Ex Parte Miller et al

Patent Trial and Appeal Board

Jun 22, 2016

12746754 (P.T.A.B. Jun. 22, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
121746,754 07/30/2010 Warren Kenyon Miller
24197 7590 06/24/2016
KLARQUIST SPARKMAN, LLP
121 SW SALMON STREET
SUITE 1600
PORTLAND, OR 97204
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
8191-92856-01 1154
EXAMINER
SASAN, ARADHANA
ART UNIT PAPER NUMBER
1615
NOTIFICATION DATE DELIVERY MODE
06/24/2016 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
tanya.harding@klarquist.com
docketing@klarquist.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte WARREN KENYON MILLER, DANIEL SMITHEY,
BENJAMIN LEE FRANKAMP, and RALPH TADDAY 1
Appeal2014-003478
Application 12/746,754
Technology Center 1600
Before ERIC B. GRIMES, JOHN G. NEW, and
JACQUELINE T. HARLOW, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 1-3 and 5-17. 2 Specifically, claims
1-3, 5-7, and 11-16 stand rejected as unpatentable under 35 U.S.C. § 103(a)
as being obvious over Ahmed et al. (US 2007/0190129 Al, August 16,
2007) ("Ahmed").
1 Appellants state the real party-in-interest is Bend Research, Inc. App. Br. 1.
2 Claims 4 and 21 have been canceled. Claims 18-20 have been withdrawn.
App. Br. 1.
Appeal2014-003478
Application 12/746,754
Claims 8-9 and 17 stand rejected as unpatentable under 35 U.S.C.
§ 103 (a) as being obvious over the combination of Ahmed and Khanna et al.
(US 4,857,336, August 15, 1989) ("Khanna").
Claim 10 stands rejected as unpatentable under 35 U.S.C. §103(a) as
being obvious over the combination of Ahmed and Anderson et al. (US
5,508,276, April 16, 1996) ("Anderson").
We have jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to a pharmaceutical composition
comprising nanoparticles comprising a poorly water-soluble drug and a
poorly aqueous soluble polymer, and a resuspending material selected from
the group consisting of hydroxypropyl methyl cellulose acetate succinate,
carboxymethyl ethylcellulose, and pharmaceutically acceptable salt forms
thereof. Abstract.
REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal, and recites:
1. A solid pharmaceutical composition comprising:
(a) nanoparticles comprising a poorly water soluble
drug and a poorly aqueous soluble polymer, wherein
(i) said poorly water soluble drug has a
solubility in water of less than 5 mg/ml over the pH range
of 6.5 to 7.5;
(ii) at least 90 wt% of said drug in said
nanoparticles is in a non-crystalline form; and
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(iii) said nanoparticles have an average size of
less than 500 nm; and
(b) a resuspending material selected from the group
consisting of hydroxypropyl methyl cellulose acetate succinate,
carboxymethyl ethylcellulose, and pharmaceutically acceptable
salt forms thereof;
wherein said resuspending material constitutes from 5 wt% to 90
wt% of the combined mass of (1) said resuspending material and
(2) said nanoparticles, and wherein said composition comprises
particles comprising both said nanoparticles and said
resuspending material.
App. Br. 13.
ISSUES AND ANALYSES
We agree with, and adopt, the Examiner's findings and conclusion
that the appealed claims are prima facie obvious over the cited prior art
references. We address the arguments raised by Appellants below.
A. Claims 1-3, 5-7, and 11-16
Issue 1
Appellants argue the Examiner erred in finding that Ahmed teaches
the resuspension recited in claim 1.
Analysis
Appellants dispute the Examiner's conclusion that "it would have
been obvious to one of ordinary skill in the art ... to ... suspend or resuspend
the nanoparticles in a material such as HPMCAS [hydroxypropyl methyl
cellulose acetate succinate ], [ ... ] as suggested by Ahmed" and that "[ o ]ne of
ordinary skill in the art would have been motivated to do this because
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Application 12/746,754
Ahmed ... teach[ es] the mixing of active ingredient with the polymer
solution and then suspending in HPMCAS." App. Br. 3 (quoting Final Act.
4). Appellants point out that paragraph [0208] of Ahmed, cited by the
Examiner, goes on to explain that the suspension of the drug crystals in the
HPMCAS solution was pumped to a spray drier to coat the crystals. Id. at 4.
Appellants therefore contend there is no HPMCAS suspension in the final
product. Id.
Appellants also argue the starting drug crystals in the embodiment
described in paragraphs [0207]-[0208] of Ahmed have a mean particle size
of "about 10 µm," and that the final coated particle diameter is 4 2 µm. Id.
(citing Ahmed, Table in i-f 208). Appellants argue these particle sizes are
distinguishable from the nanoparticle size recited in claim 1 of "less than
5 00 nm." Id.
The Examiner responds that Ahmed explicitly teaches resuspending
materials such as HPMCAS and carboxymethyl ethyl cellulose ("CMEC")
and suspending ziprasidone in HPMCAS. Ans. 33 (citing Ahmed i-fi-194, 97-
100, 207). The Examiner finds Ahmed also teaches that excellent absorption
of ziprasidone is achieved by delivering the drug along with HPMCAS. Id.
(citing Ahmed i-f 100). The Examiner points out that the claims on appeal
are drawn to a solid pharmaceutical composition and not a suspension. Id.
The Examiner further finds Ahmed teaches the suspension is spray dried in
paragraph [0208], which leads to the formation of a solid pharmaceutical
composition, and which meets the limitation of the solid pharmaceutical
3 The Examiner's Answer lacks page numbers. We therefore designate page
numbers seriatim, with the cover sheet of the Answer serving as "page 1."
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composition comprising particles "comprising both said nanoparticles and
said resuspending material" as recited in claim 1.
With respect to particle size, the Examiner finds Ahmed teaches
nanoparticles having an average particle size of less than 500 nm. Ans. 4
(citing Ahmed i-f 41 ). The Examiner finds Ahmed teaches that one method
of preparing nanoparticles of the drug comprises suspending ziprasidone in a
liquid dispersion medium and applying mechanical means in the presence of
grinding media to reduce the particle size of the drug substance to the
effective average particle size. Id.
We are not persuaded by Appellants' arguments. In describing the
exemplary formation of ziprasidone crystals coated with precipitation-
inhibiting polymers (i.e., HPMCAS or CMEC), Ahmed teaches:
Ziprasidone coated crystals comprising 35% active
ziprasidone hydrochloride monohydrate coated with the
precipitation-inhibiting polymer HPMCAS, were prepared as
follows. A spray suspension was first formed by dissolving
HPMCAS-H (AQOAT H grade, available from Shin Etsu,
Tokyo Japan) in acetone in a container equipped with a top-
mounted mixer. Crystalline particles of ziprasidone
hydrochloride monohydrate, having a mean particle size of about
10 µm, were then added to the polymer solution and mixing
continued with a top-mounted mixer.
Ahmed i-f 207 (emphasis added). Appellants point out that the subsequent
paragraph of Ahmed teaches:
The suspension was then pumped using a high pressure
pump to a spray drier (a Niro type XP Portable Spray-Dryer with
a Liquid-Feed Process Vessel ("PSD-1")), equipped with a
pressure nozzle (Spraying Systems Pressure Nozzle and Body-
SK 74-20). The PSD-1 was equipped with a 5-foot 9-inch
chamber extension. The chamber extension was added to the
spray dryer to increase the vertical length of the dryer.
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Ahmed il 208. Appellants contend that because, "the suspension of the drug
crystals in the HPMCAS solution was pumped to a spray drier to coat the
crystals," there is no HPMCAS suspension in the final product.
We are not persuaded. We see nothing in the teachings of Ahmed
cited above, or in the succeeding paragraphs to indicate that the HPMCAS is
removed from the particles of the poorly water-soluble drug (Ziprasidone ).
On the contrary, Ahmed explicitly teaches that the drug particles are coated
with HPMCAS (it is the acetone that is removed by the drying process).
Moreover, because Appellants do not explicitly define the claim term
"suspension" in their Specification, we employ the broadest reasonable
definition consistent with the Specification. See In re ICON Health &
Fitness, Inc., 496 F.3d 1374, 1379 (Fed. Cir. 2007). We find that drug
particles coated with (i.e., suspended in) the poorly water-soluble polymer
meets a broadly reasonable definition of the claim term "resuspension."
This is consistent with the disclosures of Appellants' Specification, which
recites:
The use of HPMCAS or CMEC as the resuspending
material has the advantage that after nanoparticles are formed,
the nanoparticles retain their size during processing, so that they
may be formulated into dry, solid compositions. In addition,
upon administration of the dry, solid pharmaceutical
compositions to an aqueous environment, such as the
gastrointestinal tract, the resuspending material rapidly dissolves
in a neutral pH.
Spec. 3.
We agree with the Examiner that the teaching of Ahmed concerning
formation of the polymer-coated drug (i.e., the resuspension) would teach or
suggest to a person of ordinary skill the composition recited in claim 1.
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With respect to particle size, we also agree with the Examiner that
Ahmed teaches:
In another embodiment, the ziprasidone may be in the form of
nanoparticles. The term "nanoparticle" refers to ziprasidone in
the form of particles generally having an effective average
crystal size of less than about 500 nm, more preferably less than
about 250 nm and even more preferably less than about 100 nm.
Examples of such nanoparticles are further described in U.S. Pat.
No. 5,145,684, herein incorporated by reference.
Ahmed i-f 41. Ahmed thus teaches nanoparticles of the poorly water-soluble-
drug, corresponding to the size range recited in the claims, as an
embodiment of its invention, and we agree with the Examiner's conclusion
that it would be obvious to a person of ordinary skill to incorporate such
nanoparticles into other aspects of the teachings of Ahmed.
Issue 2
Appellants argue the Examiner erred in finding Ahmed teaches or
suggests the limitation of claim 1 reciting "at least 90 wt% of said drug in
said nanoparticles is in a non-crystalline form." App. Br. 4.
Analysis
Appellants argue paragraph [0207] of Ahmed, cited supra by the
Examiner, also teaches coating crystals of drug with HPMCAS. Appellants
point to limitation (a )(ii) of claim 1, which requires that at least 90 wt% of
the drug in the nanoparticles is in a noncrystalline form. App. Br. 4.
Appellants admit Ahmed teaches the drug ziprasidone may be in crystalline
or amorphous form in paragraph [0036], however Appellants assert that
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paragraph also states that the crystalline form is preferred, and that a
preferred amorphous form is a co-lyophile of the drug and cyclodextrin. Id.
Appellants contend that, in light of these teachings of Ahmed, a person of
ordinary skill desiring an amorphous form of the drug would have made a
co-lyophile of ziprasidone and cyclodextrin, rather than forming
nanoparticles with ziprasidone and a poorly aqueous soluble polymer in
which at least 90 wt% of the drug is in a non-crystalline state, as recited in
claim 1. Id.
The Examiner finds Ahmed would guide a person of ordinary skill in
the art towards the amorphous form since Ahmed teaches the amorphous
form improves solubility. Ans. 4 (citing Ahmed i-f 111 ). The Examiner
further finds Ahmed teaches delivering an improved-solubility form of
ziprasidone yields excellent biological absorption of ziprasidone. Id. (citing
Ahmed i-f 100). Therefore, the Examiner concludes, a person of ordinary
skill in the art would be motivated to use the amorphous, non-crystalline,
form of the drug. Id.
We agree with the Examiner. Ahmed teaches:
In one preferred embodiment, the combination comprises
particles of the solubility-improved form of ziprasidone coated
with a precipitation-inhibiting polymer. The particles may be
either ziprasidone crystals, or particles of some other solubility-
improved form such as amorphous drug or a cyclodextrin
complex. This embodiment finds particularly utility when it is
desired to provide absorption of ziprasidone in the intestines,
particularly the colon.
Ahmed i-f 111. Ahmed thus teaches a preferred embodiment using the
amorphous (non-crystalline) form of the drug. And even assuming,
arguendo, that Appellants are correct in arguing that the amorphous form of
ziprasidone is less-preferred, that, in itself, does not defeat the Examiner's
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prima facie case of obviousness. Rather, in determining whether the
teachings of the prior art would render a claim obvious to a person of
ordinary skill, "all disclosures of the prior art, including unpreferred
embodiments, must be considered." Merck & Co., Inc. v. Biocraft
Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (quoting In re
Lamberti, 545 F.2d 747, 750 (C.C.P.A. 1976)). In the instant appeal, we
agree with the Examiner that a person of ordinary skill would find it
obvious, based upon the teachings of Ahmed quoted supra, to use a form of
the drug that has "at least 90 wt% of said drug in said nanoparticles is in a
non-crystalline form," as required by claim 1.
Issue 3
Appellants next argue that the Examiner erred because Ahmed teaches
an erodible matrix and not a nanoparticle formulation as recited in claim 1.
App. Br. 4.
Analysis
Appellants argue the Examiner relies upon paragraphs [0041], [0123]
and [0125] of Ahmed as teaching "nanoparticles comprising a poorly water
soluble drug and a poorly aqueous soluble polymer." App. Br. 4.
Appellants assert that, to the contrary, paragraphs [0123] and [0125] of
relate to erodible matrix sustained release dosage forms, as discussed in
detail in paragraphs [0121]-[0126] of Ahmed. Id. Appellants contend the
polymers listed in paragraphs [0123] and [0125] are examples of matrix
polymers that may be used in an erodible matrix sustained release dosage
form, and are not part of a nanoparticle formulation. Id.
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Appellants argue further that paragraph [O 165] of Ahmed teaches
multiparticulates ranging in size from "about 10 µm" at the low end, which
greatly exceeds the requirement of claim 1 that the nanoparticles "have an
average size of less than 500 nm." Id. at 4--5.
The Examiner finds that, in addition to teaching an erodible matrix,
Ahmed additionally teaches the preparation of multi particulates "by any
known process ... to form multiparticulates of the desired size." Ans. 6
(quoting Ahmed i-f 166). The Examiner finds Ahmed teaches that polymers
such as HPMCAS may be constituents of the erodible matrix or
precipitation-inhibiting polymers. Id. (citing Ahmed i-fi-1123; 94; 97-100;
207). The Examiner finds that, because Ahmed teaches that inclusion of
precipitation-inhibiting polymers such as HPMCAS improves the solubility
and yields excellent absorption of the drug, and also teaches particles of
solubility-improved form of the drug coated with a precipitation-inhibiting
polymer, an artisan of ordinary skill in the art would find it obvious to
prepare multiparticulates, comprising the drug and polymers, such as
HPMCAS which improve the solubility and yield excellent absorption of the
drug. Id. (citing Ahmed i-fi-1 100, 111 ).
We are not persuaded by Appellants' arguments. First, we have
already found that Ahmed teaches the use of nanoparticles in various
preferred embodiments. Moreover, Ahmed teaches:
In one preferred embodiment, the combination comprises
particles of the solubility-improved form of ziprasidone coated
with a precipitation-inhibiting polymer. The particles may be
either ziprasidone crystals, or particles of some other solubility-
improved form such as amorphous drug or a cyclodextrin
complex. This embodiment finds particularly utility when it is
desired to provide absorption of ziprasidone in the intestines,
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particularly the colon. Without wishing to be bound by theory,
when the polymer and ziprasidone are released into the intestinal
use environment, the polymer may begin to dissolve and gel prior
to dissolution of the drug.
Ahmed i-f 111. The "multiparticulates" decried by Appellants may be, as the
Examiner finds, and as described in the quoted passage, a collection of
polymer-coated particles coated with polymers (i.e., resuspensions) of the
sort taught by Ahmed in paragraphs [0207]-[0209]. Furthermore,
Appellants' Specification discloses:
In one aspect, a dry, solid pharmaceutical composition comprises
(a) a plurality of nanoparticles comprising a poorly water-soluble
drug and a poorly aqueous soluble polymer, and (b) a
resuspending material selected from HPMCAS, CMEC, or
pharmaceutically acceptable salt forms thereof. As used herein,
the term "dry, solid pharmaceutical composition" means that the
composition is in a solid form and substantially free of liquids.
Spec. 4. Ahmed teaches that: "[ m ]ultiparticulates generally refer to dosage
forms that comprise a multiplicity of particles or granules that may range in
size from about 10 µm to about 2 mm, more typically about 50 µm to 1 mm
in diameter" although, as related supra, Ahmed also teaches nanoparticles
may be used in preferred embodiments. Ahmed i-fi-1 165, 141. We
consequently agree with the Examiner that Appellants' arguments are not
persuasive.
Issue 4
Appellants argue that Ahmed does not teach enabling methodology
for a person of ordinary skill to practice Appellants' claimed invention.
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Analysis
Appellants contend Ahmed does not provide detailed enabling
methodology for one of ordinary skill to practice the claimed invention, and
argue Ahmed does not provide evidence that such modification would be
successful. App. Br. 5. Appellants allege the Examiner has picked and
chosen, then combined several different solubility-improved forms from
Ahmed to support the finding of obviousness, which is impermissible. Id.
(citing In re Wesslau, 353 F 2d 238, 241 (C.C.P.A. 1965)).
We are not persuaded. Apart from the arguments presented supra,
which we have addressed, Appellants adduce no evidence from the record
that a person of ordinary skill would not be able to practice Appellants'
invention based upon the teachings of Ahmed. Instead they simply assert
that this is so and that the Examiner has selectively picked and chosen from
Ahmed and ignored the rest of Ahmed's teachings. However, a mere
assertion of lack of enablement in Ahmed, unsupported by evidence, is
insufficient to sustain their allegation. See In re De Blauwe, 736 F.2d 699,
705 (Fed. Cir. 1984) (Arguments and conclusions unsupported by factual
evidence carry no evidentiary weight). Consequently, and for the reasons set
forth with respect to the issues supra, we affirm the Examiner's rejection of
claims 1-3, 5-7, and 11-16.
B. Claims 8-9 and 17
Issue
Appellants argue the Examiner erred because a person of ordinary
skill would not be motivated to combine the teachings of Ahmed and
Khanna.
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Analysis
Appellants repeat their arguments presented with respect to claims 1-
3, 5-7, and 11-16. App. Br. 5. Additionally, Appellants argue Khanna
teaches using the drug ( carbamazepine) in an anhydrous crystal form, with
an average particle size of 5 µm, an order of magnitude larger than the
claimed nanoparticles. Id. at 5---6. Appellants therefore contend a person of
ordinary skill would not be motivated to combine the teachings of Khanna
with those of Ahmed. Id. at 6.
The Examiner states that Khanna is not relied upon as teaching the
average particle size of the nanoparticles, rather, Ahmed is relied upon as
teaching that limitation. Ans. 8 (citing Ahmed i-f 41 ). The Examiner states
Khanna is relied upon as teaching the salt form of the resuspending material.
Id. (citing Khanna col. 4, 11. 10-18). Specifically, the Examiner finds the
references are properly combined because the simple substitution of one
known element, CMEC (as taught by Ahmed) for its salt, sodium CMEC (as
taught by Khanna) to obtain a predictable results would be obvious to a
person of ordinary skill. Id. (citing MPEP § 2141).
We agree with the Examiner. The Examiner explicitly cites Khanna
as teaching "dispersible cellulose ethers such as carboxymethyl
alkylcellulose in salt form, e.g.[,] sodium carboxymethyl ethylcellulose."
Final Act. 12 (citing Khanna col. 4, lines 10-18). Appellants' argument is
therefore inapposite as it attacks Khanna for not teaching a limitation for
which the Examiner relies on a separate reference. "[O]ne cannot show non-
obviousness by attacking references individually where ... the rejections are
based on combinations of references." In re Keller, 642 F.2d 413, 426
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(C.C.P.A. 1981): (citing Application of Young, 403 F.2d 754, 757 (1968).
We consequently affirm the Examiner's rejection of claims 8-9 and 17.
C. Claim 10
Appellants argue claim 10 separately, but rely upon the same
arguments presented with respect to claims 1-3, 5-7, and 11-16. For the
reasons presented with respect to the latter claims, we similarly affirm the
Examiner's rejection of claim 10.
DECISION
The Examiner's rejection of claims 1-3 and 5-20 as unpatentable
under 35 U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l ). See 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
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