Desk Reference (PDR®), Lacy, Bernini, Harris,
Osbakken, Doi,
6
and Meade
7
(Ans. 16-18).
C. The Examiner rejected claims 75 and 76 under 35 U.S.C. § 103(a) as
obvious over Physician’s Desk Reference (PDR®), Lacy, Bernini, Harris,
Osbakken, Walker,
8
and Hamuy
9
(Ans. 19-21).
A. 35 U.S.C. § 103(a) over PDR, Lacy, Bernini, Harris, and Osbakken
The Examiner finds that “FLONASE® was a commercially available
product at least as early as 1999” (Ans. 7). The Examiner finds that Bernini
teaches “preparation of suspensions of drug particles for inhalation delivery,

1
Physician’s Desk Reference (PDR), Flonase entry, accessed on
December 1, 2007 at
www.thomsonhc.com/pdrel/librarian/ND_PR/Pdr/SBK/l//PFPUI/0
SlHrZu2aVaNqC/DDAK (We will hereinafter refer to this
reference as “PDR”).
2
Lacy, C. et al., Drug Information Handbook, (Lexi-Comp, Inc.;
Cleveland; 1999) 445-446.
3
Bernini et al., US 6,464,958 B1, issued Oct. 15, 2002.
4
Harris et al., WO 99/18971 A1, published Apr. 22, 1999.
5
Osbakken et al., US 2002/0061281 A1, published May 23, 2002.
6
Doi, K., US 6,368,616 B1, issued Apr. 9, 2002.
7
Meade et al., US 6,608,054 B2, issued Aug. 19, 2003.
8
Walker, S. Management of allergic rhinitis, 99 NURS. TIMES 60-
61 (2003) Abstract only.
9
Hamuy et al., Topical antiviral agents for herpes simplex virus
infections, 34 DRUGS TODAY 1013-25 (1998) Abstract Only.
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providing optimized particle size and distribution” (Ans. 7). The Examiner
finds that “Harris teaches that the preferred micronization technique is jet
milling and that this technique may be used to reproducibly obtain desired
distributions of micron and submicron sized particles” (Ans. 9). The
Examiner finds that “Osbakken teaches that it had been suggested previously
in the prior art to use small aerosol particles of about 2-4 microns in the
treatment of sinusitis” (Ans. 10). The Examiner finds that Osbakken teaches
a formulation which “comprises amphotericin beta (10 mg unit dose),
hydrocortisone sodium succinate (50 mg dose in 3 ml sterile water) together
with an anti-inflammatory agent” (Ans. 11).
The Examiner finds it obvious, based on the prior art, to “modify
FLONASE® to incorporate a therapeutically effective amount of an anti-
fungal agent and/or an antibacterial to obtain a composition suitable for
treating not only the inflammation resulting from an infection” (Ans. 13).
The Examiner finds “that optimization of particle sizes is routine in the field
of inhalable formulations” (Ans. 15).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that the cited prior art renders Claim 1 obvious?
(ii) If so, has Appellant presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?

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Findings of Fact
The following findings of fact (“FF”) are supported by a
preponderance of the evidence of record.
1. Flonase teaches that:
FLONASE Nasal Spray, 50 mcg is an aqueous suspension
of microfine fluticasone propionate for topical
administration to the nasal mucosa by means of a metering,
atomizing spray pump. FLONASE Nasal Spray also
contains microcrystalline cellulose and
carboxymethylcellulose sodium, dextrose, 0.02% w/w
benzalkonium chloride, polysorbate 80, and 0.25% w/w
phenylethyl alcohol, and has a pH between 5 and 7.

(Flonase 1).
2. The Examiner finds that Lacy teaches that “FLONASE® was a
commercially available product at least as early as 1999. The DIH also sets
forth that neomycin sulfate . . . and that acyclovir (pgs. 26-28), ganiciclovir
(pgs. 463-464), foscarnet (pgs. 454-456), cidofovir (pgs. 225-226), and
formivirsen (pgs. 453-454) were all known . . . agents at the time of
Appellant’s invention” (Ans. 7).
3. Bernini teaches that “[o]ne of most critical parameters
determining the proportion of inhalable drug which will reach the lower
respiratory tract of a patient is the size of the particles emerging from the
device” (Bernini, col. 1, ll. 30-33).
4. Bernini teaches that “[o]ther important characteristics for a
correct administration and therefore for the therapeutic efficacy, are the size
distribution and the homogeneous dispersion of the particles in the
suspension” (Bernini, col. 1, ll. 39-42).
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5. Bernini teaches that “in case of steroids, it is possible to tighten
the distribution particle curve in such a way as that the mean diameter of at
least 90% of the particles is lower than or equal to 5 µm by keeping the
operating pressures between 500 and 1000 bar” (Bernini, col. 2, ll. 44-48).
6. Table 2 of Bernini is partially reproduced below:

Table 2 shows particle sizes for the inhaled steroid BDP where 10% was
0.76 µm, 50% was 3.01 µm, and 90% was 9.42 µm.
7. Harris teaches that “[u]se of inhaled therapeutic substances has
become common for the treatment of airway disorders, such disorders
including, without limitation thereto, asthma, infections, emphysema and
various inflammatory conditions” (Harris 1, ll. 18-20).
8. Harris teaches that “it is possible to reproducibly create desired
distributions of micron- and submicron-sized particles” (Harris 10, ll. 6-7).
9. Osbakken teaches that “the sinus passages must be open to
allow drainage and the circulation of air through the nasal passage. When
one or more of these processes or factors are amiss, causing obstruction of
the sinus passage, an infection called sinusitis develops” (Osbakken 1 ¶
0004).
10. Osbakken teaches that the “most common cause for sinusitis is
a viral cold or flu that infects the upper respiratory tract and causes
obstruction. Obstruction creates an environment that is hospitable for
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bacteria, the primary cause of acute sinusitis . . . Fungi are an uncommon
cause of sinusitis, but its incidence is increasing” (Osbakken 1 ¶¶ 0007-
0008).
11. Osbakken teaches “using a nebulizer to treat sinusitis patients . .
. Kondo et al. suggests that the preferred aerosol particle size is about 2-4
µm in diameter for deposition of a higher level of antibiotic in the maxillary
sinus” (Osbakken 3 ¶¶ 0027, 0029).
12. Osbakken teaches the “use of synergistic antibiotic
combinations allows for the treatment of those more difficult infections at
lower dosage levels than otherwise possible” (Osbakken 5 ¶ 0066).
13. Osbakken teaches “that aerosolized anti-infective particles are
surprisingly effective therapeutically when they have a mass median
aerodynamic diameter (MMAD) of about 1.0 to 5.0 microns for deposition
in the sinuses in a preferred size range” (Osbakken 6 ¶ 0081).
14. Osbakken teaches that “[a]nti-inflammatory agents
contemplated by the present invention include, but are not limited to
steroidal and non-steroidal anti-inflammatory agents, and mast cell
inhibitors. Antifungal agents contemplated by the present invention include,
but are not limited to amphotericin B, and azole antifungal” (Osbakken 7 ¶
0085).
15. Osbakken teaches that “[e]xamples of steroidal anti-
inflammatories include, but are not limited to . . .fluticasone” (Osbakken 10
¶ 0139).
16. Osbakken teaches that after “determining the medications to be
used in the formulation, each ingredient is weighed/measured out
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individually, added together, mixed with diluent, for example, sterile water,
and filtered with a coarse filter and then a fine filter (5 micron, 2 micron, 1
micron, 0.45 micron, or 0.22 micron)” (Osbakken 8 ¶ 0104).
17. Osbakken teaches that as “a third example, amphotericin B is
formulated in 10 mg unit doses along with hydrocortisone sodium succinate
in 50 mg unit doses in 3 ml sterile water to provide an antifungal agent
together with an anti-inflammatory agent” (Osbakken 11 ¶ 0178).
18. Figure 3 of Chemimage
10
is reproduced below:

Figure 3 shows the particle size of fluticasone in Flonase and in a generic
equivalent.

10
Chemimage, Comparison of Drug Particle Sizing of Innovator
and Generic Nasal Spray Formulation Based on Raman Chemical
Imaging, www.chemimage.com (2009).
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Principles of Law
“In proceedings before the Patent and Trademark Office, the
Examiner bears the burden of establishing a prima facie case of obviousness
based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992).
“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 lnc., 550 U.S. 398, 416 (2007). “If a person of
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” Id. at 417.
Analysis
Prima Facie Obviousness
Osbakken teaches treatment of fungus induced sinusitis in a mammal
(FF 9-10) comprising the use of the anti-inflammatory fluticasone (FF 15)
where the anti-inflammatory drugs may be used in combination with
antifungal drugs such as amphotericin B (FF 17). While Osbakken does not
teach the precise particle size distribution profile of claim 1, Osbakken
teaches “that aerosolized anti-infective particles are surprisingly effective
therapeutically when they have a mass median aerodynamic diameter
(MMAD) of about 1.0 to 5.0 microns for deposition in the sinuses in a
preferred size range” (Osbakken 6 ¶ 0081; FF 13).
The particle size distribution of Flonase, as disclosed by Chemimage,
is d10 1, d50 4.7, d90 13.5 (FF 18). Bernini and Harris teach that particle
size distributions are optimizable variables, where Bernini teaches that
“[o]ne of most critical parameters determining the proportion of inhalable
drug which will reach the lower respiratory tract of a patient is the size of the
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particles emerging from the device” (Bernini, col. 1, ll. 30-33; FF 3). Harris
teaches that “it is possible to reproducibly create desired distributions of
micron- and submicron-sized particles” (Harris 10, ll. 6-7; FF 8).
We conclude that the person of ordinary skill and creativity would
have predictably optimized the distribution of fluticasone particles for the
treatment of sinusitis in combination with an antifungal agent since the prior
art references suggest that particle size distributions were known as a results
effective variable, critical for determining the deposition of the particles into
the sinus (FF 3, 4, 8, 11, 13). “[W]here the general conditions of a claim are
disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456
(CCPA 1955) (citing In re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite,
168 F.2d 104 (CCPA 1948)).
Appellant contends that “one skilled in the art would have no rational
basis for modifying Flonase to have the particular particle size distribution
recited in each of the currently pending independent claims. Such a
modification would require a substantial alteration of the Flonase particle
size distribution, particularly considering the lack of any teaching in the art
to make such a modification.” (App. Br. 14; emphasis omitted).
We are not persuaded. Osbakken teaches “that aerosolized anti-
infective particles are surprisingly effective therapeutically when they have a
mass median aerodynamic diameter (MMAD) of about 1.0 to 5.0 microns
for deposition in the sinuses in a preferred size range” (Osbakken 6 ¶ 0081;
FF 13). This is a direct suggestion that the maximum size of the particles
should fall within instant Claim 1’s D90 of less than 5.3 microns. The
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discovery of an optimum value of a results-effective variable in a known
process is normally obvious. In re Antonie, 559 F.2d 618, 620 (CCPA 1977).
As discussed above, particle size distributions for sinusitis drugs were
known, results-effective variables (FF 3, 4, 8, 11, 13) and Osbakken
suggests particle sizes overlapping with the distribution claimed by
Appellant. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“In
cases involving overlapping ranges, we and our predecessor court have
consistently held that even a slight overlap in range establishes a prima facie
case of obviousness.)
Unexpected Results
Appellant contends that “[c]omparison of the Dey FP Low Dose
Group with the Flonase Low Dose Group shows that the currently claimed
invention provides a notable and surprising improvement from the
symptoms of SAR despite both groups receiving the same amount of
active.” (App. Br. 15; emphasis omitted).
Appellant “submits that one skilled in the art (and one suffering from
the symptoms of seasonal allergic rhinitis) would recognize the
aforementioned percentages of TNSS improvement as not merely a minor
difference of degree” (App. Br. 16). Table 1 in Appellant’s brief shows a
range of improvements from 9% to 38% between the claimed particle
distribution and the Flonase low dose group, based upon data in the figures
(see App. Br. 16).
We are not persuaded. We have reviewed figures 1-4 and Example 6
of the Specification and do not find that the results are unexpected.

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Figure 1 is reproduced below:

FIG. 1 shows the change from baseline in AM and PM reflective TNSS over
time in the ITT population over a 14 day study period. A careful review of
Figure 1 supports the position of the Examiner, which is that the Dey
fluticasone low values were substantially the same as those of Flonase low
values, with minimal difference over the 14 days. This is consistent with the
evidence of Example 6 of the Specification. Example 6 directly rebuts the
unexpected results argument of Appellant, since Example 6 states that
“[t]here was no statistically significant differences between Dey-FP and
FLONASE High and Low Dose groups for any efficacy endpoint analysis
(relief of signs and symptoms of SAR)” (Amdt. to Spec. filed Jan. 6, 2011,
page 6). See In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (“[i]t is not
enough to show that results are obtained which differ from those obtained in
the prior art: that difference must be shown to be an unexpected difference”).
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Conclusion of Law
(i) The evidence of record supports the Examiner’s conclusion that the
cited prior art renders Claim 1 obvious.
(ii) Appellant has not presented evidence of secondary considerations,
that when weighed with the evidence of obviousness, is sufficient to support
a conclusion of non-obviousness.
B. and C. 35 U.S.C. § 103(a) Rejections
The Examiner provides sound fact-based reasoning for adding the
additional Doi, Meade, Walker and Hamuy references. We adopt the fact
finding and analysis of the Examiner as our own. Appellant argues the
underlying obviousness rejection over Physician’s Desk Reference (PDR®),
Lacy, Bernini, Harris, Osbakken, but Appellant does not identify any
material defect in the Examiner’s reasoning for combining Doi, Meade,
Walker and Hamuy with these references. Since Appellant only argues the
underlying rejection which we affirmed above, we affirm these rejections for
the reasons stated by the Examiner.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over Physician’s Desk Reference (PDR®), Lacy, Bernini,
Harris, and Osbakken. Pursuant to 37 C.F.R. § 41.37(c)(1), we also affirm
the rejection of claims 4-6, 10-13, 22-25, 27-30, 35, and 77 as these claims
were not argued separately.

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We affirm the rejection of claims 71-74 under 35 U.S.C. § 103(a) as
obvious over Physician’s Desk Reference (PDR®), Lacy, Bernini, Harris,
Osbakken, Doi, and Meade.
We affirm the rejection of claims 75 and 76 under 35 U.S.C. § 103(a)
as obvious over Physician’s Desk Reference (PDR®), Lacy, Bernini, Harris,
Osbakken, Walker, and Hamuy.

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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