Ex Parte Namburi et al

Board of Patent Appeals and Interferences

Aug 10, 2011

10617350 (B.P.A.I. Aug. 10, 2011)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
10/617,350 07/11/2003 Ranga R. Namburi 27493U 2736
90434 7590 08/11/2011
Glaxo Smith Kline
c/o The Nath Law Group
112 South West St.
Alexandria, VA 22314-2825
EXAMINER
ANDERSON, JAMES D
ART UNIT PAPER NUMBER
1629
MAIL DATE DELIVERY MODE
08/11/2011 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 RANGA R. NAMBURI, ALLEN L. LAWSON,
and JOHN E. KERR
__________

Appeal 2011-003678
Application 10/617,350
Technology Center 1600
__________

Before TONI R. SCHEINER, ERIC GRIMES, 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 method
of manufacturing a water-insoluble azole antifungal active agent oral dosage
form. The Examiner rejected the claims as anticipated and obvious, and for
obviousness-type double patenting. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm the rejections for anticipation and obviousness-type
double patenting.

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Statement of the Case
Background
The “invention provides a process of converting crystalline active
compounds into an amorphous state during coating or spray coating
of core particles” (Spec. 2, l. 32 to 3, l. 1). The Specification teaches “a
preparation containing an active compound or drug in amorphous state,
which allows water insoluble drugs (including poorly water soluble drugs) to
have a more rapid speed of dissolution and greater uptake efficiency in the
gastro-intestinal tract, and which preparation is convenient to produce as a
pharmaceutical formulation.” (Spec. 3, ll. 1-5).
The Claims
Claims 1-7, 15-20, 22, 23, and 42 are on appeal. Claims 1 and 23 are
representative and read as follows:
1. A method of manufacturing a water-insoluble
azole antifungal active agent-oral dosage form, said
method comprising the steps of:
providing a single phase working solution
comprising a water-insoluble azole antifungal active
agent, water, a water-soluble polymer and a solvent, said
solvent selected from the group consisting of alcohol,
acetone, and mixtures thereof;
providing core particles formed from a
pharmaceutically acceptable material;
combining said working solution with said
particles to produce water-insoluble azole antifungal
active agent-coated particles;
drying said water-insoluble azole antifungal active
agent-coated particles; and
forming said dried particles into an oral dosage
form;
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wherein said working solution is essentially free of
methylene chloride, and said oral dosage form is
essentially free of methylene chloride.

23. A pharmaceutically acceptable particle produced
by the process of claim 1.

The issues

A. The Examiner rejected claim 23 under 35 U.S.C. § 102(b) or 103(a) as
either anticipated or obvious over Gilis1 (Ans. 4-5).
B. The Examiner rejected claims 1-6, 15, 16, 18-20, 22, 23, and 42 under
35 U.S.C. § 103(a) as obvious over Gilis, Ishibashi,2 Lynenskjold,3 and
Nara4 (Ans. 5-9).
C. The Examiner rejected claim 7 under 35 U.S.C. § 103(a) as obvious
over Gilis, Ishibashi, Lynenskjold, Nara, and Vladyka5 (Ans. 9-10).
D. The Examiner rejected claim 17 under 35 U.S.C. § 103(a) as obvious
over Gilis, Ishibashi, Lynenskjold, Nara, and Martindale6 (Ans. 10).
E. The Examiner rejected claims 1-7, 15-20, 22, 23, and 42 on the
ground of nonstatutory obviousness-type double patenting as being
unpatentable over claims 1-17 of U.S. Patent No. 6,663,897 (Ans. 11).
A. U.S.C. § 102(b) or 103(a) over Gilis

1 Gilis et al., WO 00/03697 A1, published Jan. 27, 2000.
2 Ishibashi et al., US 2003/0012815 A1, published Jan. 16, 2003.
3 Lynenskjold et al., US 2003/0211168 A1, published Nov. 13,
2003.
4 Nara et al., US 6,245,351 B1, issued Jan. 12, 2001.
5 Vladyka, Jr. et al., US 6,497,905 B1, issued Dec. 24, 2002.
6 Sweetman, Sean, Martindale The complete drug reference 1344-
1349 (2002).
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The Examiner finds that Gilis teaches “pharmaceutically acceptable
particles comprising a water-insoluble azole antifungal agent and a water-
soluble polymer coated onto core particles” (Ans. 5). The Examiner finds
that Gilis teaches “residual dichloromethane content of less than 600 ppm,
preferably less than 250 ppm, which reasonably meets the limitation ‘.. said
oral dosage form is essentially free of methylene chloride’” (Ans. 5).
Appellants contend that as “shown at page 3, lines 24-31 of the instant
specification, by being ‘essentially free’ of methylene chloride, the particle
of claim 23 can contain less than 200, 100, 50, 20, or even 10 ppm
methylene chloride” (App. Br. 12). Appellants contend that “some residual
methylene chloride, then, will inherently remain in the product produced by
the Gilis et al. process” (App. Br. 13). Appellants contend that “Gilis et al.
does not provide any solution that would result in the reduction of methylene
chloride to the extent taught by Appellants, and does not provide a
reasonable expectation that it can be modified to eliminate methylene
chloride in the final product. (App. Br. 13). Appellants contend that “using
the microwave drying process disclosed by Gilis et al. could not achieve
greater reductions in methylene chloride levels (such as the ‘essentially free’
level required by the present claims, as described above) without burning or
degrading the product itself” (App. Br. 13).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Gilis renders obvious an antifungal
which “is essentially free of methylene chloride”?

Findings of Fact
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1. The Specification teaches that the
active agent oral dosage form and the single phase working
solution used in the process of making such dosage form are
preferably substantially free of residual methylene chloride
(e.g., contains less than 200 ppm methylene chloride, less
than 100 ppm methylene chloride, less than 50 ppm
methylene chloride, less than 20 ppm methylene chloride, or
even less than 10 ppm methylene chloride)

(Spec. 3, ll. 24-27).
2. Gilis teaches providing a single phase working solution where a
“stainless steel vessel (101) was charged with methylene chloride (4.722 kg)
and ethanol (3.147 kg) through a filter (5 µ). Itraconazole (300 g) and
hydroxypropyl methylcellulose 2910 5 mPa.s (450 g) were added while
stirring” (Gilis 14, ll. 30-34).
3. Gilis teaches that a “fluidized-bed granulator (Glatt, type WSG
1) equipped with a 6 inch Wurster (bottom spray) insert was loaded with
710-850 µm (20-25 mesh) sugar cores (575 g) . . . The itraconazole spraying
solution was then sprayed on the cores moving in the apparatus” (Gilis 15, ll.
5-11).
4. Gilis teaches that when “the spraying process was completed,
the coated cores were dried by further supplying dry air of 60°C for about 2
minutes” (Gilis 15, ll. 13-14).
5. Gilis teaches that in “order to reduce residual solvent levels, the
coated cores were then transferred to a vacuum processor (Gral 25) equipped
with a microwave generator (Collette) and irradiated during 1 hour at 25 kPa
and 1 to 1.2 kW. The pellets were stirred every three minutes so as to obtain
homogenous drying” (Gilis 15, ll. 20-24).
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6. Gilis teaches that the “drug coated pellets were filled into hard-
gelatin capsules (size 0) using standard automatic capsule filling machines”
(Gilis 15, ll. 37-38).
7. Gilis teaches that “[s]amples of the pellets dried following the
procedure of paragraph d) yielded the following data” where the conditions
before drying showed a dichloromethane concentration in ppm of 2,550,
while after 1 hour of drying, the dichloromethane concentration is <250
(Gilis 16, ll. 34-38).
8. Gilis teaches that “the concentration of dichloromethane in said
pellets is less than 600 ppm, preferably less than 300 ppm and most
preferably less than 250 ppm” (Gilis 4, ll. 31-32).
Principles of Law
“[A] prima facie case of obviousness exists when the claimed range
and the prior art range do not overlap but are close enough such that one
skilled in the art would have expected them to have the same properties.” In
re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003).
Analysis
Gilis teaches the oral dosage form of a particle where the particle
comprises a water-insoluble azole antifungal agent which is sprayed over
core particles and dried (FF 2-8). Gilis teaches particles where after 1 hour
of drying, the dichloromethane concentration is <250 (Gilis 16, ll. 34-38; FF
7).
We agree with Appellants that “by being ‘essentially free’ of
methylene chloride, the particle of claim 23 can contain less than 200, 100,
50, 20, or even 10 ppm methylene chloride” (App. Br. 12). We also agree
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that “some residual methylene chloride, then, will inherently remain in the
product produced by the Gilis et al. process” (App. Br. 13). We therefore
agree that Gilis does not anticipate.
We disagree, however, with Appellants’ contention that “Gilis et al.
does not provide any solution that would result in the reduction of methylene
chloride to the extent taught by Appellants, and does not provide a
reasonable expectation that it can be modified to eliminate methylene
chloride in the final product.” (App. Br. 13).
Gilis teaches that one hour of microwave drying reduces the level of
dichloromethane at least 10 fold, from 2,550 ppm to < 250 ppm (FF 7).
Gilis also teaches that it is desirable to have as low a level of
dichloromethane as possible, rendering the claimed range obvious (FF 8).
There is no requirement that the prior art must suggest the claimed range
“ipsissimus verbis,” but rather “where the general conditions of a claim are
disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456
(CCPA 1955). In this situation, there is no evidence that selection of the
desired range for a particle “essentially free” of dichloromethane requires
anything more than routine experimentation with microwave drying times
(FF 7).
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Appellants contend that “using the microwave drying process
disclosed by Gilis et al. could not achieve greater reductions in methylene
chloride levels (such as the ‘essentially free’ level required by the present
claims, as described above) without burning or degrading the product itself”
(App. Br. 13).
We are not persuaded. Appellants provide no evidence that the
additional amount of drying time, if any, required to reduce the levels of
dichloromethane in the Gilis product to below 200 ppm would require
burning or degrading the product (see App. Br. 13). See In re Pearson, 494
F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take
the place of evidence.”).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that Gilis
renders obvious an antifungal which “is essentially free of methylene
chloride”.
B. 35 U.S.C. § 103(a) over Gilis, Ishibashi, Lynenskjold, and Nara
The Examiner finds that “Gilis et al. differ from the claims only with
respect to the solvent used in the coating solution. Whereas Gilis et al. used
a solvent comprising a water-soluble polymer, methylene chloride, and an
alcohol, the instant claims recite a solvent comprising a water-soluble
polymer, water, and alcohol, acetone, or mixtures thereof” (Ans. 7). The
Examiner finds that Ishibashi teaches “that the solvent system should
dissolve both the hydrophobic organic compound and water-soluble
polymer” (Ans. 7). The Examiner finds that Lynenskjold teaches that the
“active drug substance will generally be applied to the spray-dried pellets in
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the form of a solution or dispersion in a physiologically tolerable solvent or
solvent mixture” (Ans. 8). The Examiner finds that Lynenskjold teaches
“Methylene chloride, as taught in Gilis et al. cited supra, may be used but is
generally not preferred” (Ans. 8). The Examiner finds that Nara teaches
“solvents for coating solutions may be water, an organic solvent, or mixtures
thereof” (Ans. 8).
The Examiner finds that the ordinary artisan “would immediately see
the benefit of using a coating solution that omits methylene chloride, such as
a coating solution comprising water, a water-soluble polymer, and a solvent
selected from an alcohol, acetone, and mixtures thereof as motivated by the
cited prior art” (Ans. 9).
Appellants contend that “Gilis et al. reference does not disclose a
working solution containing both the drug and water, as required by the
present claims” (App. Br. 15). Appellants contend that “[n]one of the
examples provided in the Lynenskjold et al. reference disclose the use of any
of these solvents with water” (App. Br. 16). Appellants contend that Nara
“is different from the presently claimed process, which requires both the
drug and the polymer in the same layer” (App. Br. 17).
Appellants contend that “[n]one of the references, taken alone or in
combination, contain all the elements of the presently pending claims in the
same working solution, and thus cannot render these claims obvious” (App.
Br. 17). Appellants contend that “the skilled artisan would have no
motivation to modify Gilis et al. or Ishibashi et al. to incorporate the solvent
system of Lynenskjold et al. or the solvent coating system of Nara et al”
(App. Br. 21).
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The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Gilis, Ishibashi, Lynenskjold, and
Nara render obvious the method of claim 1?
Findings of Fact
9. Ishibashi teaches that “the rate of the drug release can be
adjusted by increasing or decreasing the number of layers” (Ishibashi 6 ¶
0051).
10. Ishibashi teaches that “[t]here are no particular restrictions on
the solvent of the coating solution provided that it dissolves both the
hydrophobic organic compound and water-soluble polymer, examples of
which include alcohols . . . , hydrocarbons . . . , ketones . . . , halogenated
hydrocarbones . . . , esters . . . , and ethers” (Ishibashi 6 ¶ 0057).
11. Lynenskjold teaches “a process for the production of drug
carrier pellets comprising spay-drying a solution of a physiologically
tolerable cellulosic binder containing a physiologically tolerable inert
particulate carrier having a particle size D(v, 0.5) of less than 50 µm”
(Lynenskjold, abstract).
12. Lynenskjold teaches that the “active drug substance coated onto
or impregnated into the spray-dried pellets . . . may be any active drug
substance . . . Examples of such drug substances are . . . antifungals (e.g.
ketoconazole)” (Lynenskjold 4 ¶ 0046).
13. Lynenskjold teaches that “the use of aqueous solutions or
dispersions is preferred but organic solvents . . . may also be used.
Chlorinated hydrocarbons (such as methylene chloride) may be used but are
generally not preferred” (Lynenskjold 5 ¶ 0058).
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14. Nara teaches that the “solvent for the coating solution may be a
water, an organic solvent or a mixture thereof. The mixing ratio of water and
organic solvent (water/organic solvent, ratio by volume) may be varied
between 1 and 100%” (Nara, col. 6, ll. 34-37).
15. Nara teaches that the “surface of the resulting core may be
coated with a protecting agent in order to separate the drug from the coating
composition” (Nara, col. 6, ll. 1-3).

Principles of Law
“[R]ejections 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 lnc., 550 U.S. 398, 418 (2007).
Analysis
The Examiner finds that “the only difference between the Gilis et al.
reference and the claimed invention is the solvent system used to coat the
core particles” (Ans. 14).
While this is correct, we agree with Appellants that none of the cited
references teach the formation of a single phase working solution which
comprises the water-soluble azole antifungal agent, water, a water-soluble
polymer and an alcohol or acetone solvent.
The Examiner finds that it “would take no more than routine
experimentation to test different solvent systems for coating core particles
with a water-insoluble antifungal agent and water-soluble polymer” (Ans.
15).
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We are not persuaded. We agree with Appellants that “the skilled
artisan would have no motivation to modify Gilis et al. or Ishibashi et al. to
incorporate the solvent system of Lynenskjold et al. or the solvent coating
system of Nara et al” (App. Br. 21). That is, the Examiner has not provided
any reason why the ordinary artisan would choose to incorporate water into
the organic solvent system of Gilis (FF 2). For example, while Ishibashi
teaches the use of an organic solvent, the choice is based upon the need to
spray coat a hydrophobic organic compound (FF 10) and the Examiner does
not identify any teaching to incorporate water into the spraying solution of
Ishibashi (see Ans. 7-8). Similarly, while Lynenskjold teaches both
aqueous and organic solvents (FF 13), Lynenskjold provides no teaching to
mix aqueous and organic solvents.
The only teaching which even suggests mixing the aqueous and
organic solvents is Nara, who teaches that the “solvent for the coating
solution may be a water, an organic solvent or a mixture thereof” (Nara, col.
6, ll. 34-35; FF 14). However, Nara is drawn to a significantly different
process, where the active drug is found in the core, and the “core may be
coated with a protecting agent in order to separate the drug from the coating
composition” (Nara, col. 6, ll. 1-3; FF 15). Thus, Nara suggests a solvent
system in which the drug is not present in the coating, a situation unlike that
of Gilis.
We therefore agree with Appellants that “a prima facie case of
obviousness has not been established because the skilled artisan would have
no motivation to modify Gilis et al. or Ishibashi et al. to incorporate the
solvent system of Lynenskjold et al. or the solvent coating system of Nara et
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al.” (App. Br. 21). In particular, the Examiner does not provide any
articulated reasoning which explains what benefit, reason, advantage,
equivalence, or other rationale would be served by the addition of water to
the solvent system of Gilis. Simply identifying other systems that exist does
not address this concern.

Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that Gilis, Ishibashi, Lynenskjold, and Nara render obvious the method of
claim 1.
C. 35 U.S.C. § 103(a) over Gilis, Ishibashi, Lynenskjold, Nara, and
Vladyka
Having reversed the obviousness rejection over Gilis, Ishibashi,
Lynenskjold, and Nara for the absence of a reason to incorporate water into
the solvent system of Gilis, we necessarily reverse the obviousness rejection
further including Vladyka since Vladyka does not address the deficiency of
the rejection upon which it depends.
D. 35 U.S.C. § 103(a) over Gilis, Ishibashi, Lynenskjold, Nara, and
Martindale
Having reversed the obviousness rejection over Gilis, Ishibashi,
Lynenskjold, and Nara for the absence of a reason to incorporate water into
the solvent system of Gilis, we necessarily reverse the obviousness rejection
further including Martindale since Martindale does not address the
deficiency of the rejection upon which it depends.

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E. Double patenting
We summarily affirm the obviousness-type double patenting
rejections. See Manual of Patent Examining Procedure § 1205.02 (“If a
ground of rejection stated by the examiner is not addressed in the appellant's
brief, that ground of rejection will be summarily sustained by the Board.”);
See also In re Berger, 279 F.3d 975, 984 (Fed. Cir. 2002) (in which the
Board affirmed an uncontested rejection of claims under 35 U.S.C. 112,
second paragraph, and on appeal the Federal Circuit affirmed the Board's
decision and found that the appellant had waived his right to contest the
indefiniteness rejection by not presenting arguments as to error in the
rejection on appeal to the Board).
SUMMARY
In summary, we affirm the rejection of claim 23 under 35 U.S.C. §
103(a) as obvious over Gilis.
We reverse the rejection of claims 1-6, 15, 16, 18-20, 22, 23, and 42
under 35 U.S.C. § 103(a) as obvious over Gilis, Ishibashi, Lynenskjold, and
Nara.
We reverse the rejection of claim 7 under 35 U.S.C. § 103(a) as
obvious over Gilis, Ishibashi, Lynenskjold, Nara, and Vladyka.
We reverse the rejection of claim 17 under 35 U.S.C. § 103(a) as
obvious over Gilis, Ishibashi, Lynenskjold, Nara, and Martindale.
We affirm the rejection of claims 1-7, 15-20, 22, 23, and 42 on the
ground of nonstatutory obviousness-type double patenting as being
unpatentable over claims 1-17 of U.S. Patent No. 6,663,897.
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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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