Ex Parte Chow et al

Patent Trial and Appeal Board

Apr 17, 2017

12220364 (P.T.A.B. Apr. 17, 2017)

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.
12/220,364 07/24/2008 Diana Shu-Lian Chow D6810CIP2 6889
7590
Benjamin Aaron Adler
ADLER & ASSOCIATES
8011 Candle Lane
Houston, TX 77071
EXAMINER
ANDERSON, JAMES D
ART UNIT PAPER NUMBER
1629
MAIL DATE DELIVERY MODE
04/17/2017 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 DIANA SHU-LIAN CHOW,
PRANAV GUPTA, YULAN QI, JAYMIN SHAH,
and PETER WISNIECKI
Appeal 2016-001979
Application 12/220,3641
Technology Center 1600
Before FRANCISCO C. PRATS, TAWEN CHANG, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims to a
nano suspension formulation for improving the bioavailability of a
benzimidazole derivative in lung tissue. The Examiner rejected the claims
for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The following rejections are before us for review:
1 Appellants identify The University of Houston System as the real party in
interest. Br. 3.
Appeal 2016-001979
Application 12/220,364
(1) Claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as
unpatentable over Van Den Bossche,2 Shah,3 and Deschamps4 (Ans.
3—13); and
(2) Claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as
unpatentable over Van Den Bossche, Kipp,5 and Deschamps (Ans.
13-24).
Claim 1 is representative and reads as follows (App. Br. A-l, A-2):
Claim 1: A nanosuspension formulation for
improving the bioavailability of a benzimidazole
derivative in lung tissue, comprising:
a) a benzimidazole derivative having the formula:
wherein R1 is OH, Cl, SH, carbamate, or piperidin-
4-yl;
R2 is hydrogen, a-methylvinyl, 3-chloropropyl or
piperidin-4-yl;
R3 is selected from the group consisting of
hydrogen, carboxyl (-CO2H), hydroxyl, amino, chloro,
difluormethoxy, benzoyl, phenyl-thio, pyridinyl, propyl-
thio, diphenyl, 5-methoxy, fluorophenylmethyl-2-chloro,
propenyl, chloropropyl, and esters (CO2R4);
2 Hugo Van Den Bossche et al., Mebendazole and Related Anthelmintics, 19
Adv. Pharmacol. Chemother. 67—128 (1982).
3 WO 2006/109177 Al (published Oct. 19, 2006).
4 WO 2007/144362 Al (published Dec. 21, 2007).
5 US 6,884,436 B2 (issued Apr. 26, 2005).
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Application 12/220,364
R4 is selected from the group consisting of alkoxy,
haloalkyl, alkenyl, and cycloalkyl, wherein the alkyl
groups have from 1 to 8 carbons, or the alkyl groups are
CH3CH2(OCH2CH2)n-, or CHsCHsCHsCOCHsCHsCHsjn-,
or (CH3)2CH(OCH(CH3)CH2)n-, wherein n is from 1— 3 [,]
or the pharmaceutically effective organic or
inorganic salts thereof, or mixtures thereof:
b) a block copolymer; and
c) a surfactant;
wherein particle size of the benzimidazole
derivative within the nanosuspension is configured as
about 167 nm, about 400 nm, about 700 nm, or about
1700 nm to manipulate the release rate and
bioavailability of the benzimidazole derivative in the
lung tissue.
OBVIOUSNESS-
VAN DEN BOSSCHE, SHAH, AND DESCHAMPS
The Examiner’s Prima Facie Case
The Examiner’s position, essentially, is that Shah teaches or suggests
a nanosuspension-type composition having all of the features of the
formulations recited in claims 1, 6—8, 10, and 15—19, “except for the claimed
benzimidazoles (e.g. mebendazole).” Ans. 12.
The Examiner finds, however, based on the teachings of Van Den
Bossche, that an ordinary artisan would have recognized that mebendazole
was “a compound that meets all of the requirements disclosed in Shah et al.
for a compound that would benefit from formulation in the nanosuspensions
disclosed [in Shah].” Id. The Examiner cited Deschamps as further
evidence of the suitability of including benzimidazoles in nanosuspensions
that contain surfactants encompassed by the rejected claims. See id.
Based on the references’ combined teachings, the Examiner concludes
that “[tjaking a well-known water-insoluble, poorly bioavailable compound
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Application 12/220,364
such as mebendazole and applying a well-known method of increasing the
water solubility and bioavailability of water-insoluble, poorly bioavailable
compounds, i.e., formulation in a nanosuspension, would have been prima
facie obvious to one of ordinary skill in the art.” Ans. 13.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
Appellants do not persuade us that the Examiner’s conclusion of
obviousness is not supported by a preponderance of the evidence. To the
contrary, we adopt as our own the Examiner’s findings as to the scope and
content of the prior art, the Examiner’s reasoning as to how and why an
ordinary artisan would have combined the cited teachings of the references,
and the Examiner’s conclusion, summarized above, that representative claim
1 would have been prima facie obvious over the cited combination of
references. We provide the discussion below for emphasis.
Representative claim 1 recites a nanosuspension formulation for
improving the bioavailability of a benzimidazole derivative in lung tissue,
the formulation containing three ingredients: (a) a benzimidazole derivative
having a formula that encompasses the compound mebendazole, (b) a block
copolymer, and (c) a surfactant. Br. 16—17.
Claim 1 requires the particle size of the benzimidazole derivative
within the nanosuspension to be either about 167 nm, about 400 nm, about
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Application 12/220,364
700 nm, or about 1700 nm, to manipulate the release rate and bioavailability
of the benzimidazole derivative in the lung tissue. Br. 17.
Turning to the prior art, Shah discloses a formulation composed of
“(1) a low solubility drug or pharmaceutically acceptable salt thereof; (2) a
pharmaceutically acceptable carrier; and (3) at least two surface stabilizers.”
Shah, 3:22-23.
As required by Appellants’ claim 1, one of Shah’s surface stabilizers
may be a block copolymer surfactant, such as “Pluronic FI08®.” Id. at
10:2. As also required by Appellants’ claim 1, Shah’s second surface
stabilizer may be another surfactant, such as “Tween® 80,” which is
combined with the Pluronic FI08 block copolymer. Id. at 17:3—5; see also
id. at 27:30-28:26 (Shah’s Examples 6—8 using a combination of Pluronic
FI08 (block copolymer) and Tween 80 (surfactant)).
As to the particle size requirement of Appellants’ claim 1, Shah
discloses that the average particle size of the low solubility compound in its
formulations should be less than about 2000 nm (id. at 12:33—36), and more
particularly discloses that suitable average particle sizes can be less than
about 1500 nm, less than about 1000 nm, less than about 500 nm, and even
more particularly in a range from about 120 nm to about 400 nm. Id. at
14:12-19.
Shah, thus, differs from representative claim 1 only in that Shah does
not expressly include a benzimidazole, such as mebendazole, in its
formulations. Nonetheless, Shah broadly discloses that it is advantageous to
include a wide variety of drugs having low water solubility in its
compositions:
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Application 12/220,364
The compound may be a pharmaceutical, including, without
limitation, biologies such as proteins, peptides and nucleic acids
or a diagnostic, including, without limitation, contrast agents.
In one embodiment, the compound . . . has low water solubility.
In another embodiment, the logP of the compound is at least
about 3 or greater. . . .
A compound having “low water solubility” refers to any
compound having a solubility in water, measured at 37°C, not
greater than about 10 mg/ml. In another embodiment, the
measured solubility is not greater than about 1 mg/ml. In
another embodiment, the measured solubility is not greater than
about 0.1 mg/ml. A synonymous term is “low aqueous
solubility.”
Exemplary compounds include, without limitation,
compounds from the following classes: . . . anthelminthics ....
Shah, 5:3—7:32 (emphasis added).
As the Examiner finds, Van Den Bossche discloses that mebendazole,
a known anthelminthic, “is almost insoluble in water” and has a logP of 3.1.
Van Den Bossche, 76.
Thus, given the breadth of compounds taught in Shah as being
desirable for inclusion in its formulations, and further given that
mebendazole was known in the art to be an anthelminthic meeting the low
water solubility and logP value suitability criteria for use in Shah’s
formulations, we agree with the Examiner that an ordinary artisan had ample
reason for, and a reasonable expectation of success in, including
mebendazole in Shah’s formulations, thus yielding the formulation required
by Appellants’ claim 1. To that end, we note that Deschamps provides
further evidence of the suitability of including mebendazole in surfactant-
containing nanoparticulate emulsion formulations, similar to those taught in
Shah. See, e.g., Deschamps Abstract (disclosing “a pharmaceutical
composition for drinking water administration comprising benzimidazole
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Application 12/220,364
carbamate particles having an effective average particle size of less than 450
nm and a Tween-type surfactant”); id. 149 (well known benzimidazole
carbamates include mebendazole).
Turning to Appellants’ arguments, we are not persuaded that
ziprasidone is “the only drug taught by Shah.” Br. 7. Nor are we persuaded
that, because of the asserted differences in solubility between ziprasidone
and mebendazole, an ordinary artisan lacked motivation to incorporate
mebendazole, a benzimidazole encompassed by claim 1, into Shah’s
formulations. See id. at 7—8.
It might be true that ziprasidone is the only drug compound used in
Shah’s examples. It is well settled, however, that “[a]ll the disclosures in a
reference must be evaluated, including nonpreferred embodiments, and a
reference is not limited to the disclosure of specific working examples.” In
re Mills, 470 F.2d 649, 651 (CCPA 1972) (citations omitted).
In the present case, as noted above, Shah broadly discloses that a wide
variety of different compounds are useful in its compositions. See Shah,
5:3—7:32 (quoted above). As also noted above, moreover, Van Den Bossche
discloses that mebendazole meets a number of the criteria outlined in Shah
for suitability for inclusion in its formulations, including low water
solubility, a logP value over 3, and its recognition in the art as an
anthelminthic. See Van Den Bossche, 76. Given these teachings, we are not
persuaded that an ordinary artisan lacked an adequate reason for, or a
reasonable expectation of success in, including mebendazole in Shah’s
formulations. Moreover, because the reason for including mebendazole in
Shah’s formulations would have been derived from the prior art, we are not
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persuaded that the Examiner’s rejection of claim 1 is based on improper
hindsight.
As to Appellants’ contentions regarding pages 2 and 123 of the Liu
reference6 (Br. 8—9), we acknowledge the disclosure in Liu that a “water-
insoluble drug” can encompass a variety of solubility ranges. See Liu, 2.
We acknowledge also Liu’s disclosure that the “nanosuspension technique
usually does not work well for basic compounds with high pH-dependent
solubility.” Id. at 123. We acknowledge further Liu’s disclosure that
nanosuspensions can experience problems, such as precipitation and
agglomeration, and that not all compounds can form nanosuspensions. Id.
Appellants do not, however, advance specific evidence showing that
mebendazole is a basic compound with high pH-dependent solubility. Nor
do Appellants explain adequately why Liu’s definition of a water-insoluble
drug would have led an ordinary artisan to ignore Shah’s teachings about the
suitability of including drugs with low water solubility in its formulations.
Although it might be true that an ordinary artisan knew that not all
compounds were amenable to Shah’s nanosuspension technique, it is well
settled that “[ojbviousness does not require absolute predictability of
success. . . . Lor obviousness under § 103, all that is required is a reasonable
expectation of success.” In re Kubin, 561 L.3d 1351, 1360 (Led. Cir. 2009)
(quoting In re O’Farrell, 853 L.2d 894, 903-04 (Led. Cir. 1988) (emphasis
removed). In the present case, given the wide variety of different
compounds taught by Shah as being desirable for inclusion in its
formulations, we are not persuaded that an ordinary artisan lacked a
6 Water-Insoluble Drug formulation (Rong Liu ed., 2008).
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Application 12/220,364
reasonable expectation that mebendazole also would have been
advantageously included in Shah’s formulations.
In sum, for the reasons discussed, Appellants do not persuade us that
the Examiner failed to make out a prima facie case of obviousness as to
representative claim 1. Because Appellants do not advance specific
secondary evidence of nonobviousness, a preponderance of the evidence
supports the Examiner’s conclusion that the formulation recited in claim 1
would have been obvious to an ordinary artisan in view of Van Den
Bossche, Shah, and Deschamps. We, therefore, affirm the Examiner’s
rejection of claim 1 over those references. Claims 6—8, 10, and 15—19 fall
with claim 1 because they were not argued separately. See 37 C.F.R.
§ 41.37(c)(l)(iv).
OBVIOUSNESS-
VAN DEN BOSSCHE, KIPP, AND DESCHAMPS
The Examiner’s Prima Facie Case
As to this rejection, the Examiner’s position, essentially, is that Kipp
teaches or suggests a nanosuspension-type composition having all of the
features of the formulations recited in claims 1, 6—8, 10, and 15—19, “except
for the claimed benzimidazoles (e.g. mebendazole).” Ans. 23.
The Examiner finds, however, based on the teachings of Van Den
Bossche, that an ordinary artisan would have recognized that mebendazole
was “a compound that meets all of the requirements disclosed in Kipp et al.
for a compound that would benefit from formulation in the nanosuspensions
disclosed [in Kipp].” Id. The Examiner cited Deschamps as further
evidence of the suitability of including benzimidazoles in nanosuspensions
that contain surfactants encompassed by the rejected claims. See id. at 23—
24.
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Application 12/220,364
Based on the references’ combined teachings, the Examiner concludes
that “[tjaking a well-known water-insoluble, poorly bioavailable compound
such as mebendazole and applying a well-known method of increasing the
water solubility and bioavailability of water-insoluble, poorly bioavailable
compounds, i.e., formulation in a nanosuspension, would have been prima
facie obvious to one of ordinary skill in the art.” Ans. 24.
Analysis
Appellants do not persuade us that a preponderance of the evidence
fails to support the Examiner’s conclusion that claim 1 would have been
obvious in view of Van Den Bossche, Kipp, and Deschamps. To the
contrary, we adopt as our own the Examiner’s findings as to the scope and
content of the prior art, the Examiner’s reasoning as to how and why an
ordinary artisan would have combined the cited teachings of the references,
and the Examiner’s conclusion, summarized above, that representative claim
1 would have been prima facie obvious over the cited combination of
references. We provide the discussion below for emphasis.
Similar to Shah, Kipp is directed to addressing difficulties involved in
administering drugs with low water solubility. See Kipp, 1:30-36. To
address those difficulties, Kipp dissolves the drug in a first solvent, then
adds a second solvent to make a “pre-suspension,” and then “add[s] energy
to the pre-suspension to form particles having an average effective particle
size of less than about 2 pm [2000 nm].” Id. at 3:54—56. As is evident, the
particle size range taught in Kipp encompasses the particle sizes recited in
claim 1.
As required by claim 1, Kipp discloses that the second solution it
forms can contain one or more surfactants, one of which can be a block
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copolymer. Id. at 8:1—44; see also id. at 14:8—16:60 (Examples 1—4 using
combination of block copolymer (Pluronic F-68) and surfactant (sodium
deoxycholate)).
Also similar to Shah, Kipp broadly discloses that a wide variety of
drugs are amenable to inclusion in its formulations:
It should be understood . . . that the process conditions such as
choice of surfactants or combination of surfactants, amount of
surfactant used, temperature of reaction, rate of mixing of
solutions, rate of precipitation and the like can be selected to
allow for any drug to be processed under any one of the
categories discussed next. . . .
An organic compound for use in the process of this
invention is any organic chemical entity whose solubility
decreases from one solvent to another. This organic compound
might be a pharmaceutically active compound from various
groups such as, but not limited to: . . . antimicrobials ....
Kipp 7:8—23; see also id. at 14:8—26:41 (Kipp’s Examples using four
different drug compounds (itraconazole, carbamazepine, prednisolone,
nabumetone)).
Thus, given the breadth of compounds taught in Kipp as being
desirable for inclusion in its formulations, and further given that
mebendazole was known in the art to be an antimicrobial with low water
solubility and, thus, desirably included in Kipp’s formulations, we agree
with the Examiner that an ordinary artisan had ample reason for, and a
reasonable expectation of success in, including mebendazole in Kipp’s
formulations, thereby yielding the formulation required by Appellants’ claim
1. To that end, we note again that Deschamps provides further evidence of
the suitability of including mebendazole in surfactant-containing
nanoparticulate emulsion formulations, similar to those taught in Kipp. See,
e.g., Deschamps, abstract (disclosing “a pharmaceutical composition for
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drinking water administration comprising benzimidazole carbamate particles
having an effective average particle size of less than 450 nm and a Tween-
type surfactant”); id. 149 (well known benzimidazole carbamates include
mebendazole).
Appellants’ arguments, similar to those directed to the rejection
discussed above, do not persuade us that the evidence of record fails to
support the Examiner’s prima facie case of obviousness.
As to Appellants’ contention that Kipp fails to teach or suggest the
concentrations of block copolymer and surfactant required in the claims (Br.
12), we note that representative claim 1 does not recite specific
concentrations as to those ingredients, see Br. 16—17, and Appellants do not
argue any of the remaining claims separately. See Br. generally.
As to Appellants’ contention that Kipp’s four exemplified compounds
differ in structure from mebendazole (Br. 12—14), as discussed above, a prior
art reference is not limited to the teachings in its working examples. See In
re Mills, 470 F.2d at 651. Given the breadth of Kipp’s disclosure as to
compounds useful in its compositions, and further given Kipp’s
exemplification of four compounds of varying structure, we are not
persuaded that the Examiner erred in finding that an ordinary artisan had a
good reason for, and a reasonable expectation of success in, including
mebendazole in Kipp’s formulations.
Lastly, as to Appellants’ assertion that an ordinary artisan would have
understood from Liu that mebendazole would not work in nanosuspensions
of the type described in Liu (Br. 13—14 (citing Liu, 123)), we again note that
Appellants have not advanced specific evidence showing that mebendazole
is a basic compound with high pH-dependent solubility, the type of
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compound taught in Liu as not being amenable to formulation in
nanosuspensions. As noted above, moreover, “[ojbviousness does not
require absolute predictability of success. .. . For obviousness under § 103,
all that is required is a reasonable expectation of success.” In re Kubin, 561
F.3d at 1360. Given the wide variety of different compounds taught by Kipp
as being desirable for inclusion in its formulations, we are not persuaded that
an ordinary artisan lacked a reasonable expectation that mebendazole would
have been advantageously included in Shah’s formulations.
In sum, for the reasons discussed, Appellants do not persuade us that
the Examiner failed to make out a prima facie case of obviousness as to
representative claim 1. Because Appellants do not advance specific
secondary evidence of nonobviousness, a preponderance of the evidence
supports the Examiner’s conclusion that the formulation recited in claim 1
would have been obvious to an ordinary artisan in view of Van Den
Bossche, Kipp, and Deschamps. We, therefore, affirm the Examiner’s
rejection of claim 1 over those references. Claims 6—8, 10, and 15—19 fall
with claim 1 because they were not argued separately. See 37 C.F.R.
§ 41.37(c)(l)(iv).
SUMMARY
For the reasons discussed, we affirm the Examiner’s rejection of
claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as unpatentable over
Van Den Bossche, Shah, and Deschamps.
For the reasons discussed, we also affirm the Examiner’s rejection of
claims 1, 6—8, 10, and 15—19, under 35 U.S.C. § 103(a), as unpatentable over
Van Den Bossche, Kipp, and Deschamps.
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TIME PERIOD
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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