Ex Parte Zalit et al

Patent Trial and Appeal Board

Nov 20, 2012

11481962 (P.T.A.B. Nov. 20, 2012)

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.
11/481,962 07/07/2006 Ilan Zalit 1662/80002 5886
26646 7590 11/20/2012
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK, NY 10004
EXAMINER
CHANNAVAJJALA, LAKSHMI SARADA
ART UNIT PAPER NUMBER
1611
MAIL DATE DELIVERY MODE
11/20/2012 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 ILAN ZALIT, FANNY LESKA, MALI KADOSH,
DORIT MARCO, and YONIT MESSER-TRIGER
__________

Appeal 2011-012690
Application 11/481,962
Technology Center 1600
__________

Before TONI R. SCHEINER, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
compressed pharmaceutical dosage form. The Examiner rejected the claims
as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

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Statement of the Case
Background
“This invention relates in general to compressed solid dosage form
manufacturing methods and solid dosage forms such as tablets and caplets
produced therefrom” (Spec 1 ¶ 0001).
The Claims
Claims 1-4, 26, 29, 53-56, 58-64, and 71-74 are on appeal. Claim 1 is
representative and reads as follows:
1. A compressed pharmaceutical dosage form comprising:
a) raloxifene hydrochloride, and
b) starch in an amount of greater than 25 weight percent of
the dosage form, wherein the raloxifene hydrochloride has a
particle size distribution such that d(50) is greater than or equal to
35 µm and d(90) is less than or equal to 100 µm, as measured by
laser light scattering.

The issue

The Examiner rejected claims 1-4, 26, 29, 53-56, 58-64, and 71-74
under 35 U.S.C. § 103(a) as obvious over Arbuthnot,
1
Trubiano,
2
and
Shangraw
3
(Ans. 4-8).
The Examiner finds that Arbuthnot teaches “raloxifene containing
compressed formulations, in the form of tablets comprising starch” (Ans. 4).
The Examiner finds that Arbuthnot teaches with “respect to the claimed
amounts of starch, example 3 recites 45 mg/tablet for a tablet containing

1
Arbuthnot et al., US 6,458,811 B1, issued Oct. 1, 2002.
2
Trubiano et al., US 4,551,177, issued Nov. 5, 1985.
3
Shangraw, R., Compressed Tablets by Direct Compression, 2
TABLETS 195-209 (1989).
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between 25-100 mg of raloxifene” (Ans. 4-5). The Examiner finds that even
though Arbuthnot prefers
a particle size of 5 to 20 microns, [Arbuthnot] provide[s] a
description of various particle sizes of raloxifene and their
dissolution profiles (tested by the same methods of instant
claims). In this regard, the attention is directed to the
composition of [Arbuthnot] (table 6, #3 in col. 25 and lot 5a
in table 9 in col. 26) that contains a mean particle size of
48.1 microns

(id. at 5).
The Examiner finds that Trubiano teaches “compressible dosage
forms prepared by various granulation techniques such as dry and wet
granulations, employing starch as a binder in the tablet or capsule
compositions.” (Id. at 6.) The Examiner finds that Trubiano teaches starch
in amounts of “15-85%, preferably 45-85% or most preferably 75%” (id ).
The Examiner finds that Shangraw teaches “direct compression in the
process of preparing tablets employing binders such as starch” (id.).
The Examiner finds it obvious to
prepare a compressed tablet formulation of raloxifene (of
[Arbuthnot]) containing raloxifene of optimum particle size
and with a high amount of starch (such as 40-85%) in the
composition as a binder and flow aid because [Trubiano]
suggests that starches provide stable, non-hygroscopic, non-
reactive and provides excellent compression as well as
superior binding and disintegrating properties

(Ans. 7).
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The issue with respect to this rejection is: Does the evidence of record
support the Examiner‟s conclusion that Arbuthnot, Trubiano, and Shangraw
render the composition of claim 1 obvious?

Findings of Fact
1. Arbuthnot teaches that “[r]aloxifene is now in Phase III clinical
trials for osteoporosis. Indications thus far . . . point to raloxifene‟s potential
not only as an osteoporosis therapy, but also of potential use in lowering
LDL(serum lipid) levels, inhibiting endometriosis and uterine fibrosis, and
preventing breast cancer” (Arbuthnot, col. 2, ll. 34-39).
2. Arbuthnot teaches that:
It would seem reasonable that the best way to deal with any
slightly soluble compound would be to mill it to the smallest
size possible; however, this is not always practical or
desirable. The milling process has an economic cost not only
it the direct cost of the process, itself, but also with other
associated factors. For example, very finely divided material
presents difficulties and cost in capsule filling or tablet
preparation

(Arbuthnot, col. 22, ll. 35-43).
3. Arbuthnot teaches that “there is always dynamic between the
properties which yield the maximum bioavailability (particle surface area)
and the practical limits of manufacture. The point of compromise which
marks this „best solution‟ is unique to each situation and unique as to its
determination” (Arbuthnot, col. 22, ll. 51-55).
4. Arbuthnot teaches that
To further investigate the impact of particle size of
raloxifene HCl on drug product performance as measured by
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in vitro dissolution and in vivo absorption, a single dose,
plasma concentration versus time study was designed in
cynomolgus monkeys. The study compared absorption from
two bulk lots of raloxifene which possessed mean particle
sizes of 48.1 and 9.0 microns. The lots were formulated into
granulation matrices representative of granulations being
compacted into tablets for human use

(Arbuthnot, col. 26, ll. 21-29).
5. Table 9 of Arbuthnot is reproduced below:

Table 9 shows a comparison of particle sizes between Lot 5A and Lot 5B
(Arbuthnot, col. 26, ll. 33-43).
6. Table 10 of Arbuthnot is reproduced below:

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Table 10 shows that the “differences in particle size distribution again
produced significant differences in the dissolution profile in the aqueous
0.1% polysorbate 80 dissolution medium” (Arbuthnot, col. 26, ll. 50-65).
7. Arbuthnot teaches that “mean particle size, as determined by
laser light diffraction, should be less than about 25 microns. . . . Preferably,
the size is between about 5 and about 20 microns, and 90% of the particles
have a size of less than about 35 microns” (Arbuthnot, col. 27, ll. 55-61).
8. Arbuthnot teaches, in formulation 3, that:
Raloxifene, starch, and cellulose are passed through a
No. 45 mesh U.S. sieve and mixed thoroughly . . . . The
granules so produced are dried at 50-60° C. and passed
through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc,
previously passed through a No. 60 U.S. sieve, are then
added to the granules which, after mixing, are compressed
on a tablet machine to yield tablets.

(Arbuthnot, col. 32, ll. 31-41.)
9. The ingredient list for formulation 3 is reproduced below:

Formulation 3 is a tablet containing both 25-1000 mg of Raloxifene and 45
mg of starch (Arbuthnot, col. 32, ll. 21-29).
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10. Trubiano teaches that “[s]tarch as a binder should not be
confused with starch as a disintegrant or diluent since different properties are
required for each use. The most important property required in a binder is
compressibility.” (Trubiano, col. 2, ll. 31-34.)
11. Trubiano teaches that:
In another embodiment, it provides a starch-
containing admixture, useful as a binder for tablets prepared
by direct compression, dry granulation or wet granulation or
as a binder-diluent for capsules, which is an admixture of the
above compressible starch and an effective amount of a wet
granulation binder, e.g., pregelatinized starch. The
admixture is prepared by dry blending about 15-85%,
preferably 40-85%, most preferably 75%, of the
compressible starch powder with about 15-85%, preferably
15-50%, most preferably 25%, of the wet granulation binder,
the percentages being by weight and totaling 100%.

(Trubiano, col. 4, ll. 1-12.)
12. Shangraw teaches that the “most obvious advantage of direct
compression is economy. . . . Two unit processes are common to both wet
granulation and direct-compression tableting: blending and compression.
Prior micronization of the drug may be necessary in either process”
(Shangraw 198).
Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992).
A reference may be said to teach away when a person of
ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference,
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or would be led in a direction divergent from the path that
was taken by the applicant. The degree of teaching away
will of course depend on the particular facts; in general, a
reference will teach away if it suggests that the line of
development flowing from the reference's disclosure is
unlikely to be productive of the result sought by the
applicant.

In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
Analysis
While we can agree with the Examiner that Arbuthnot suggests a
compressed dosage of raloxifene tablets with starch, Arbuthnot specifically
discourages the use of tablets with a particle size distribution d(50) that is
greater than or equal to 35 µm, since Arbuthnot teaches that “mean particle
size, as determined by laser light diffraction, should be less than about 25
microns. . . . Preferably, the size is between about 5 and about 20 microns,
and 90% of the particles have a size of less than about 35 microns”
(Arbuthnot, col. 27, ll. 55-61; FF 7).
The Examiner responds by a finding that “attention is directed to the
composition of [Arbuthnot] (table 6, #3 in col. 25 and lot 5a in table 9 in
col. 26) that contains a mean particle size of 48.1 microns” (Ans. 5).
However, the Examiner does not find that the raloxifene tablet in Table 9
contains starch, so this tablet does not anticipate claim 1.
Regarding this argument and obviousness, Arbuthnot teaches in Table
10, which analyzes the tablets of Table 9, that “the differences in particle
size distribution again produced significant differences in the dissolution
profile in the aqueous 0.1% polysorbate 80 dissolution medium” (Arbuthnot,
col. 26, ll. 50-65; FF 6). In fact, the dissolution of the larger 48.1 micron
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particles in Lot 5A dissolved roughly half as fast over the first 20 minutes,
and remained slower dissolving over the 30 and 45 minute time points
relative to the 9 micron particles in Lot 5B (FF 6). This also supports
Appellants‟ position that Arbuthnot prefers smaller rather than larger
particles.
This is not a situation where the prior art could not have synthesized a
raloxifene tablet with starch and the claimed size constraints, but rather a
situation where the prior art teaches away from the use of the claimed size
constraints (FF 7), and the Examiner has advanced no positive reason to do
so. The Examiner provides no reason why a particle size distribution such
that d(50) is greater than or equal to 35 µm and d(90) is less than or equal to
100 µm would have been selected by one of skill in the art given the
teachings of the prior art. The evidence of Arbuthnot establishes that this
distribution is not equivalent to the lower particle size distribution preferred
by Arbuthnot. “Rejections 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.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
Here, no such reasoning to increase the particle size distribution is provided.
Conclusion of Law
The evidence of record does not support the Examiner‟s conclusion
that Arbuthnot, Trubiano, and Shangraw render the composition of claim 1
obvious.

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SUMMARY
In summary, we reverse the rejection of claims 1-4, 26, 29, 53-56,58-
64, and 71-74 under 35 U.S.C. § 103(a) as obvious over Arbuthnot,
Trubiano, and Shangraw.

REVERSED

cdc