Ex Parte Kolter et al

Patent Trial and Appeal Board

Aug 12, 2016

13319575 (P.T.A.B. Aug. 12, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/319,575 11/09/2011 Karl Kolter
48394 7590 08/16/2016
SERVILLA WHITNEY LLC
33 WOOD A VE SOUTH
SUITE 830
!SELIN, NJ 08830
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
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EXAMINER
LEVIN, MIRIAM A
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
08/16/2016 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte KARL KOLTER, DEJAN DJURIC, and STEFAN FISCHER
Appeal2014-009359
Application 13/319,575 1
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and
KRISTI L. R. SA WERT Administrative Patent Judges.
SA WERT, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the rejection of claims
1-3, 6-9, 15-17, 19, and 20 of U.S. Patent Application No. 13/319,575 ("the
'575 application"). We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.
1 Appellants identify BASF SE as the real party in interest. Appeal
Br. 3.
Appeal2014-009359
Application 13/319,575
STATEMENT OF THE CASE
Claims 1-3, 6-9, 15-17, 19, and 20 are on appeal. Claims 4, 5, 10-
14, and 18 are withdrawn from consideration for being drawn to a non-
elected invention. Claims 1-3, 9, 15, and 17 stand rejected as unpatentable
under 35 U.S.C. § 103(a) over Mertoglu2 in view ofKolter3 and Leuner. 4
Answer 2. Claims 6-8, 16, 19, and 20 stand rejected as unpatentable under
35 U.S.C. § 103(a) over Mertoglu in view of Kolter and Leuner, and further
in view of Suzuki5 and Hasegawa6.
We choose claims 1 and 6 as representative. See 37 C.F.R.
§ 41.37(c)(l)(iv). Claim 1 provides:
1. A dosage form comprising preparations of slightly water-soluble
active substances in a polymer matrix comprising a polyether copolymer and
at least one slightly water-soluble polymer, the polyether copolymer being
obtained by free radical polymerization of a mixture of from 30 to 80% by
weight ofN-vinyUactam, from 10 to 50% by weight of vinyl acetate and
2 Murat Mertoglu et al., U.S. Patent Publication No. 2010/0204425 Al
(Aug. 12, 2010) ("Mertoglu").
3 Karl Kolter et al., U.S. Patent Publication No. 2008/02481117 Al
(Oct. 9, 2008) ("Kolter").
4 Christian Leuner and Jennifer Dressman, Improving Drug Solubility
for Oral Delivery Using Solid Dispersions, EUR. J. PHARM. BIOPHARM.,
50:47---60 (2000) ("Leuner").
5 Hideshi Suzuki et al., Solid Dispersions of Benidipine
Hydrochloride, I. Preparations Using Different Solvent Systems and
Dissolution Properties, CHEM. PHARM. BULL., 44(2):364--371 (1996)
("Suzuki").
6 Akihiko Hasagawa et al., Physical Properties of Solid Dispersions of
Poorly Water-Soluble Drugs with Enteric Coating Agents, CHEM. PHARM.
BULL., 33(8):3429-35 (1985) ("Hasagawa").
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Application 13/319,575
from 10 to 50% by weight of a polyether, wherein the slightly water-soluble
active substance is present in amorphous form in the polymer matrix, and
wherein the preparations remain amorphous after storage for 6 months at
30°C/70% relative humidity.
Appeal Br. 19. Claim 6 provides:
6. The dosage form according to claim 1, wherein the ratio of the
polyether copolymer to the slightly water-soluble polymer is from 99: 1 to
10:90.
Id.
We limit our consideration of the merits of the appealed rejections to
the elected species. See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BP AI
1987). Thus, we read claims 1 and 6 as limited to the use of the elected
species of:
N-vinylcaprolactam (the species ofN-vinyllactum recited in claim 1 );
PEG 6000 (the species of polyether copolymer recited in claim 1 );
ethyl acrylate+ methyl methacrylate (Eudragit®) (the species of
slightly water-soluble polymer recited in claim 1 ); and
clotrimazole (the active substance).
See Final Off. Act. 2.
DISCUSSION
We have reviewed Appellants' arguments in the Briefs, the
Examiner's final Office Action, and the Examiner's Answer to the
Appellants' arguments. Upon review of the record, we find that the
Examiner did not establish by a preponderance of the evidence that the
claimed invention would have been obvious over the combined prior-art
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Application 13/319,575
references. For this reason, we reverse the rejection of the claims 1-3, 6-9,
15-17, 19, and 20 under 35 U.S.C. § 103.
Background
The claimed invention is directed to a dosage form for preparations of
slightly water-soluble active substances (elected species: clotrimazole ). The
dosage form comprises a polymer matrix of a polyether copolymer (elected
species: PEG 6000) and at least one slightly-water soluble polymer (elected
species: ethyl acrylate and methyl methacrylate) "which [is] capable of
influencing the stability of the formulation and/or the release of the
biologically active substance." Appeal Br. 19 (claim 1 ); see also Spec. 1
(11. 6-19).
The polyether copolymers are obtained by free radical polymerization
of a mixture ofN-vinyllactum (elected species: N-vinylcaprolactam), vinyl
acetate, and polyether. Appeal Br. 19 (claim 1); see also Spec. 4 (11. 19-24).
And, the slightly-water soluble polymer is present in an amorphous form in
the polymer matrix. Appeal Br. 19 (claim 1 ); see also Spec. 4 (11. 7-9). As
claimed, the preparations remains amorphous after storage for 6 months at
30°C/70% relative humidity. Appeal Br. 19 (claim 1); see also Spec. 1 (11.
6-19).
The Specification explains that "[a Jn important requirement" for
preparations of slightly water-soluble active substances "is that they are
stable even on storage over a relatively long time" because slightly-soluble
active substances tend to crystallize during storage. Spec. 1 (1. 43)-2 (11. 1-
2). Crystallization is a "major problem" that exerts control over the release
of the active substance. Id. at 2 (11. 13-17). According to the Specification,
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the claimed invention solves this problem by formulating the slightly-soluble
active substance with both a polyether copolymer and a slightly water-
soluble polymer. Id. at 4 (11. 3-9). The Specification explains that polyether
copolymers "act as solublizers for the slightly water-soluble biologically
active substances," id. at 1 (11. 14--15), and that the slightly water-soluble
polymers "are capable of influencing the stability of the formulation and/ or
the release of the biologically active substance," id. (11. 9-10).
The Specification states that the preparations of the claimed
invention-using both a polyether copolymer and at least one slightly water-
soluble polymer-were surprisingly stable. Specifically, the active
substances remained "in the molecularly disperse[ d] or colloidally
disperse[d] amorphous state ... and d[id] not crystallize." Id. at 13 (11. 6-9).
Even "[a]fter storage for 6 months at 30°C/70% relative humidity, the
preparations were still amorphous." Id. at 18 (11. 29-30).
The Examiner rejected representative claim 1 for obviousness over
Mertoglu in view of Kolter and Leuner. Final Off. Act. 3. Mertoglu
discloses "copolymers for use as solubilizers for slightly water-soluble
substances." Mertoglu i-f 1. Specifically, Mertoglu teaches that the
copolymers are "suitable for use as solubilizer[ s] in pharmaceutical
preparations of any type, which may comprise one or more drugs which are
slightly soluble or insoluble in water." Id. at i-f 109. Mertoglu lists
"clotrimazole" as an example of a "slightly soluble drug." Id. at i-f 9.
Mertoglu teaches that suitable copolymers include polyethylene glycols, id.
at i-fi-1 42--44, such as PEG 6000, id. at i-f 126. And Mertoglu teaches that
these copolymers may be obtained by free-radical polymerization of a
mixture ofN-vinyllactum, vinyl acetate, and polyether. Id. at i-f 1.
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Mertoglu does not teach the addition of "at least one slightly-water
soluble polymer" (e.g., the elected species ethyl acrylate and methyl
methacrylate polymers) to the polymer matrix. Final Off. Act. 8-9. The
Examiner relied on Leuner and Kolter to make up for this deficiency. Id. at
9.
Leuner provides an overview of the use of solid dispersions for the
oral delivery of poorly-soluble drugs. Leuner 47 (Abstract). Leuner notes
that "the number of poorly soluble drug candidates has risen sharply and the
formulation of poorly soluble compounds for oral delivery now presents one
of the most frequent and greatest challenges to formulation scientists in the
pharmaceutical industry." Id. (Introduction). "The most attractive option,"
Leuner explains, "is improvement of the solubility through formulation
approaches." Id. And of the formulation approaches, Leuner discusses solid
solutions and solid dispersions in detail, but eventually concludes that "[ t ]wo
trends strongiy favour an increasing roie for soiid dispersions in
pharmaceutical development":
the increasing number of drug candidates which are poorly
soluble, and the substantial improvements in the manufacturing
methods for solid dispersions that have been made in the last
few years. . . . Another advantage of solid dispersions over
other approaches is that many of the carriers that can be applied
are already extensively used in the pharmaceutical industry as
excipients, so additional toxicity studies above and beyond
what is required for the drug itself should not be required. The
possibility of combining several carriers to produce an
optimized product further extends the range of possibilities for
formulation. Yet another advantage of solid dispersions over
other approaches is that the increases in solubility and release
rate that can be achieved are often much, much greater (up to
orders of magnitude). This could potentially lead to an increase
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in bioavailability that is so great that the dose administered
could be lowered.
Id. at 58 (Summary).
Leuner describes "amorphous solid solutions" as a type of solid
solution where "the solute molecules are dispersed molecularly but
irregularly within the amorphous solvent." Id. at 45 (Definitions). Leuner
then describes several "polymer carriers" used to formulate such solutions,
including polyacrylates and polymethacrylates. See id. at 52-57 (Carriers).
Leuner also provides a"[ c ]haracterization of solid dispersions," and defines
"solid dispersions" as "dispersions in which drug is only partly molecularly
dispersed." Id. at 57. Solid dispersions, Leuner explains, differ from solid
solutions in that solid solutions have molecularly dispersed drug. Id.
Kolter teaches a process for making solid solutions comprising
poorly-soluble active substances, such as clotrimazole. Kolter i-fi-f l, 29.
Kolter expiains that siightiy-soiubie active ingredients "are extremeiy
difficult to formulate" and that "[ o ]ne of the most promising approaches is to
form solid solutions in which the active ingredient is incorporated in the
form of a molecular dispersion." Id. at i12. Kolter teaches that the solid
solutions comprise, in addition to the active ingredient, "at least one water-
soluble matrix excipient," "one or more surfactants," cosolubilizers, and
"further excipients." Id. at i-fi-130-35. Out of the examples of water-soluble
polymers, Kolter states that "[i]t is also preferred to use alkyl methacrylates
or alkyl acrylates" as the polymeric matrix excipients. Id. at i1 57.
It is the Examiner's position that, because Mertoglu teaches that
"other excipients, diluents, cosolvents and/or stabilizers may be included," a
skilled artisan would have been motivated to add at least one slightly water-
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soluble polymer to Mertoglu's preparations. Final Off. Act. 9. The
Examiner further explains that Leuner' s disclosure of polyacrylates and
polymethacrylates as polymer carriers "provides the ... motivation to use
polyacrylates and polymethacrylates in solid dispersions." Id. at 10. And,
Leuner's statement that "several carriers" can be combined "to produce an
optimized product" provides the motivation to "use combinations of carriers
in a polymer matrix for a solid solution." Id. at 11. As to Kolter, the
Examiner stated that because that reference teaches "at least one" water-
soluble matrix excipient, "this provides the ... motivation to use
combinations of polymers in a solid solution." Id. at 12. As to the claim
limitation "wherein the preparations remain amorphous after storage for 6
months," the Examiner stated that the burden shifted to Appellants to show
that the combined prior art does not result in a preparation that remains
amorphous. Id. at 14.
Discussion
The issue in this case is whether an ordinarily-skilled artisan would
have been motivated to add the claimed "at least one slightly water-soluble
polymer"-specifically, the elected species ethyl acrylate and methyl
methacrylate polymers-to the polymer matrix of Mertoglu. We agree with
Appellants that the Examiner did not adequately set forth a reason
explaining why a skilled artisan would have selected ethyl acrylate and
methyl methacrylate polymers. Thus, we reverse the rejection of the claims.
The Federal Circuit has explained that"[ w ]here a skilled artisan
merely pursues 'known options' from 'a finite number of identified,
predictable solutions,' the resulting invention is obvious under Section 103."
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Application 13/319,575
In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
Litig., 676 F.3d 1063, 1070 (Fed. Cir. 2012) (quoting KSR Int'! Co. v.
Teleflex Inc., 550 U.S. 398, 421 (2007)). In our view, the Examiner has not
persuasively explained how Kolter and Leuner point the skilled artisan in the
direction of the presently-claimed ethyl acrylate and methyl methacrylate
polymers.
The Examiner reasoned that an ordinarily-skilled artisan would have
been motivated to select the claimed slightly water-soluble polymer because:
While Mertoglu et al. do not explicitly teach a polymer matrix
comprising the claimed copolymer and a slightly water-soluble
polymer, Mertoglu et al. do teach that other excipients, diluents,
cosolvents and/or stabilizers may be included. This provides
the teaching, suggestion and/or motivation to add other
ingredients to the polymer matrix, and that doing so will not
destroy the functionality of the composition.
Ans. 4 (ififl5-16).
Although Mertoglu supports the notion that an ordinarily-skilled
artisan would have been motivated to include "other excipients, diluents,
cosolvents and/or stabilizers," we find that the preponderance of the
evidence does not support the Examiner's reasoning that the artisan would
specifically chose ethyl acrylate and methyl methacrylate with a reasonable
expectation of success. Indeed, although the Examiner states that "it is
apparent that one of ordinary skill in the art would have had a reasonable
expectation of success in producing the claimed invention" "[ fJrom the
teachings of the references," Final Off. Act. 19, we find that the art suggests
otherwise: Kolter describes the formulation of poorly water-soluble drugs as
"extremely difficult," Kolter if 2, and Leuner characterizes the same as "one
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of the most frequent and greatest challenges to formulation scientists,"
Leuner 47 (Introduction).
Moreover, "[ e ]vidence of obviousness, especially when that evidence
is proffered in support of an 'obvious-to-try' theory, is insufficient unless it
indicates that the possible options skilled artisans would have encountered
were finite, small, or easily traversed, and that skilled artisans would have
had a reason to select the route that produced the claimed invention."
Cyclobenzaprine Hydrochloride, 676 F.3d at 1072 (quotations omitted).
Here, in our view, the Examiner has not provided sufficient reasoning or
evidence that one of ordinary skill would have had a reason to select at least
ethyl acrylate and methyl methacrylate from the laundry lists of polymers
disclosed in Leuner and Kolter.
Indeed, we find that neither Leuner nor Kolter reasonably suggests a
correlation between the stability of a polymer matrix and the addition of the
presentiy-ciaimed ethyi acryiate and methyi methacryiate poiymer. Leuner
only discloses polyacrylates and polymethacrylates as one of a laundry list
of polymers, and specifically, as Appellants point out, "as coatings to
modify the release of the drug from the dosage form." Leuner 55 (i-f 3.2.5);
see also Appeal Br. 13. And even then, it is unclear on this record whether
Leuner suggests the same polymer carriers for a solid solution as for a solid
dispersion. Leuner 55 (i-f 3.2.5). Moreover, Kolter only discloses a broad
class of water-soluble polymers including polyacrylates and
polymethacrylates, rather than the slightly water-soluble polymers presently
claimed. Kolter i1i138--41; see also Appeal Br. 14. Although the Examiner
states that Kolter's polymers are the same as those claimed, see Final Off.
Act. 20, we find that Appellants cast enough doubt on that assertion such
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that we cannot say that a preponderance of the evidence supports it, see
Appeal Br. 14--15. For example, the Examiner states that Kolter "may
consider a polymer that is swellable or that has pH dependent solubility to be
water soluble," rather than slightly water-soluble, and "leaves open the
possibility" that the polymers are slightly water-soluble. Ans. 16 (emphases
added). But without evidence or other sound scientific reasoning, we find
these statements speculative and unsupported by a preponderance of the
evidence.
The Examiner also rejected representative claim 6 for obviousness
over Mertoglu in view of Kolter and Leuner, and further in view of Suzuki
and Hasegawa. Final Off. Act. 3--4. We reverse this rejection for the same
reasons we reverse the rejection of claim 1 over Mertoglu in view of Kolter
and Leuner.
SUMMARY
We reverse the rejection of claims 1-3, 6-9, 15-17, 19, and 20 under
35 U.S.C. § 103.
REVERSED
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