Ex Parte Merisko-Liversidge

Patent Trial and Appeal Board

Jun 27, 2013

12292395 (P.T.A.B. Jun. 27, 2013)

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.
12/292,395 11/18/2008 Elaine Merisko-Liversidge 029318-1916 7670
31049 7590 06/28/2013
Elan Drug Delivery, Inc. c/o Foley & Lardner
3000 K Street, N.W.
Suite 500
Washington, DC 20007-5109
EXAMINER
CHANNAVAJJALA, LAKSHMI SARADA
ART UNIT PAPER NUMBER
1611
MAIL DATE DELIVERY MODE
06/28/2013 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte ELAINE MERIKO-LIVERSIDGE
__________

Appeal 2012-001378
Application 12/292,395
Technology Center 1600
__________

Before LORA M. GREEN, FRANCISCO C. PRATS, and
ERICA A. FRANKLIN, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal1 under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 126-143. We have jurisdiction under 35
U.S.C. § 6(b).
We affirm.

1 The Real Party in Interest is Elan Pharma International, Ltd. (App. Br. 2).
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STATEMENT OF THE CASE
Claim 126 is the only independent claim on appeal, and reads as
follows:
126. A method of making a nifedipine composition comprising contacting
particles of nifedipine or a salt thereof with at least one surface stabilizer for
a time and under conditions sufficient to provide a nifedipine composition
comprising nifedipine particles having an effective average particle size of
less than about 2000 nm.

The following ground of rejection is before us for review:
Claims 126-143 stand rejected under 35 U.S.C. § 103(a) as being
rendered obvious by the combination of either Doi2 or Calanchi3 with
Liversidge4 (Ans. 4).

ISSUE
Does the preponderance of the evidence of record support the
Examiner’s conclusion that the combination of either Doi or Calanchi with
Liversidge renders the method of making a nifedipine composition as set
forth in claim 126 obvious?

FINDINGS OF FACT
FF1. The Specification teaches that nifedipine is sparingly soluble in water,
and thus conventional forms of microcrystalline nifedipine have a poor
dissolution profiles (Spec. 6, ¶ 12).

2 Doi et al., US 4,665,081, issued May 12, 1987.
3 Calanchi et al., EP 0 220 760, published May 6, 1987.
4 Liversidge et al., US 5,145,684, issued September 8, 1992.
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FF2. Thus, the “invention relates to a novel composition of nifedipine,
comprising nifedipine particles having an effective average particle size of
less than about 2000 nm and at least one surface stabilizer that is preferably
adsorbed to or associated with the surface of the nifedipine particles” (id. at
1, ¶ 2).
FF3. The Specification teaches that a broad range of surface stabilizers may
be used (see, e.g., id. at 28-33, ¶¶ 110-119).
FF4. The Specification also teaches that an exemplary method of making
the nanoparticulate nifedipine compositions is described in U.S. patent No.
5,145,684 (id. at 36, ¶ 136).
FF5. The Examiner rejects claims 126-143 over the combination of Doi or
Calanchi as combined with Liversidge (Ans. 4). As Appellant does not
argue the claims separately, we focus our analysis on claim 126, and claims
127-143 stand or fall with that claim. 37 C.F.R. § 41.37(c)(1)(vii).
FF6. The Examiner finds that “Doi teaches solid nifedipine preparations as
vasodilating agents with excellent dissolution and control over the
dissolution rate, by pulverizing the drug together with the excipients into
very fine particles” (Ans. 4-5).
FF7. In the background section, Doi notes that proposed means for
enhancing the dissolution of a sparingly soluble active pharmacologically
active substance include fine pulverization in manufacturing solid
preparations (Doi, col. 1, ll. 32-39).
FF8. Doi notes, however, that with nifedipine, pulverizing it did not
remarkably increase its dissolution properties, and that the fine particulate
form had poor stability (id. at col. 1, ll. 42-52).
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FF9. Doi notes that the fine particulate of nifedipine was mixed with
additives such as microcrystalline cellulose and a surfactant for purposes of
manufacturing the solid form, but again the dissolution rate was not high,
and the preparation had inferior stability (id. at col. 1, ll. 52-64).
FF10. Doi thus teaches that “a fine particulate solid preparation of nifedipine
which is excellent in dissolution of nifedipine can be obtained by mixing
nifedipine with casein and one or more inorganic excipients and subjecting
the mixture to co-pulverization without using any liquid vehicle” (id. at col.
3, ll. 51-56). Thus, Doi teaches that the disclosed method is different from
that previously reported (see FF9) in which nifedipine was separately
pulverized (id. at col. 4, ll. 8-13).
FF11. The Examiner notes that while Doi teaches crystalline nifedipine
particles, Doi does not teach the claimed particle size (Ans. 5 (citing Doi,
col. 5, ll. 2-10)).
FF12. The Examiner finds that Calanchi teaches nifedipine formulations that
have high bioavailability that consist of nifedipine with polyethylene glycol
(id. at 5-6).
FF13. The Examiner notes that while Calanchi teaches preparing fine
particles of nifedipine, it fails to teach the particle size required by claim 126
(Ans. 6).
FF14. The Examiner finds that “Liversidge teaches preparation of
nanoparticulate drug compositions in which the drug is surface modified by
addition of one or more surface stabilizers” (Ans. 6).
FF15. Specifically, the Examiner finds that Liversidge teaches:
In order to improve the stability of the dispersed particles,
without flocculation, Liversidge suggests wet milling and
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grinding in conjunction with a surface modifier, and further
states that such grinding would render the particles crystalline
with the surface stabilizer absorbed on the particles (col. 2 & 3).
Liversidge teaches preparing particles of less than 400 nm (col.
2). Liversidge suggests employing the process of preparing
particles for a number of poorly soluble drug substances and
include several classes of drugs include g vasodilators (lines
bridging col. 3-4)., Liversidge teaches all of the surface
modifiers that are disclosed and claimed in the instant
application ….

(Id.)
FF16. Liversidge teaches a method of preparing stable, dispersible,
nanoparticles by wet milling in the presence of grinding media in
conjunctions with a surface modifier (Liversidge, col. 2, ll. 32-35).
According to Liversidge, the particulates can then be formulated into
pharmaceutical compositions “exhibiting remarkably high bioavailability”
(id. at col. 2, ll. 35-37).
FF17. Liversidge teaches that suitable drugs can be selected from a variety
of known classes of drugs (id. at col. 3, l. 53-col. 4, l. 14). Liversidge also
provides a list of surface modifiers that may be used (id. at col. 4, l. 34-col.
5, l. 12).
FF18. Liversidge notes that “not every combination of surface modifier and
drug substance provides the desired results” (id. at col. 7, ll. 21-23). Thus,
Liversidge discloses “a simple screening process whereby compatible
surface modifiers and drug substances can be selected which provide stable
dispersions of the desired particles” (id. at col. 7, ll. 23-27).
FF19. The Examiner concludes that it would have been obvious to prepare
nanoparticles having a particle size of 400 nm as taught by Liversidge using
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nifedipine as taught by Doi or Calanchi because “Liversidge teaches that the
wet milling and grinding of poorly water soluble drugs together with any of
the surface stabilizers (see examples of Liversidge) results in the stability of
the insoluble drug particles and Liversidge further states that the
compositions also exhibit unexpectedly high bioavailability” (Ans. 7).

ANALYSIS
Appellant argues that Doi teaches away from the combination with
Liversidge (App. Br. 10). Specifically, Appellant asserts that Doi
considered “‘very fine particle’ technology as an attempt to render
nifedipine more soluble and summarily dismissed this process’” (id.).
According to Appellant, Doi teaches that the dissolution rate of nifedipine
“‘is not increased so remarkably by merely pulverizing it into very fine
particles,’” and the preparations have inferior stability (id. (quoting Doi, col.
1, ll. 48-51)). Given the above teachings of Doi, Appellant argues that the
ordinary artisan would not look to Liversidge and its methods of making
nanoparticles (id.).
Appellant further asserts that the Examiner’s “fall-back position” is
that it would have been “obvious to try” (id. at 11). Appellant reiterates that
one would not even try given the teaching away of Doi (id.). Specifically,
Appellant argues that Doi tried milling, and dismissed it (id. at 12)
Appellant’s arguments are not convincing. As noted by the Examiner
(Ans. 8), the portions of Doi that Appellant is relying upon to demonstrate a
teaching away from using fine particulate referred to the use of pulverizing
nifedipine alone, without the addition of any stabilizers (FFs8 and 10). In
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fact, Doi distinguishes its method from the prior art method on the basis that
nifedipine is co-pulverized in the presence of casein and one or more
inorganic excipients (FF10).
Appellant argues further that “[e]xamples A-F of Liversidge
demonstrate considerable unpredictability and unsuccessful attempts to
create a nanoparticulate active agent composition through milling in the
presence of a surface stabilizer” (App. Br. 11).
This argument is also unpersuasive. First, “comparative examples”
are, by definition, for comparison to examples representing the invention.
Liversidge’s comparative examples resulted in particles that aggregated but
Liversidge does not describe any of the examples representing its inventive
particles as unsatisfactory (see Liversidge, col. 8, l. 35 to col. 13, l. 52).
Liversidge’s comparative examples therefore do not cast doubt on the
expectation that using nifedipine in Liversidge’s particles would be
successful.
In addition, although Liversidge states that “not every combination of
surface modifier and drug substance provides the desired results” (FF18),
“[o]bviousness does not require absolute predictability of success…. For
obviousness under § 103, all that is required is a reasonable expectation of
success.” In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).
Liversidge supports a reasonable expectation of successfully making its
particles with nifedipine because it names a wide variety of active agents
that are suitable for use in its particles, and it discloses “a simple screening
process whereby compatible surface modifiers and drug substances can be
selected” (FFs 17 and 18).
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As to the combination with Calanchi, Appellant argues that the
approach of Calanchi is very different, as “Calanchi considers a ‘very fine
particle’ to be 0.71 mm,” which is 2 orders of magnitude larger than the
nanoparticles of Liversidge, as well as the claimed nanoparticles (App. Br.
12). Appellant argues further that Calanchi teaches that the disclosed
method provides a solution to poor bioavailablity, and thus there would be
no reason to use the method of Liversidge to obtain fine nanoparticles (id.).
Appellant asserts that is especially true in view of Doi’s teaching away from
smaller particles (id.).
Appellant’s arguments are not convincing. The ordinary artisan
would have used the method of Liversidge to obtain fine particles of
nifedipine because of Liversidge’s teaching that a remarkable increase in
bioavailability may be obtained (FF16). See, e.g. In re Peterson, 315 F.3d
1325, 1329 (Fed. Cir. 2003) (noting that it is the “normal desire of scientists
or artisans to improve upon what is already generally known”). Appellant’s
arguments regarding Doi are not found to be convincing for the reasons set
forth above.

CONCLUSION OF LAW
We conclude that the preponderance of the evidence of record
supports the Examiner’s conclusion that the combination of either Doi or
Calanchi with Liversidge renders the method of making a nifedipine
composition as set forth in claim 126 obvious. We thus affirm the rejection
of claim under 35 U.S.C. § 103(a) as being rendered obvious by the
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Application 12/292,395

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combination of either Doi or Calanchi with Liversidge. Claims 127-143 fall
with claim 126.

TIME PERIOD FOR RESPONSE
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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