Ex Parte Theobald et al

Board of Patent Appeals and Interferences

Mar 19, 2012

10564932 (B.P.A.I. Mar. 19, 2012)

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.
10/564,932 01/13/2006 Frank Theobald 03/058 LTSBOE 4048
7590 03/19/2012
Cathy R Moore
Propat
425 C South Sharon Amity Road
Charlotte, NC 28211
EXAMINER
RAO, SAVITHA M
ART UNIT PAPER NUMBER
1629
MAIL DATE DELIVERY MODE
03/19/2012 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 FRANK THEOBALD, WOLFGANG LAUX, BEATRIX PLATT,
and REGINE KAUFMANN
__________

Appeal 2011-010474
Application 10/564,932
Technology Center 1600
__________

Before DEMETRA J. MILLS, ERIC GRIMES, and MELANIE L.
McCOLLUM, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
transdermal system for drug administration. The Examiner has rejected the
claims for obviousness and lack of adequate written description. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm the obviousness rejection
and reverse the written description rejection.
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STATEMENT OF THE CASE
The Specification discloses “a transdermal therapeutic system (TTS)
for administering pramipexol” (Spec. 1:4-5), which is a therapeutic agent
used to treat Parkinson’s disease (id. at 2:6-15).
Claims 1-3, 6-12, and 14-20 are on appeal. Claim 1 is representative
and reads as follows:
1. A transdermal therapeutic system for continuous administration of
pramipexol comprising
a backing layer and a first active ingredient-containing polymer layer
disposed directly on the backing layer which comprises the active ingredient
pramipexol, wherein the first active ingredient-containing polymer layer
comprises at least one pressure-sensitive adhesive polymer selected from
carboxyl group-free polyacrylates, where the active ingredient pramipexol is
present in said first active ingredient-containing polymer layer in a
proportion of between 25 to less than 75 % by weight,
and said transdermal therapeutic system includes a second active
ingredient-containing polymer layer disposed on the first active ingredient-
containing polymer layer, said second active ingredient-containing polymer
layer comprising at least one pressure-sensitive adhesive polymer selected
from carboxyl group-free polyacrylates, where the active ingredient
pramipexol is present in said second active ingredient-containing polymer
layer in a proportion of between 2 and 10 % by weight, whereby the
transdermal therapeutic system releases the active ingredient pramipexol
with a flux rate greater than 5 μg/cm2 hr over the period between 24 hours
after administration to 72 hours after administration.

The claims stand rejected as follows:
• Claims 1-3, 6-12, 14-17, 19, and 20 under 35 U.S.C. § 112, first
paragraph, for lack of adequate written description in the Specification;
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• Claims 1-3, 6-12 and 14-20 under 35 U.S.C. § 103(a) in view of
Beier,1 Durif,2 Hoffmann,3 Zierenberg,4 and Patel;5 and
• Claim 16 under 35 U.S.C. § 103(a) Beier, Durif, Hoffman,6
Zierenberg, Patel and Wick.7,
I.
The Examiner has rejected claims 1-3, 6-12, 14-17, 19, and 20 under
35 U.S.C. § 112, first paragraph, as lacking adequate written description in
the Specification. The Examiner finds that the Specification does not
support the limitation of “a first active ingredient-containing polymer layer
disposed directly on the backing layer” (Answer 4-5; emphasis added)
because, although the Specification describes a transdermal therapeutic
system that consists of a backing layer and two active ingredient layers, it
does not describe direct disposition of an active ingredient-containing layer
on the backing layer.

1 Beier et al., Patent Application Publication US 2004/0247656 A1,
Dec. 9, 2004
2 Durif et el., US 5,939,094, Aug. 17, 1999
3 Hoffmann et al., US 4,769,028, Sept. 6, 1988
4 Zierenberg et al., US 5,112,842, May 12, 1992
5 Patel, WO 96/39136, Dec. 12, 1996
6 The Examiner’s statement of the rejection did not include Hoffman
(Answer 18). However, the Examiner states that the “[t]eachings of Beier et
al., Durif et al., Hoffmann et al., Zierenberg et al. and Patel are as discussed
supra and are applied here in the same manner” (id.) and thus we understand
Hoffman to be relied on and inadvertently omitted from the statement of the
rejection.
7 Wick et al., US 5,238,944, Aug. 24, 1993
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Appellants argue that the Specification discloses a TTS “‘consisting
of backing layer and two active ingredient-containing layers.’ … The
specification … states that the resulting laminate … consists of a ‘backing
layer, reservoir layer and a pressure-sensitive adhesive layer.’” (Appeal Br.
11, citing Spec. 12.) Appellants argue that this TTS is limited to three layers
and thus the active ingredient-containing reservoir layer is disposed directly
on the backing layer (id.).
We agree with Appellants that the Specification demonstrates to those
of ordinary skill in the art that the inventors were in possession of what is
claimed. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351
(Fed. Cir. 2010)(en banc) (“[T]he test for sufficiency is whether the
disclosure of the application relied upon reasonably conveys to those skilled
in the art that the inventor had possession of the claimed subject matter as of
the filing date.”). “It is not necessary that the application describe the claim
limitations exactly … but only so clearly that persons of ordinary skill in the
art will recognize from the disclosure that appellants invented processes
including those limitations.” In re Wertheim, 541 F.2d 257, 262 (CCPA
1976).
As argued by Appellants, the Specification discloses an example in
which a transdermal therapeutic system is constructed with two active
ingredient containing layers and a backing layer (Spec. 12). Thus, the
Specification reasonably indicates that an active ingredient layer is
“disposed directly on the backing layer” as recited in claim 1. We reverse
the rejection of claims 1-3, 6-12, 14-17, 19, and 20 under 35 U.S.C. § 112,
first paragraph.
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II.
Issue
The Examiner has rejected claims 1-3, 6-12, and 14-20 under 35
U.S.C. § 103(a) as being obvious in view of Beier, Durif, Hoffmann,
Zierenberg, and Patel. Claim 18 was argued separately; the other rejected
claims stand or fall with claim 1. 37 C.F.R. § 41.37(c)(1)(vii). The
Examiner has also rejected claim 16 under 35 U.S.C. § 103(a) as being
obvious in view of Beier, Durif, Hoffman, Zierenberg, Patel and Wick.
Because Appellants rely on the same arguments with respect to both
rejections, we will consider them together.
The Examiner finds that Beier discloses a transdermal therapeutic
system (TTS) for the administration of pramipexol (Answer 9). The
Examiner finds that a “matrix-TTS according to Beier … consists of an
impermeable cover layer, [and] one or more self-adhesive matrix
layer(s) containing the active-ingredient” at “2-15% by weight of the
matrix” (id.). The Examiner finds that Beier discloses that “matrix formers
customary in medicine are used e.g. polyacrylates” (id.). The Examiner
finds that Durif discloses an apomorphine TTS “in which the concentration
of apomorphine … varies in adjacent layers” (id. at 10-11) and the skin
contact adhesive layer contains “a relatively low concentration of
apomorphine” (id. at 11).
The Examiner finds that Hoffman similarly discloses a TTS that
comprises a reservoir layer and an adhesive layer, where the “adhesive layer
… can contain the active agent in a concentration lower than in the reservoir
layer” (id. at 11-12). The Examiner finds that Zierenberg and Patel disclose
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the advantages of transdermal drug delivery systems, with Zierenberg
specifically disclosing the advantages of drug delivery systems for
pramipexol (id. at 14-15).
The Examiner concludes that it would have been obvious for one of
ordinary skill in the art “to develop a therapeutic transdermal system as
instantly claimed” because Beier discloses that “a matrix-Transdermal
Therapeutic System comprising pramipexole … is to a large extent stable
towards decomposition if a self adhesive matrix based on polyacrylates is
used,” Durif and Hoffman disclose multi-layered transdermal systems with
different concentrations of active ingredient in the different layers, and
Zierenberg and Patel disclose the advantages of transdermal systems for
drug delivery (id. at 16-17).
Appellants contend that the cited references would not have made
obvious a first polymer layer containing between 25 to 75% pramipexol and
directly disposed on the backing layer (Appeal Br. 14), or a flux rate greater
than 5 μg/cm2 hr over the period between 24 hours after administration to 72
hours after administration (id. at 15). Appellants also argue that one of skill
in the art would not have been motivated to combine the cited references
because they administer different active agents (id. at 19).
The issue presented is: Does the evidence of record support the
Examiner’s conclusion that the transdermal therapeutic system of claim 1
would have been obvious in view of the cited references?
Findings of Fact
1. Beier discloses a transdermal therapeutic system for delivery of
pramipexol (Beier 1, ¶ 0001).
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2. Beier discloses that the system “consists of an impermeable cover
layer, one or more self-adhesive matrix layer(s) containing the active
ingredient and, where applicable, permeation enhancers/solubilisers, or one
or more matrix layer(s) that are coated with a pressure-sensitive adhesive,
and a peel-off protective layer” (id. at 1, ¶ 0016).
3. Beier discloses that the transdermal therapeutic system contains
pramipexol in an amount that “ranges from 2 to 15% by weight of the
weight of the matrix” (id. at 2, ¶ 0018).
4. Beier discloses that “matrix formers customary in medicine are
used, such as polyacrylates, polyisobutylene.... Preferably, a self-adhesive
matrix that is based on solvent containing polyacrylates … is used.” (Id. at
2, ¶ 0021.)
5. Beier exemplifies a composition for a self-adhesive matrix that
contains, by weight, 2.5% pramipexol, 7.5% Copherol ® F1300, and 90%
Durotak ® 387-2287 (id. at 2, ¶ 0030).
6. Copherol® F1300 (natural vitamin E) is a permeation enhancer
and/or solubiliser (id. at 2, ¶ 0028).
7. The Examiner finds that Beier’s Durotak ® 387-2287 is the same
as Durotak 2287, which is described in the instant Specification as a
carboxyl group-free polyacrylate pressure-sensitive adhesive polymer
(Answer 10; see Spec. 7:34 to 8:5). Appellants do not dispute this finding.
8. Hoffman discloses a TTS that consists of
(a) an impermeable backing layer,
(b) a reservoir layer adjacent to and in close contact with,
this backing layer and supersaturated with the therapeutically
active agent or agents said reservoir layer comprising a polymer
matrix…, [and]
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(c) an adhesive layer adjacent to and in close contact
with, said reservoir layer and permeable to said therapeutically
active agent or agents.

(Hoffman, col. 2, ll. 4-21.)
9. Hoffman discloses that “the reservoir layer … consists of a
multitude of individual layers and that the concentration of the
therapeutically active agent or agents in these individual layers increases …
with increasing distance from the adhesive layer” (id. at col. 2, ll. 23-29).
10. Hoffman discloses that the “increase of active agent concentration
… may cause a decrease in the adhesive power between the outer surface of
the reservoir layer and the backing layer.… In this case … stability is
improved by providing an additional adhesive intermediary layer.” (Id. at
col. 4, ll. 26-34.)
11. Hoffman discloses that the rate of release of the active agent can
be controlled by:
Composition of the polymer matrixes,
total of concentration of active agent in the reservoir and,
possibly, adhesive layer,
active agent concentration gradiant [sic] over the
individual layers of the reservoir layer,
number of the individual layers of the reservoir layer,
thickness of the individual layers of the reservoir layer,
size of the medical plaster, [and]
kind and amount of carrier agents added to the reservoir
layer.
Some or all of these feature[s] may be individually
adjusted thereby allowing to meet all desired medical needs.

(Id. at col. 5, ll. 14-31.)
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12. Hoffman discloses that its TTS can be used with a variety of
active agents (id. at col. 4, ll. 16-25).
13. Durif discloses a TTS “in which the pressure-sensitive adhesive
matrix provides contact with the skin surface of a patient and acts as a
reservoir of apomorphine” (Durif, col. 7, ll. 45-49).
14. Durif discloses an embodiment in which “the concentration of
apomorphine … in the adhesive matrix varies in adjacent layers” (id. at col.
8, ll. 22-25).
15. Durif discloses that, in a preferred embodiment, the “skin contact
adhesive layer contain[s] … a relatively low concentration of apomorphine
.… [and] each successive layer has … a relatively higher concentration of
apomorphine” (id. at col. 8, ll. 34-41).
16. Zierenberg discloses a TTS for the administration of pramipexol
(Zierenberg, col. 1, ll. 39-42).
17. Zierenberg discloses that the system “consists of a backing layer
which is impervious to the active substance and is simultaneously formed as
a covering plaster to secure the system to the skin, a reservoir containing the
active substance and a removable protective film” (id. at col. 2, ll. 11-16).
18. Zierenberg discloses that the proportion of pramipexol in the
reservoir “is between 5 and 30% by weight, the preferred range being
between 7 and 15% by weight” (id. at col. 2, ll. 19-22).
19. Zierenberg discloses that “by transdermal administration of
Pramipexole…, doses of 2 mg per day can be administered without any
orthostatic side effects.… This corresponds to 10 times the amount which
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can usually be administered by oral application of the substance (200 µg per
day) without orthostatic side effects.” (Id. at col. 1, ll. 31-38.)
20. Patel discloses transdermal administration of ropinirole to treat
Parkinson’s disease (Patel 1:3-7).
21. Patel discloses that transdermal administration provides
controlled drug release over a prolonged period (id. at 1:29-32).
22. Patel discloses that “a suitable target skin flux will be in the range
of 5 to 25, preferably 10 to 15 µg/cm2/hr” (id. at 3:10-12).
Analysis
Claim 1 is directed to a transdermal therapeutic system (TTS) that
comprises a backing layer and two polymer layers that each comprise a
pressure-sensitive adhesive polymer that is a carboxyl group-free
polyacrylate. Claim 1 also requires that the first polymer layer is disposed
directly on the backing layer and comprises 25-75% by weight of
pramipexol, the second polymer layer is disposed on the first polymer layer
and comprises 2-10% by weight of pramipexol, and the TTS releases
pramipexol with a flux rate greater than 5 μg/cm2 hr over the period between
24 hours and 72 hours after administration.
Beier discloses a TTS for the delivery of pramipexol that consists of
an impermeable cover layer and one or more self-adhesive matrix layers
containing pramipexol, where the amount of pramipexol ranges from 2 to
15% by weight of the matrix layer. Beier exemplifies a self-adhesive matrix
composition that contains, by weight, 2.5% pramipexol, 7.5% Copherol ®
F1300 (a solubility enhancer), and 90% Durotak ® 387-2287. The
Examiner finds, and Appellants do not dispute, that Durotak® 387-2287 is a
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“pressure-sensitive adhesive polymer selected from carboxyl group-free
polyacrylates,” as recited in claim 1.
Beier does not disclose a reservoir layer with 25-75% by weight
pramipexol directly on the cover layer. Hoffman and Durif disclose TTSs
with more than one active-ingredient containing layer, where the amount of
active ingredients is higher in layers that are farther from the skin contacting
face of the TTS. Hoffman also discloses that the release rate (i.e., flux rate)
of an active agent from a TTS can be controlled by the active agent
concentration gradient over the reservoir layers and by the number and
thickness of the reservoir layers. Zierenberg discloses that transdermal
administration of pramipexol reduces side-effects compared to oral delivery,
and discloses a TTS that contains between 5 and 30% pramipexol. In view
of these disclosures, it would have been obvious to one of ordinary skill in
the art to modify Beier’s TTS to contain an additional layer disposed on the
cover layer and having up to 30% pramipexol because Hoffman and Durif
disclose TTSs with reservoir layers, and Zierenberg discloses a TTS having
this amount of pramipexol.
Appellants argue that the cited references would not have made
obvious a first polymer layer containing between 25 to 75% pramipexol that
is directly disposed on the backing layer because Beier discloses lower
amounts of pramipexol, Hoffman teaches that elevated amounts of active
ingredient result in a loss of adhesion to the backing layer, and Zierenberg
teaches a different type of polymer layer for higher concentrations of
pramipexol (Appeal Br. 15).
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This argument is not persuasive. Beier discloses self-adhesive layer
of a TTS that includes a carboxyl group-free polyacrylate pressure-sensitive
adhesive polymer and up to 15% by weight of pramipexol, and Zierenberg
discloses a TTS containing 5-30% pramipexol. These teachings would have
reasonably suggested the claimed layer of carboxyl group-free polyacrylate
pressure-sensitive adhesive polymer containing at least 25% pramipexol.
Appellants argue that Hoffman indicates that higher levels of active
ingredient in a self-adhesive polymer layer require an additional adhesive
layer between the backing layer and the polymer layer (Appeal Br. 15, 18).
This argument is also not persuasive. Hoffman suggests a variety of self-
adhesive polymers for the matrix (Hoffman, col. 3, ll. 50-60), in
combination with any of a wide range of therapeutic agents (id. at col. 4, ll.
16-25). As Appellants point out, Hoffman discloses that, at some
concentrations, the active agent in the reservoir layers can cause a decrease
in adhesive power. However, Hoffman does not indicate any particular
concentration, for any agent, that is likely to cause a decrease in adhesive
properties. In view of Zierenberg’s disclosure of a TTS that consists of a
backing layer, a reservoir layer containing up to 30% pramipexol, and a
protective film (Zierenberg, col. 2, ll. 11-22), Hoffman’s nonspecific
warning about decreased adhesion would not have led one of skill in the art
to expect that pramipexol in an amount of 25% would adversely affect the
adhesive properties of a self-adhesive layer based on carboxyl group-free
polyacrylates.
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Appellants also argue that the cited references would not have made
obvious a transdermal system with a flux rate greater than 5 μg/cm2 hr up to
72 hours after administration, as recited in claim 1 (Appeal Br. 15, 19).
This argument is not persuasive. We agree with the Examiner
(Answer 13-15) that the claimed flux rate would have been obvious based on
Patel’s disclosure of a flux rate of 5-25 µg/cm2/hr for ropinirole, which like
pramipexol is administered to treat Parkinson’s disease. In addition,
Hoffman makes clear that the flux rate from a TTS can be readily optimized
by varying the concentration gradient over the layers and by varying the
thickness and the number of the layers. Thus, determining the optimal flux
rate for a particular TTS would be routine optimization.
Appellants also argue that one of skill in the art would not have been
motivated to combine the teachings of Beier, Zierenberg, Durif, Hoffmann,
and Patel because “one skilled in the art would not transfer the teachings
from other active ingredients, e.g. apomorphine (Durif), anti-migraine agents
and the like (Hoffmann), ropinirole (Patel), to pramipexol, as these active
ingredients have a significantly different chemical constitution and
associated physical properties” (Appeal Br. 19).
This argument is not persuasive. Hoffman discloses that its multi-
layered TTS can be used to administer a wide variety of systemically active
agents including antibiotics, hormones, antipyretics, antidiabetics, coronary
dilatatory agents, and heart active glycosides. Thus, one of skill in the art
would understand that multi-layered TTSs as described in Hoffman and
Durif could also be used for the delivery of pramipexol.
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Appellants provide separate arguments with respect to claim 18.
Independent claim 18 is similar to claim 1 but adds the limitations that the
flux rate of greater than 5 μg/cm2 hr is achieved “in the absence of an
excipient or penetration-promoter” and that the TTS has “no additional
pressure sensitive adhesive top plaster for fixing to the skin.” The full text
of claim 18 is reproduced in the Claims Appendix of the Appeal Brief.
Appellants argue that claim 18 would not have been obvious in view
of the cited references because a transdermal therapeutic system that
“includes no excipient, penetration promoter or top plaster… is not in the
prior art” (Appeal Br. 14). Appellants argue that “Beier clearly teaches…
the incorporation of penetration enhancers for pramipexol in … acrylic
matrices, while Zierenberg teaches the use of a top plaster in combination
with pramipexol formulations” (id.). See also id. at 20 (arguing that
Hoffman, Durif, and Patel also fail to disclose these limitations).
These arguments are not persuasive. Beier discloses that both
penetration enhancers and a pressure-sensitive adhesive coating are optional
in its TTS (FF 2). Zierenberg also discloses a TTS for pramipexol delivery
that does not include a penetration enhancer (see Zierenberg, col. 2, ll. 30-52
(working examples containing only pramipexol, polyacrylate, and solvent)).
Thus, one of skill in the art would understand from Beier and Zierenberg
that neither a penetration enhancer nor a covering plaster for adhesive
purposes is required in the disclosed TTSs; therefore, omitting these
elements would have been obvious.
With regard to the Examiner’s rejection of claim 16 based on Beier,
Durif, Hoffman, Zierenberg, Patel, and Wick, Appellants argue that one of
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skill in the art would not have been motivated to combine the cited
references (Appeal Br. 21) and that Wick does not cure the deficiency of
Beier, Durif, Hoffman, Zierenberg, and Patel (id.). These arguments are not
persuasive for the reasons discussed above with regard to the rejection of
claim 1.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
transdermal therapeutic system of claim 1-3, 6-12, and 14-20 would have
been obvious in view of the cited references.
SUMMARY
We reverse the rejection of claims 1-3, 6-12 and 14-17, 19, and 20
under 35 U.S.C. § 112, first paragraph. However, we affirm the rejection of
claims 1-3, 6-12, and 14-20 under 35 U.S.C. § 103(a).
TIME PERIOD FOR RESPONSE
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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