Ex Parte Perc et al

Board of Patent Appeals and Interferences

Jul 8, 2011

10531540 (B.P.A.I. Jul. 8, 2011)

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.
10/531,540 04/15/2005 Stanka Perc 4061-27PUS 1415
27799 7590 07/08/2011
Cozen O''Connor
277 Park Avenue, 20th floor
NEW YORK, NY 10172
EXAMINER
JEAN-LOUIS, SAMIRA JM
ART UNIT PAPER NUMBER
1627
MAIL DATE DELIVERY MODE
07/08/2011 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte STANKA PERC, IVANKA BANKO,
and IVANKA KOLENC
__________

Appeal 2011-003119
Application 10/531,540
Technology Center 1600
__________

Before DEMETRA J. MILLS, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
olanzapine pharmaceutical composition. 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
The Claims
Claims 34-51 are on appeal. Claim 34 is representative and reads as
follows:
1. A pharmaceutical formulation comprising a
homogeneous mixture of: (a) uncoated olanzapine
or a pharmaceutically acceptable salt thereof as an
active ingredient; (b) a monosaccharide and/or
oligosaccharide and/or a reduced or oxidized form
thereof; (c) a polysaccharide and optionally; d) one
or more additional excipients.

The issues
A. The Examiner rejected claims 34-51 under 35 U.S.C. § 103(a) as
obvious over Morris
1
and Nakajima
2
(Ans. 5-8).
B. The Examiner rejected claims 34-51 under 35 U.S.C. § 103(a) as
obvious over Chakrabarti
3
and Rubinstein
4
(Ans. 8-12).
A. 35 U.S.C. § 103(a) over Morris and Nakajima
The Examiner finds that Morris teaches “an oral formulation where
the active ingredient olanzapine is subcoated and mixed with acceptable
excipients” (Ans. 5). The Examiner finds that Morris teaches “that the oral
formulation can contain diluents such as lactose, binders such as
crospovidone and microcrystalline cellulose, disintegrants such as
crospovidone, and lubricants and glidants such as magnesium stearate” (Ans.

1
Morris et al., EP 0830858 A1, published Mar. 25, 1998.
2
Nakajima et al., US 3,926,817, issued Dec. 16, 1975.
3
Chakrabarti et al., US 5,229,382, issued Jul. 20, 1993.
4
Rubinstein, M. H., Pharmaceutics: The Science of Dosage Form
Design, 304-321 (2002).
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5). The Examiner finds that Morris teaches that “uncoated olanzapine stored
in polyethylene bottles do not show discoloration until exposed to air thus
suggesting that non-coated olanzapine can be envisioned in oral
formulations” (Ans. 6). The Examiner “contends that it would be within the
skilled artisan to formulate the tablets as uncoated tablets if the intended use
is for rapid usage of the formulation before the discoloration period and/or
for rapid dissolution” (Ans. 7).
Appellants contend that “Morris does not disclose a formulation
comprising uncoated olanzapine. Morris in fact contains many statements
that would discourage or teach away a person of ordinary skill in the art
from making an uncoated olanzapine formulation” (App. Br. 4). Appellants
contend that “a person of ordinary skill in the art would not leave olanzapine
uncoated, which would result in undesirable color change and appearance, in
particular considering that the olanzapine formulation would be used for a
patient suffering from hallucinations, delusions, and being out of touch with
reality” (App. Br. 5). Appellants contend that “if one would use uncoated
olanzapine for rapid consumption, as suggested by the Examiner, s/he
should at least warn physicians and patients that the uncoated olanzapine
product should be consumed as soon as possible after the package is opened.
In case that the package is opened and the product is not used up
immediately, the unused product will have to be abandoned due to the
occurrence of discoloring” (App. Br. 8).
Appellants contend that “it is Appellants, not others, who surprisingly
discovered that a tablet formulation comprising a homogeneous mixture of
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uncoated olanzapine and other excipients in accordance with the present
invention has good stability” (App. Br. 10).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner‟s conclusion that Morris and Nakajima render obvious
the uncoated formulation of claim 34?
Findings of Fact
1. Morris teaches that “improved oral formulations were desired in
light of the moisture sensitive, metastable nature of olanzapine, the tendency
of olanzapine to undesirably discolor in the known tablet formulation”
(Morris 2, ll. 8-9).
2. Morris teaches that the
discoloration and mottled appearance does not produce an
increase in the number of total related substances; however,
the color change and appearance is not generally considered
pharmaceutically desirable. The color change could be
particularly undesirable for patients suffering from a
psychotic conditions. Indeed, the patient most likely to
receive olanzapine is a patient suffering from hallucinations,
delusions, and loss of touch with reality. Thus, a formulation
having consistent color and appearance is most desired.

(Morris 2, ll. 14-18).
3. Morris teaches that “directly coating the olanzapine substance
with one or more carefully selected polymers can provide drug material that
is resistant to such discoloration when formulated as a granule” (Morris 2, ll.
19-20).
4. Morris teaches that “[u]ncoated tablets stored at ambient
conditions (approximately 23°C and 40% relative humidity) in amber, high
density polyethylene bottles do not show signs of discoloration after 24
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months; however, if the bottle is opened such that the tablets are exposed to
open air ambient conditions then discoloration occurs within 5 days” (Morris
4, ll. 46-48).
Principles of Law
“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,
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 Morris teaches an example of an uncoated tablet with
olanzapine (FF 4), Morris also teaches that such uncoated tablets will
discolor, and that this discoloration may be particularly damaging to the
psychotic patient population for whom olanzapine is appropriate (FF 1-3).
Thus, Morris discourages the use of uncoated tablets and is reasonably
understood to teach way from the use of such uncoated olanzapine tablets.
See Gurley, 27 F.3d at 553.
The Examiner “maintains that obviousness does not hinge on whether
better choices existed but rather whether such formulation can be reasonably
made and be made successfully” (Ans. 13). The Examiner also argues that
“if the desire is to provide a formulation of olanzapine that is rapidly
consumed or consumed within 5 days, then one of ordinary skill in the art
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would have indeed found it obvious to formulate an uncoated olanzapine
formulation” (Ans. 13).
We are not persuaded. While we agree with the Examiner that the
prior art does not need to show that the particular embodiment is the most
preferred or desirable (see In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir.
2004)), when evaluating claims for obviousness, “the prior art as a whole
must be considered. The teachings are to be viewed as they would have been
viewed by one of ordinary skill.” In re Hedges, 783 F.2d 1038, 1041 (Fed.
Cir. 1986). Here, Morris strongly teaches away from the use of uncoated
olanzapine due to the discoloration (FF 1-3).
Regarding the Examiner‟s asserted reason that a desire for a rapidly
consumed formulation of olanzapine would have been obvious, the
Examiner has not provided any evidence supporting this position. If, for
example, the Examiner had provided evidence of a packaging mode for
individual pills for olanzapine which would have avoided the discoloration,
such evidence might have balanced the teaching away in Morris, but no
evidence supporting the Examiner‟s reasoning was provided.
Conclusions of Law
The evidence of record does not support the Examiner‟s conclusion
that Morris and Nakajima render obvious the uncoated formulation of claim
34.
B. 35 U.S.C. § 103(a) over Chakrabarti and Rubinstein
The Examiner finds that Chakrabarti teaches “the use of olanzapine of
formula I in the treatment of disorders of the central nervous system” (Ans.
8). The Examiner finds that Chakrabarti teaches
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the uncoated olanzapine tablet formulation without any
solvent in example 4 where the tablet is made by mixing
appropriate diluents such as starches at 68%, lubricants and
glidants such as magnesium stearate at 0.3%, disintegrants
such as microcrystalline cellulose at 25%, and binders such
as povidone at 5.0%, and wherein the tablet is then
compressed.

(Ans. 9). The Examiner finds that Rubinstein teaches “the monosaccharide,
lactose, as the principal diluent used in the art for bulking the tablet” (Ans.
10). The Examiner finds that “it is well within the purview of the skill of the
artisan at the time of the invention to adjust the concentration and percentage
of the ingredients in the composition during the course of routine
experimentation so as to obtain the desirable type of product” (Ans. 10).
Appellants contend that “Chakrabarti fails to disclose a homogeneous
mixture of: (a) uncoated olanzapine or a pharmaceutically acceptable salt
thereof as an active ingredient; (b) a monosaccharide and/or oligosaccharide
and/or a reduced or oxidized form thereof; (c) a polysaccharide and
optionally; and d) one or more additional excipients” (App. Br. 14).
Appellants contend that “Chakrabarti‟s method of granulating does not lead
to a homogenous mixture of olanzapine with other excipients . . . Therefore,
the tablets made by granulation are not a homogenous mixture, because the
ingredients are not evenly distributed at different position or depth of the
tablets” (App. Br. 14).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner‟s conclusion
that Chakrabarti and Rubenstein render obvious the uncoated formulation of
claim 34?
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(ii) and if so, have Appellants provided evidence of secondary
considerations that outweighs the evidence supporting a conclusion of
obviousness?
Findings of Fact
5. Chakrabarti teaches olanzapine (the compound of Formula I)
which “is useful in treating psychotic conditions such as schizophrenia,
schizophreniform diseases and acute mania. At lower doses the compound is
indicated for use in the treatment of mild anxiety states” (Chakrabarti, col. 2,
ll. 25-57).
6. Chakrabarti teaches that the “active ingredient will usually be
mixed with a carrier” (Chakrabarti, col. 8, ll. 23-24).
7. Chakrabarti teaches that “[w]hen the carrier serves as a diluent,
it may be solid . . . examples of suitable carriers are lactose, dextrose,
sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, syrup, methyl cellulose” (Chakrabarti, col. 8,
ll. 26-34).
8. Chakrabarti teaches that a “tablet formulation is made by
granulating the active with appropriate diluent, lubricant, disintegrant and
binder and compressing” (Chakrabarti, col. 11, ll. 28-30, Example 4).
9. Chakrabarti teaches in Example 4, the following components

Example 4 shows the use of an (a) component which may include uncoated
olanzapine; a (c) component which is the polysaccharide, starch; and
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additional excipient such as magnesium stearate and povidone (Chakrabarti,
col. 9).
10. Rubinstein teaches that “[d]iluents or „bulking agents‟ are
„inert‟ substances which are added to the active ingredient in sufficient
quantity to make a reasonably sized tablet. . . . The principal substance
employed as a diluent is lactose” (Rubinstein 309, col. 2).
11. Rubinstein teaches that “[d]ry methods and in particular direct
compression are superior to those methods employing liquids, since dry
processes do not require the equipment and handling expenses required in
wetting and drying procedures and can avoid hydrolysis of water-sensitive
drugs” (Rubinstein 307, col. 1).
12. Rubinstein teaches that “[t]ablets are produced by mixing the
drug with the compression vehicle in a blender. The powder mix is then
compressed directly on a tableting machine” (Rubinstein 307, col. 1).
Principles of Law
“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 Inc., 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
Claim 34
Chakrabarti teaches a pharmaceutical formulation comprising
uncoated olanzapine (FF 5) mixed with diluents such as lactose (FF 7), a
polysaccharide and additional excipients (FF 6, 8-9). Rubenstein teaches the
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use of lactose as a diluent (FF 10) and teaches formation of tablets by
mixing the components in a blender and then directly compressing the
blended material to form tablets (FF 11-12).
Applying the KSR standard of obviousness to the findings of fact, we
conclude that the person of ordinary creativity would have predictably
followed the teachings of Chakrabarti and Rubenstein to form homogenous
(FF 11) mixtures of uncoated olanzapine with the monosaccharide lactose
(FF 5, 7, 10), the polysaccharide starch (FF 9) and additional excipients (FF
6-10). Such a combination is merely a “predictable use of prior art elements
according to their established functions.” KSR, 550 U.S. at 417.
Appellants contend that “Chakrabarti fails to disclose a homogeneous
mixture of: (a) uncoated olanzapine or a pharmaceutically acceptable salt
thereof as an active ingredient; (b) a monosaccharide and/or oligosaccharide
and/or a reduced or oxidized form thereof; (c) a polysaccharide and
optionally; and d) one or more additional excipients” (App. Br. 14).
Appellants contend that “Chakrabarti‟s method of granulating does not lead
to a homogenous mixture of olanzapine with other excipients . . . Therefore,
the tablets made by granulation are not a homogenous mixture, because the
ingredients are not evenly distributed at different position or depth of the
tablets” (App. Br. 14).
We are not persuaded. Chakrabarti teaches granulating all of the
components together prior to compressing (FF 8). Appellants argue that
Chakrabarti‟s granulation does not result in a homogenous mixture, but this
argument lacks any basis in evidence or fact, and simply represents attorney
argument. See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974)
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(“Attorney‟s argument in a brief cannot take the place of evidence.”).
Additionally, given Rubenstein‟s teaching to combine all of the ingredients
into a blender, prior to compression (FF 12), the ordinary artisan following
the combined teachings of Chakrabarti and Rubenstein would reasonably
have blended the components together, prior to compression to form the
tablet, so the resulting tablet is reasonably interpreted as a “homogenous”
composition.
Appellants contend that “the Examiner still fails to articulate a reason
why a person of skilled in the art would disregard specific granulating
technique disclosed in Chakrabarti and select the technique of „direct
compression‟ from among many other conventional techniques disclosed in
Rubinstein to arrive at the present invention” (Reply Br. 8-9).
We are not persuaded. Rubenstein expressly teaches that “[d]ry
methods and in particular direct compression are superior to those methods
employing liquids, since dry processes do not require the equipment and
handling expenses required in wetting and drying procedures and can avoid
hydrolysis of water-sensitive drugs” (Rubinstein 307, col. 1; FF 11). This is
a particular reason to select the technique of “direct compression”. Further,
“If a person of ordinary skill can implement a predictable variation, § 103
likely bars its patentability.” KSR at 417.
Unexpected results
Appellants contend that “[w]ithout knowing the surprising discovery
by the present inventors, a person of ordinary skill in the art would not
simply mix olanzapine with other excipients evenly to make a homogenous
mixture by, e.g., direct compression” (App. Br. 15).
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We are not persuaded. Appellants have not demonstrated an
unexpected result relative to the disclosure of Chakrabarti and Rubenstein.
Appellants have not compared their asserted improved stability with the
composition of Chakrabarti. See In re Baxter Travenol Labs., 952 F.2d 388,
392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.”).
Further, even if we would accept that the result shown in Example 3
of the Specification is unexpected, relative to Example 2 of the
Specification, the claims are not commensurate in scope with the asserted
unexpected result of improved stability, since the only difference between
Examples 2 and 3 in the Specification is the use of 20 mg less of cellactose
(see Spec 9-10). See In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005)
(Unexpected results must also be “commensurate in scope with the degree of
protection sought by the claimed subject matter.”)
Claim 35
Appellants contend that “[n]either Chakrabarti nor Rubinstein
discloses, suggests, or teaches preparation of an olanzapine formulation by
direct compression of a mixture into tablets in the absence of any solvent”
(App. Br. 17).
We are not persuaded. Rubenstein expressly teaches that “[t]ablets
are produced by mixing the drug with the compression vehicle in a blender.
The powder mix is then compressed directly on a tableting machine”
(Rubinstein 307, col. 1; FF 12). This is a direct compression of the mixture
into tablets without solvent.
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Claims 50-51
Appellants content that “[n]either Chakrabarti nor Rubinstein
discloses, suggests, or teaches a matrix composition” (App. Br. 18).
Appellants also contend that “[n]either Chakrabarti nor Rubinstein discloses,
suggests, or teaches an olanzapine formulation that is in a tablet form and
does not have a layered structure” (App. Br. 18).
We are not persuaded. Appellants Specification defines “direct
compression” as “a process, wherein the various components of a tablet are
blended, optionally milled, sieved and then compressed into tablets” (Spec.
4). The Specification also teaches that the “active ingredient is evenly
distributed in a matrix formed by the other ingredients of the formulation.
The tablets do not have a layered structure” (Spec. 4).
Thus, when Chakrabarti and Rubenstein combine the same
components using the same “direct compression” process, the Examiner
reasonably finds that “the matrix is formed by the components in the
formulation” (Ans. 18). Further, since the same “direct compression”
process of tablet formation is taught by Rubenstein as that claimed, the result
must be identical and yield tablets which do not have layered structures. See
In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (“Where, as here, the claimed
and prior art products are identical or substantially identical, or are produced
by identical or substantially identical processes, the PTO can require an
applicant to prove that the prior art products do not necessarily or inherently
possess the characteristics of his claimed product.… Whether the rejection is
based on „inherency‟ under 35 U.S.C. § 102, on „prima facie obviousness'
under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the
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same, and its fairness is evidenced by the PTO‟s inability to manufacture
products or to obtain and compare prior art products.)
Conclusions of Law
(i) The evidence of record supports the Examiner‟s conclusion that
Chakrabarti and Rubenstein render obvious the uncoated formulation of
claims 34, 35, 50 and 51.
(ii) Appellants have not provided evidence of secondary
considerations that outweighs the evidence supporting a conclusion of
obviousness.
SUMMARY
In summary, we reverse the rejection of claims 34-51 under 35 U.S.C.
§ 103(a) as obvious over Morris and Nakajima.
We affirm the rejection of claims 34, 35, 50 and 51 under 35 U.S.C.
§ 103(a) as obvious over Chakrabarti and Rubinstein. Pursuant to 37
C.F.R. § 41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 36-
49, as these claims were not argued separately.

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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