Ex Parte Curatolo et al

Board of Patent Appeals and Interferences

Sep 20, 2010

10176462 (B.P.A.I. Sep. 20, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte WILLIAM J. CURATOLO and DWAYNE T. FRIESEN
__________

Appeal 2010-004230
Application 10/176,462
Technology Center 1600
__________

Before TONI R. SCHEINER, DONALD E. ADAMS, and
DEMETRA J. MILLS, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL1

This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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STATEMENT OF CASE
The following claim is representative.
1. A composition comprising:
(a) a drug in a solubility-improved form which provides, when
administered to a use environment, at least one of a dissolved drug
concentration in said use environment that exceeds an equilibrium
concentration of a lowest solubility form of said drug in said use
environment and a dissolution rate that exceeds a dissolution rate of
said lowest solubility form of said drug in said use environment; and
(b) a concentration-enhancing polymer selected from the group
consisting of hydroxypropyl methyl cellulose acetate succinate,
cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,
and cellulose acetate trimellitate wherein said concentration-
enhancing polymer is present in a sufficient amount so that said
composition provides, after introduction to said use environment, a
maximum concentration of said drug in said use environment that is at
least 1.25-fold a maximum concentration of said drug provided by a
control composition, wherein said control composition is an
equivalent quantity of said drug in said solubility-improved form
alone;
wherein said solubility-improved form is selected from the group consisting
of drug in nanoparticulate form, absorbed drug, drug in a nanosuspension, a
supercooled melt of drug, cyclodextrin/drug form, gelatin form, softgel
form, and three phase form; and
wherein said drug in said nanoparticulate form comprises a surface modifier
adsorbed on said surface of said drug, and said concentration enhancing
polymer is separate from said surface modifier.

Cited References

Liversidge et al. US 5,145,684 Sep. 8, 1992
Rathi et al. US 6,117,949 Sep. 12, 2000
Kim et al. US 6,232,304 B1 May 15, 2001
Kath et al. WO 99/40061 Aug. 12, 1999

Grounds of Rejection
1. Claims 1-4, 11-14, 16 and 17 are rejected under 35 U.S.C. § 103(a)
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for obviousness over Liversidge in view of Kim and Rathi.
2. Claim 16 is rejected under 35 U.S.C. § 103(a) as being unpatentable
over Liversidge in view of Kath.

Discussion
ISSUE
The Examiner concludes that
it would have been obvious to one of ordinary skill in the art to
use a surfactant and a polymer to improve a composition
containing a hydrophobic drug. The motive would be the
disclosure of Rathi that the system will cause minimal toxicity
and minimal mechanical irritation to the surrounding tissue due
to the biocompatibility of the materials and also that the drug
release is controllable through adjustment of the concentration
of polymer in the drug delivery liquid.

(Ans. 5.)
Appellants argue that there is no motivation in Liversidge, Kim,
Rathi, or the knowledge generally available in the art to modify Liversidge
to make the claimed invention. Appellants argue that a skilled artisan would
have no reasonable expectation of success, since Rathi forms a gel and a gel
would not be expected to lead to concentration enhancement.
The issue is: Is there motivation to combine the cited references?

FINDINGS OF FACT
1. “Liversidge teaches a composition made of nanoparticulate
suspension or dispersion (col. 3, line 26, and example 1) of
hydrophobic drugs, the drug is poorly soluble, the drug substance has
a solubility in the liquid dispersion medium of less than about 10
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mg/ml (col. 3, lines 43-45), and preferably of less than about 1
mg/ml.” (Ans. 3.)
2. “Liversidge also used suitable surface modifiers, which can
preferably be selected from known organic and inorganic
pharmaceutical excipients. Such excipients include various polymers,
low molecular weight oligomers, natural products and surfactants (col.
4, lines 34-39).” (Id.)
3. The Examiner finds that

nanoparticulates and cyclodextrin complexes are equivalent
drug carriers as required by claim 4. The surface modifier is
adsorbed on the surface of the drug substance in an amount
sufficient to maintain an effective average particle size (col. 5,
lines 13-15). Using this composition yields plasma drug levels
of relative bioavailability of drug from the nanoparticulate
dispersion was 15.9 fold higher than from the drug prepared by
conventional airjet milling (col. 10, lines 1-11), which reads on
the drug provided by an equivalent quantity of said solubility-
improved form alone recited in the claims of the current
application. Examples of the polymers that are used by
Liversidge hydroxypropylmethyl cellulose phthalate (col. 4,
lines 50-55).

(Id. at 3-4.)
4.
Further, Liversidge discloses that the drug particle substance
having a non-crosslinked surface modifier adsorbed on the
surface (claim 1) can be added to a pharmaceutically acceptable
carrier (claim 14).
Liversidge is deficient in disclosing the specific drugs
disclosed by the current application, further he did not disclose
a preference of using a polymer different from the surface
modifier.

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(Id. at 4.)
5. “Rathi teaches biodegradable low molecular weight triblock poly
(lactide-co-glycolide) polyethylene glycol copolymers having reverse
thermal gelation properties.” (Ans. 4.)
6. “The [Rathi] reference teaches also that when the drug is partially
dissolved, or when the drug is essentially insoluble, the drug exists in
a colloidal state such as a suspension or emulsion (col. 11, lines 24+)
such as Ziprasidone (col. 13, lines 49+).” (Id. at 5.)
7. “Rathi also discloses a combination of the hydrophobic A-block(s)
and hydrophilic B-block(s) render the block copolymer amphiphilic in
nature. In that regard it functions much as a soap or surfactant (col.
12, lines 7+).” (Id.)
8. “Rathi teaches that the composition may be administered to a warm-
blooded animal as a liquid by parenteral, ocular, topical, inhalation,
transdermal, vaginal, transurethral, rectal, nasal, oral, pulmonary or
aural delivery means and is a gel at body temperature. The
composition may also be administered as a gel (abstract).” (Id.)
9. The Examiner finds that

Rathi did not literally disclose the exact copolymers disclosed
in the instant specification, however, the reference discloses
that copolymers are ABA triblock or AB block copolymers
composed of hydrophobic A-blocks, such as polylactide (PLA)
or poly(1actide-coglycolide)(PLGA), and hydrophilic B-blocks,
such as polyethylene glycol (PEG) or polyvinyl pyrrolidone.
The disclosure show that these polymers are equivalent in the
art (polyvinyl pyrrolidone is disclosed in the instant
specification [0053])

(id. at 4-5).
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10. The Examiner finds that

Accordingly, it would have been obvious to one of
ordinary skills in the art to use a surfactant and a polymer to
improve a composition containing a hydrophobic drug. The
motive would be the disclosure of Rathi that the system will
cause minimal toxicity and minimal mechanical irritation to the
surrounding tissue due to the biocompatibility of the materials
and also that the drug release is controllable through adjustment
of the concentration of polymer in the drug delivery liquid (col.
11, lines 38+).

(Ans. 5.)
11. The Examiner finds that

Neither of the references disclosed a cyclodextrin/drug
form of ziprasidone.
Kim teaches a cyclodextrin/drug form of ziprasidone,
which is of poor aqueous solubility and/or stability of the drug
of interest, the composition can be made into capsules. Though
the reference does not disclose specifically a softgel capsule, it
is within the skills of people of ordinary skill in the art to
modify and decide the right the right [sic] dosage form and
capsules.

(Id.)
12. The Examiner finds that

Accordingly, it would have been obvious to a skilled man
in the art at the time the invention was made to combine the
nanoparticulate dispersion or suspension disclosed by
Liversidge and the teaching of Rathi using a surfactant separate
from the polymer and apply it to Kim to advance the solubility
of insoluble drugs like ziprasidone as Kim disclosed that in
particular cyclodextrin there are solubility differences among
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particular salts of the arylheterocyclics useful (col. 2, lines 23-
26).

(Id.)
13. Kath “'061 discloses CCRl inhibitor compounds (claims 3, and 5).
The reference also teaches that for oral administration, the
pharmaceutical compositions may take the form of, for example, tablets
or capsules prepared by conventional means with pharmaceutically
acceptable excipients such as binding agents (e.g., pregelatinized maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) (page 12,
line 21, and 22).” (Ans. 6.)
14. The Examiner finds that

Because Liversidge prepared a nanoparticulate solution
that can be used with drugs of low solubility, it would have
been obvious to a skilled man in the art to combine the
knowledge Liversidge disclosed to the disclosure of '061 since
the drugs used are of low solubility to make the composition
suitable for administration to a human patient as a solution as
injectable or intranasal or rectal compositions. The expected
result would be a nanoparticulate composition containing
insoluble drug in a soft-gel form, which can be made into more
preparations and administered in humans through different
routes.

(Id.)

PRINCIPLES OF LAW
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
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Cir. 1993) (citations omitted). In order to determine whether a prima facie
case of obviousness has been established, we consider the factors set forth in
Graham v. John Deere Co., 383 U.S. 1, 17 (1966): (1) the scope and content
of the prior art; (2) the differences between the prior art and the claims at
issue; (3) the level of ordinary skill in the relevant art; and (4) objective
evidence of nonobviousness, if present.

ANALYSIS
The Examiner concludes that
it would have been obvious to one of ordinary skills in the art to
use a surfactant and a polymer to improve a composition
containing a hydrophobic drug. The motive would be the
disclosure of Rathi that the system will cause minimal toxicity
and minimal mechanical irritation to the surrounding tissue due
to the biocompatibility of the materials and also that the drug
release is controllable through adjustment of the concentration
of polymer in the drug delivery liquid.

(Ans. 5.)
Appellants argue that there is no motivation in Liversidge, Kim Rathi
or the knowledge generally available in the art to modify Liversidge to make
the claimed invention. Appellants argue that a skilled artisan would have no
reasonable expectation of success, since Rathi forms a gel and a gel would
not be expected to lead to concentration enhancement. (App. Br. 16.)
We are persuaded by Appellants’ arguments as set forth in the Brief.
We do not find that the Examiner has provided sufficient evidence or
convincing articulated reasoning why one of ordinary skill in the art would
modify the nanoparticulate drug of Liversidge having a surface modifier
with an additional and separate concentration enhancing polymer.
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CONCLUSION OF LAW
The cited references do not support the Examiner’s obviousness
rejection.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

REVERSED

cdc

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