Chiesi Farmaceutici S.p.A.

Patent Trials and Appeals Board

Oct 14, 2020

15152835 - (D) (P.T.A.B. Oct. 14, 2020)

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.
15/152,835 05/12/2016 Gaetano Brambilla 471421US68DIV 9148
22850 7590 10/14/2020
OBLON, MCCLELLAND, MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA, VA 22314
EXAMINER
HELM, CARALYNNE E
ART UNIT PAPER NUMBER
1615
NOTIFICATION DATE DELIVERY MODE
10/14/2020 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
OBLONPAT@OBLON.COM
iahmadi@oblon.com
patentdocket@oblon.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte GAETANO BRAMBILLA,
PAOLO COLOMBO, FRANCESCA BUTTINI, and
MICHELE MIOZZI

Appeal 2020-000726
Application 15/152,835
Technology Center 1600
____________

Before RICHARD M. LEBOVITZ, RYAN H. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected claim 12, 13, and 21 under 35 U.S.C. § 103 as
obvious. Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject the claims. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies the real party in interest as Chiesi
Farmaceutici S.p.A. Appeal Br. 2.
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Application 15/152,835

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STATEMENT OF THE CASE
An oral hearing was held in this appeal on September 14, 2020. A
written transcript of the hearing has been entered into the record.
The Examiner rejected claims 12, 13, and 21 in the Office Action
(“Office Act.”) under U.S.C. § 103(a) as obvious in view of Hipkiss,2 Eck,3
Amighi,4 Batycky,5 Badyal,6 Abiko,7 Crooke,8 Rairkar,9 da Rocha,10 and
Banowski.11 Office Act. 3.
Claim 12, the only independent claim on appeal, is reproduced below:
12. A process for preparing chemically stable crystalline
microparticles, comprising formoterol fumarate dehydrate
coated with myristic acid in an amount of 1.0 to 2.0% by
weight based on a total weight of the crystalline microparticles,
the process comprising:
(a) preparing a solution of myristic acid in a fluorinated
model propellant in which the formoterol fumarate dihydrate is

2 Ruecroft et al., WO 2010/007447 A1, published Jan. 21, 2010 (“Hipkiss”;
last listed inventor). We follow the Examiner’s convention of, at times,
identifying the cited prior art references by other than first-named inventors.
3 Eck, US 2007/0009445 Al, published Jan. 11, 2007 (“Eck”).
4 Vanderbist et al., EP 2 050 437 A1, published Apr. 22, 2009 (“Amighi”; 3rd
listed inventor).
5 Batycky et al., US 2003/0180283 Al, published Sept. 25, 2003
(“Batycky”).
6 Badyal and Rogueda, US 2005/0106335 A1, published May 19, 2005
(“Badyal”).
7 Abiko and Kamaishi, US 4,259,905, issued Apr. 7, 1981 (“Abiko”).
8 Crooke and Graham, US 2006/0009410 A1, published Jan. 12, 2006
(“Crooke”).
9 Rairkar et al., US 2006/0286038 A1, published Dec. 21, 2006 (“Rairkar”).
10 da Rocha et al, “Science and Technology of Pressurized Metered-Dose
Inhalers,” 165, 170 in Smyth et al., ed., 2011, Controlled Release Society:
New York (“da Rocha”).
11 Banowski et al., US 2010/0047296 A1, published Feb. 25, 2010
(“Banowski”).
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Application 15/152,835

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substantially insoluble, selected from the group consisting of
perfluoropentane, 2H,3H-perfluoropentane (HPFP),
perfluorohexane, and 1H-perfluorohexane;
(b) adding the formoterol fumarate dihydrate as a
micronized powder to the solution of myristic acid, to obtain a
mixture;
(c) mixing the mixture to obtain a homogeneous
suspension;
(d) subjecting the suspension to spray-drying, to obtain
the coated microparticles, the myristic acid forming a
continuous film on a surface of the microparticles;
(e) preparing a pharmaceutical aerosol formulation
comprising the coated microparticles in suspension in a
liquefied propellant gas; and
(f) filling the pharmaceutical aerosol formulation into a
pressurized metered dose inhaler.

REJECTION
Claim 12 is directed to a process of preparing a pharmaceutical
aerosol formulation comprising formoterol fumarate dihydrate (“FF”)
microparticles coated with myristic acid, which are filled into a pressurized
metered dose inhaler (“pMDI”). Formoterol is a beta2-agonist administered
to the lungs by inhalation to treat reversible airway obstruction,
inflammation and hyper-responsiveness. Spec. 1–2.
In the first step (a) of the claim, a solution of myristic acid is prepared
in a fluorinated model propellant. The propellant is selected from a group
consisting of four specific fluorinate propellants. The FF is required by the
claim to be substantially insoluble in the propellant.
The FF is added to the myristic acid solution (step (b)), mixed to
obtain a suspension (step (c)), and then subjected to spray-drying (step (d)).
The spray-drying results in the formation of a continuous film of myristic
acid on the surface of the FF microparticles.
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An aerosol formulation is prepared in step (e) in which the coated FF
microparticles are suspended in a liquefied propellant gas and then filled into
a pMDI in the last step (f) of the claim.
The Examiner found that Hipkiss describes FF particles prepared in a
fluorinated propellant as recited in steps (a) and (b) of claim 12, but not
coated with myristic acid as the claim requires. Office Act. 3. To reach this
limitation of the claim, the Examiner cited Eck (Office Act. 4) for its
teaching of coating fine drug particles with a surfactant by adding the
surfactant to a hydrofluoroalkane (“HFA”) and then adding the drug as in
steps (b) and (c) of the claim. Eck ¶ 45. The Examiner further cited Amighi
for describing the “preparation of coated particles for inhalation where a
suspension of the core particle is prepared in a solution of the coating
material that is then spray dried to yield coated particles,” corresponding to
step (d) of the claim. Office Act. 5.
The Examiner recognized that Eck does not disclose myristic acid as
the surfactant, but instead discloses coating the drug particles with omega-3
and/or omega-6 fatty acids. Eck ¶ 7. Eck also does not disclose any of the
propellants listed in claim 12, step (a), that are used to make the myristic
acid solution.
To meet these limitations of the claims, the Examiner cited Batycky as
teaching that fatty acids may be used to coat drug particles to reduce particle
agglomeration (Batycky ¶¶ 161, 162). Office Act. 5–6. While Batycky does
not disclose that the fatty acid is myristic acid as required by step (a) of
claim 12, the Examiner found that Rairkar and Crooke disclose that myristic
acid is compatible with the lung. Id. at 6.
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The Examiner found that Hipkiss and Eck teach using an HFA to
prepare drug particles, such as FF particles, but acknowledged that neither
publication describes one of the listed propellants in claim 12, step (a) that
are used to make the myristic acid solution used to coat the FF particles in
steps (b)–(d) of the claim. The Examiner cited Badyal for teaching that
HPFP, a propellant of claim 12, can be used in place of HFA 227, the
particular propellant described in each of Hipkiss and Eck. Office Act. 6.
The Examiner also found that Abiko teaches that, when making toner
for waterless printing plates, it is preferred to make a uniform solution of the
polymeric material and organopolysiloxane that comprise the toner. Abiko
3:20–13; Office Act. 6. To do so, Abiko teaches “it is preferable that the
difference in solubility parameter between the polymeric material and the
organopolysiloxane is smaller than 2 (cal/cm-3).” Abiko 3:13–16. The
Examiner found it would have been obvious to one of ordinary skill in the
art to apply this teaching to Eck to determine whether myristic acid is
soluble in HPFP. Final Act. 6. The Examiner looked up the solubility
parameters of myristic acid and HPFP in Banowski and da Rocha,
respectively, and using Abiko’s teaching, determined that myristic acid is
soluble in HPFP. Id.
DISCUSSION
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “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 Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007). To establish obviousness under 35 U.S.C. § 103, one of ordinary
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skill in the art must also have a reasonable expectation that the prior art,
when combined, would succeed in making the claimed invention. See, e.g.,
Acorda Therapeutics, Inc. v. Roxane Laboratories, Inc., 903 F.3d 1310,
1333 (Fed. Cir. 2018). “‘Obviousness does not require absolute
predictability of success . . . all that is required is a reasonable expectation
of success.’ [citing In re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988)].”
In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). In some cases, however,
“the evidentiary basis for an inference of reasonable expectation of success
may be inadequate.” Accorda, 903 F.3d at 1333–34.
In this appeal, the issue is whether one of ordinary skill in the art
would have had reason to select myristic acid as the surfactant with a
reasonable expectation of success that it would uniformly coat the FF
microparticles when present in a solution of HPFP and spray-dried as
required by steps (a) and (d) of claim 12.
There is no express teaching in the cited publications of using myristic
acid to coat drug particles. However, Batycky generally teaches using
surfactants to coat drug particles to reduce agglomeration,12 and specifically
discloses fatty acids as an example.13 Rairkar teaches that myristic acid is a

12 “In another embodiment of the invention particles include a surfactant. . .
Surfactants generally possess a hydrophilic moiety and a lipophilic moiety,
such that, upon absorbing to microparticles, they tend to present moieties to
the external environment that do not attract similarly-coated particles, thus
reducing particle agglomeration. Surfactants may also promote absorption of
a therapeutic or diagnostic agent and increase bioavailability of the agent.”
Batycky ¶ 161.
13 “In addition to lung surfactants, such as, for example, the phospholipids
discussed above, suitable surfactants include but are not limited to
hexadecanol; fatty alcohols such as polyethylene glycol (PEG);
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fatty acid used as a surfactant in the lungs (Rairkar ¶¶ 8, 55). Although, the
teaching is in a different context than how the fatty acids are used as particle
coatings in Eck and Batycky, the teaching by Rairkar indicates myristic acid
is compatible with the lung, the target for the aerosolized coated drug
particles of claim 12.
Based on Batycky, the Examiner found that all fatty acids would be
equivalent in being effective to coat a drug particle in the HPFP solution.
Office Act. 4, 6–7. However, in the second declaration under 37 C.F.R.
§ 1.132 by Francesca Buttini, Ph.D. (“2nd Buttini Decl.”), a co-inventor of
the appealed claims, Dr. Buttini states that while the myristic acid
concentration could be increased from 0.5% by weight of the total weight of
the crystalline microparticles to the claimed amount of “1.0 to 2.0% by
weight based on a total weight of the crystalline microparticles,” two other
fatty acids tested by her had limitations. 2nd Buttini Decl. ¶ 12. Specifically,
Dr. Buttini states that “[t]he amount of lauric acid could not be increased
[from 0.5 %] because at higher concentrations lauric acid is toxic to the
lungs and mucous membranes” and that palmitic acid “could not be
dissolved in HPFP at concentrations higher than 0.5%.” Id. ¶ 15. Thus, Dr.
Buttini undermines the Examiner’s finding that all fatty acids would behave
similarly and could be formulated in the claimed amounts of “1.0 to 2.0% by
weight based on a total weight of the crystalline microparticles.”
The Examiner cited Abiko’s teaching about using the solubility
parameters to determine whether myristic acid is soluble in HPFP. However,
we agree with Appellant that one of ordinary skill in the art would not have

polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic
acid or oleic acid.” Batycky ¶ 162.
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considered Abiko’s teaching of using a solubility difference of 2 cal/cm-3 to
determine whether a polymeric material and organopolysiloxane can make a
uniform toner solution for waterless printing as providing a reasonable
expectation of success of making a coated drug particle of a drug coated
with myristic acid as claimed. First, the Examiner did not provide evidence
that the difference of 2 cal/cm-3 in solubility of compounds used in the toner
printing art is applicable to determining the solubility of a fatty acid in
HPFP. Second, the Examiner did not establish that Abiko is reasonably
pertinent to the drug coating teachings of Eck and Batycky. A reference is
“reasonably pertinent” to the inventor’s particular problem when the
reference “is one which, because of the matter with which it deals, logically
would have commended itself to an inventor’s attention in considering his
problem.” In re Klein, 647 F.3d 1343, 1348 (Fed. Cir. 2011) (citation
omitted). The Examiner did not explain why one of ordinary skill in the art
would have looked to waterless planographic printing plates as described in
Abiko for guidance in selecting fatty acids and solvents for drug
formulation. The Examiner provided no reasoning as to why Abiko would
been considered pertinent to the problem of making drug particles coated
with myristic acid. Ans. 7–8; Office Act. 6.
The Examiner relied on Badyal for finding that HPFP is a substitute
propellant for HFA 227, the propellant described in Eck, for coating the drug
particles. Office Act. 6. However, the Examiner’s finding is misplaced. HFA
227 is used in Eck, not as a propellant, but as the solvent to coat the drug
particle with the omega-3 and/or omega-6 fatty acid.14 Badyal, however,

14 “The invention also provides methods for preparing omega-3 and/or
omega-6 fatty acid-coated particles, as well as methods for preparing and
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uses the HPFA as a propellant to aerosolize the particles and deliver to the
lungs, not as a solvent to coat drug particles with fatty acid. Badyal describes
the problem of particles sticking to the surface of a delivery device when
using HFA propellants to administer drug particles to the lung. Badyal ¶¶ 2,
3. Badyal treated the surface of the delivery device (Badyal ¶ 8) and
determined adhesion between the particles and the drug surface:
The extent of the adhesion between the particles and the treated
surfaces was tested in a fluorinated solvent, 2H, 3H
perfluoropentane (abbreviated as HPFP). This liquid is a very
good substitute for both propellants HFA227 and BFA134a. It
is used when tests can not be performed in situ in pressurised
liquids, such as AFM.
Badyal ¶ 26.
Thus, there is no teaching by Badyal that HPFP is a substitute for
HFA 227 as the solvent to coat the FF particle with myristic acid as required
by the claims (see steps (a) and (d) of claim 12).
In view of these deficiencies, we conclude that the Examiner did not
establish that it would have been obvious to one of ordinary skill to coat FF
microparticles with myristic acid using HPFP as required by all the rejected
claims.

isolating the coated particles. For example, omega-3 linoleic acid isopropyl
ester is solubilized in HFA 134a or HFA227, a fine particle medicament is
added and the suspension is homogenized and coated particles are isolated
by filtration or spray drying.” Eck ¶ 45.
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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s) Affirmed Reversed
12, 13, 21 103 Hipkiss, Eck,
Amighi, Batycky,
Badyal, Abiko,
Crooke, Rairkar,
da Rocha,
Banowski
12, 13, 21

REVERSED