NOVEN PHARMACEUTICALS, INC.

Patent Trials and Appeals Board

Sep 28, 2020

2020001376 (P.T.A.B. Sep. 28, 2020)

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.
14/208,348 03/13/2014 Jun Liao 041457-1064 1059
22428 7590 09/28/2020
FOLEY & LARDNER LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
EXAMINER
BASQUILL, SEAN M
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
09/28/2020 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):
ipdocketing@foley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JUN LIAO, TAKITO SHIMA, PUCHUN LIU, and
STEVEN DINH
__________

Appeal 2020-001376
Application1 14/208,348
Technology Center 1600
__________

Before RICHARD M. LEBOVITZ, RYAN H. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to
transdermal drug delivery systems for tertiary amine drugs, which have been
rejected as obvious. Oral argument was held on September 14, 2020. We
have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
Appellant’s Specification acknowledges that “[t]he use of a
transdermal drug delivery system, for example, a patch comprising a

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies the real party in interest as Noven
Pharmaceuticals, Inc. (Appeal Br. 3.)
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pressure-sensitive adhesive containing a drug, as a means of delivering drug
through the skin is well known.” (Spec. 1.) Appellant’s Specification
explains: “[h]owever, there remains a need for transdermal drug delivery
systems designed for the delivery of specific classes of drugs, such as
tertiary amine drugs, including rivastigmine, fentanyl and rotigotine . . .
[and] over an extended period of time, such as over a period of time of 3
days, or 7 days, or longer.” (Id.) Appellant’s invention concerns such a
drug delivery system.
Claims 1–19, 22–28, 31, and 32 are on appeal. Claims 1 and 22 are
illustrative and read as follows:
1. A transdermal drug delivery system comprising:
a polymer matrix formed by blending the free base form
of a tertiary amine drug and at least one carboxyl group-
containing compound, wherein the relative amounts of free base
and carboxyl group-containing compound is such that greater
than 50% of the free base is associated with a carboxylic acid
group to form a salt, and
a backing layer,
wherein the transdermal drug delivery system releases
drug upon application to skin, and is effective to deliver a
therapeutically effective amount of the tertiary amine drug
through skin for at least 3 days.
22. A transdermal drug delivery system comprising a polymer
matrix comprising the free base form of a tertiary amine drug, a
rate-controlling membrane, and a face adhesive comprising a
carboxyl group-containing compound, wherein the rate
controlling membrane is disposed between the polymer matrix
and the face adhesive, and wherein the system is effective to
deliver a therapeutically effective amount of the tertiary amine
drug through skin for at least 3 days.
(Appeal Br. 27, 30.)

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The prior art relied upon by the Examiner is:
Name Reference Date
Kochinke US 5,613,958 Mar. 25, 1997
Breitenbach WO 2013/072062 A1 May 23, 2003
Kanios US 7,063,859 B1 June 20, 2006
Audett US 2007/0098771 A1 May 3, 2007
Gargiulo US 2007/0128263 A1 June 7, 2007
Yum US 2009/0060986 A1 Mar. 5, 2009
Chan et al., Transdermal Delivery of Treatment for Alzheimer’s Disease,
25(9) Drugs Aging ,761–775 (2008)
Duro-Tak and Gelva Transdermal Pressure Sensitive Adhesives: Product
Selection Guide, Henkel (Sept. 2013)

The following grounds of rejection by the Examiner are before us on
review:
Claims 1–14 and 16–192 under 35 U.S.C. § 1033 as unpatentable over
Gargiulo, Duro-Tak, Chan, Audett, and Kochinke.
Claims 1–19 and 314 under 35 U.S.C. § 103(a) as unpatentable over
Gargiulo, Duro-Tak, Chan, Audett, Kochinke, and Breitenbach.

2 We conclude that the Examiner’s recitation of claim 32 in this rejection is
an inadvertent error because that claim depends from independent claim 22,
which the Examiner did not indicate is obvious over only Gargiulo, Duro-
Tak, Chan, Audett, and Kochinke.
3 The AIA amendments to § 103 took effect on March 16, 2013. The
Application on Appeal was filed on March 13, 2014, based on an
Application filed March 15, 2013. Although we cite to the post-AIA version
of § 103, the current law and respective pre-AIA law are, in all aspects
relevant to this Decision, the same.
4 We conclude that the Examiner’s recitation of claim 32 in this rejection is
an inadvertent error as well because that claim depends from independent
claim 22, which the Examiner did not indicate is obvious over only
Gargiulo, Duro-Tak, Chan, Audett, Kochinke, and Breitenbach.
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Claims 1–14, 16–19, 22–28, 31, and 32 under 35 U.S.C. § 103(a) as
unpatentable over Gargiulo, Duro-Tak, Chan, Audett, Kochinke, Kanios,
and Yum.
DISCUSSION
I. Claim 1 and dependent claims thereof
The Examiner interprets claim 1’s “wherein” clause as not
“impart[ing] to the actual matrix which is recited [in the other portions of the
claim] any particular structure or physical requirements aside from the
explicitly recited matrix components.” (Final Action 3.) Consequently, the
Examiner concludes that the wherein clause is “an intended use, rather than
affirmative limitation of the matrix otherwise fully set forth by the claim[].”
(Id.)
With the foregoing interpretation in mind, the Examiner finds that
Gargiulo teaches a transdermal therapeutic system (TDS) having a silicone
adhesive layer and a polymeric matrix containing the tertiary amine,
rivastigmine, with a carboxylate-containing acrylate copolymer that has free
carboxylate groups, such as DUROTAK 387-2353. (Final Action 4–5
(relying on DUROTAK for confirmation that this compound has free
carboxylate groups).) The Examiner finds that a specific embodiment
disclosed by Gargiulo “contains a substrate having a coat weight of 6mg/cm2
of a composition containing (all percentages are by weight) 30% free base
rivastigmine, 49.9% DUROTAK 387-2353, 20% PLASTOID B as a
thickener, and 0.1 % Vitamin E as an antioxidant, as well as a silicone
adhesive layer. [0092-101].” (Id. at 4.) The Examiner also finds that
Gargiulo teaches that dosage amounts of the active ingredient, e.g.,
rivastigmine, as well as other patch components and patch dimensions can
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be adjusted “to provide appropriate dosages and treatment durations,
including once daily administration.” (Id.; see also id. at 10 (citing Gargiulo
¶¶ 71–82).) According to the Examiner, such disclosure “would suggest
modifying the relative amounts of each of the rivastigmine and carboxylate-
containing acrylate copolymer,” to achieve duration of treatment periods of
time up to and including three and seven day periods, and doing so would be
prima facie obvious to “reduce application intervals and improve patient
compliance.” (Id. at 5–6, 10.)
The Examiner finds that Chan, Audett, and Kochinke collectively
teach that it was known that the amount of a drug incorporated into the TDS,
as well as the coating weight, are result-effective variables as to the dosage
amount to be delivered and duration of therapy. (Id. at 7–8.) The Examiner
finds that Chan “specifically indicat[es] that the rate of release from a
transdermal patch directly corresponds to the amount of drug included in the
device, while also describing alternative transdermal delivery devices
capable of delivering alternative agents useful in the treatment of
Alzheimer’s Disease as capable of delivering drug for seven days. (Pg. 770-
71).” (Id. at 7.) In addition, the Examiner finds that Audett teaches
including the active ingredient from about 1–20% by weight of the device
and selection of additional components “provides transdermal drug delivery
systems with the proper adhesive properties for effective transdermal
delivery of agents contained therein for periods of 24 hours, 3, or even 7
days.” (Id.) The Examiner finds that Kochinke teaches
the duration of the delivery phase for transdermal drug delivery
devices is determined by the total amount of drug included in
the system, which depends on the thickness of and drug
concentration within the reservoir as well as the delivery rate
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which depends on the drug itself, the composition of the
remainder of the device, and the skin permeability of the drug
itself.
(Id.) The Examiner concludes that it would have been obvious to optimize
the amount of rivastigmine and the DUROTAK of Gargiulo to achieve at
least 3 days drug delivery in order to increase patient compliance. (Id. at
10.) Regarding the claimed salification of the free base and carboxylic acid,
the Examiner contends that “[s]ince modifications to the amounts of active
and excipients included in transdermal drug delivery systems are explicitly
taught by Gargiulo, the modification of these precise parameters [to achieve
the recited salification minimum] claimed by applicants cannot be
considered an non-obvious modification of the prior art.” (Id.)
The Examiner further finds that Gargiulo teaches the TDS can have a
polyethylene backing layer that is impermeable to the active agent. (Id. at
5.)
We do not agree with the Examiner’s conclusion that the prior art
relied upon by the Examiner renders the claimed TDS obvious.
It is true that Gargulio teaches that varying the nature and amount of
excipients and active ingredients is a known way to adjust plasma profiles of
the active agent. (Gargiulo ¶ 71.) Gargiulo further teaches that formulating
a TDS should take into consideration the rate of release of an active agent as
well as lag or delay time, improving patient compliance, and reducing
application intervals. (Id. ¶¶ 75–81.) However, as Appellant notes,
“Gargiulo is directed to providing ‘once a day’ products” (Appeal Br. 18;
Gargiulo ¶¶ 70, 89), not a TDS that can be adhered for multiple days and
provide a therapeutically effective amount of drug for multiple days.
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In particular, Gargiulo teaches a goal of achieving a plasma
concentration of 1 to 30 ng/ml of rivastigmine between two to sixteen hours
after application of the TDS with a variation of the drug concentration in
blood plasma over 24 hours (“AUC24h”) between about 25 to 450 ng h/ml
with a TDS in the range of 2 to 50 cm2 (Gargiulo ¶¶ 21, 53, 69–70) and
provides an example of a TDS to achieve that result (Id. ¶¶ 92–97).
Although varying the nature and amounts of excipients and the amount of
active ingredient are known parameters that can be modified in ways that
might change the time course of drug absorption, or its bioavailability, i.e.,
pharmacokinetic properties, Gargiulo does not provide a reasonable
expectation of success as to a modification of amounts of any particular
ingredient that would provide for delivery of a therapeutically effective
amount of a tertiary amine drug through the skin to achieve the one day goal,
much less the at least three days required by claim 1. Indeed, Gargiulo
indicates that determining a TDS that could achieve the described results
was only after “extensive testing.” (Id. ¶ 84.) The only guidance in
Gargiulo concerning ranges that might accommodate the once a day goal is
the thickness of reservoir layer to adhesive layer (id. ¶ 50), an adhesive force
of the TDS (id. ¶ 51), the size range of the TDS (id. ¶ 52), and the saturation
solubility of active ingredient in the silicone adhesive (id. ¶¶ 43–45). Thus,
we agree with Appellant, that “Gargiulo does not indicate which
modifications of which parameters will achieve an intended impact on a
specific pharmacokinetic property.” (Appeal Br. 18.) In other words,
Gargiulo does not indicate, with a reasonable expectation of success, to what
extent the active ingredient or adhesive should be varied to achieve even the
24 hour goal. Thus, we agree with Appellant that “Gargiulo provides no
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guidance whatsoever or expectation of success regarding TDSs that are
effective over longer periods of time, such as at least 3 days, as recited in the
instant claims.” (Appeal Br. 18.) And, Gargiulo provides no indication that
the relative amounts of free base and carboxyl group-containing compounds
has any effect on drug delivery of the TDS.
We note that Appellant argues, relying on evidence in the
Specification (Example 1), that “[i]n the cited example of Gargiulo, the ratio
[of the free base amine drug and carboxyl group-containing compound]
results in less than 50% salification.” (Appeal Br. 16.) Appellant indicates
that the Exelon patch in Example 1 (see Spec. 28) includes the same
DUROTAK composition that is in Gargiulo’s TTS#1. (Id. (citing Gargiulo
¶¶ 94–95).) Appellant notes, however, that in the Specification Example,
the weight percentage of DUROTAK (70%) is higher than in Gargiulo’s
example (49.9%). (Id.) The amount of rivastigmine is the same in both
(30%). (Id.) Appellant explains that the Example in the Specification shows
that at a higher weight percentage of DUROTAK than in Gargiulo, the salt
percentage formed is less than 49%. (Id.) Thus, Appellant indicates that
“the cited example of Gargiulo does not even accidentally read on the
claims.” (Id. at 17.)
Furthermore, we do not find Chan, Audett, or Kochinke individually
or together, provide a reason to modify the TDS of Gargiulo so that “the
relative amounts of free base and carboxyl group-containing compound is
such that greater than 50% of the free base is associated with a carboxylic
acid group to form a salt,” much less to arrive at a TDS with such relative
amounts that is effective to deliver a therapeutically effective amount of the
tertiary amine drug through skin for at least 3 days. The Examiner did not
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point to a teaching in any of these references to suggest that it was known to
adjust the association of the free base of a tertiary amine with a carboxyl
group containing compound in order to achieve delivery of the amine in a
therapeutically effective amount for at least three days. Consequently, the
Examiner did not establish that this relationship was a known result effective
variable such that optimization thereof would have been obvious as a matter
of routine experimentation.
Moreover, we agree with Appellant that the paragraph of Audett the
Examiner relies on in the rejection (Audett ¶ 51) does not, as the Examiner
indicates, teach a TDS that is capable of delivering a therapeutically
effective amount of a drug for at least three days. (Appeal Br. 19.) Rather,
this paragraph of Audett teaches “proper selection of drug and other
ingredients (such as permeation enhancers” can be made to achieve a TDS
“with the right adhesive properties . . . such as 24 hours, 3 day, or even 7
day application.” (Audett ¶ 51 (emphasis added).) That description does not
provide one of ordinary skill in the art with sufficient information regarding
the parameters of Gargiulo’s TDS to modify to achieve a TDS “effective to
deliver a therapeutically effective amount of the tertiary amine drug through
skin for at least 3 day” with a reasonable expectation of success, much less
to arrive at a TDS with 50% of the free base of the drug being associated
with a carboxylic acid group to form a salt.
In addition, we disagree with the Examiner that Chan describes a
device that is capable of delivering alternative agents useful in the treatment
of Alzheimer’s Disease for seven days. Chan indicates that a phase III
clinical trial “is evaluating advanced adhesive polymer matrix technology to
provide 7-day transdermal delivery of phenserine.” (Chan 771.) However,
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as Appellant correctly observes, Chan “does not discuss any specific
components” of that TDS other than to mention it includes a different drug
than what is claimed. (Id. at 20.) Thus, we also do not see how Chan’s
description would provide one of ordinary skill in the art with sufficient
information regarding the parameters of Gargiulo’s TDS to modify to
achieve a TDS “effective to deliver a therapeutically effective amount of the
tertiary amine drug through skin for at least 3 day” with a reasonable
expectation of success, much less to arrive at a TDS with 50% of the free
base of the drug being associated with a carboxylic acid group to form a salt.
Finally, the portion of Kochinke relied on by the Examiner, indicates,
in pertinent part:
The duration of the delivery phase is determined by the total
amount of drug in the system which is in turn determined by the
reservoir thickness and drug concentration in the reservoir; and
the delivery rate, which is a function of the drug to be delivered,
the composition of the drug delivery device, and the skin
permeability of the drug.
(Kochinke 16:26–37). Such a general reference to drug delivery rate being a
function of the drug to be delivered, the composition of the drug delivery
device, and the skin permeability of the drug would not provide one of
ordinary skill in the art with sufficient information regarding the parameters
of Gargiulo’s TDS to modify to achieve a TDS “effective to deliver a
therapeutically effective amount of the tertiary amine drug through skin for
at least 3 day” with a reasonable expectation of success, much less to arrive
at a TDS with 50% of the free base of the drug being associated with a
carboxylic acid group to form a salt.
At best, the references suggest a number of possible parameters, albeit
those parameters do not include the relative amounts of free base and
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carboxyl group-containing compound, that might be modified in an effort to
try to achieve a TDS that is effective to deliver a therapeutically effective
amount of the tertiary amine drug through skin for at least 3 days, without
indicating which of the various parameters were critical and no direction as
to which of many possible choices is likely to be successful. Thus, we
conclude the references provide an invitation to experiment that does not
equate with obviousness under § 103. See In re Kubin, 561 F.3d 1351, 1359
(Fed. Cir. 2009).
Consequently, we do not affirm the Examiner’s rejection of claims 1–
14 and 16–19 as obvious over Gargiulo, Duro-Tak, Chan, Audett, and
Kochinke.
The Examiner relies on Breitenbach in rejecting claims 1–19 and 31
only as teaching that it was “well-known at the time of the instant
application to include plasticizers in transdermal PSA matrices containing
rivastigmine.” (Final Action 11.) That finding, even if true, does not cure
the deficiencies just discussed. Consequently we also do not affirm the
Examiner’s rejection of claims 1–19 and 31 as obvious over Gargiulo, Duro-
Tak, Chan, Audett, Kochinke, and Breitenbach.

II. Claim 22 and dependent claims thereof
Claim 22 requires a TDS to include a rate-controlling membrane, and
a face adhesive including a carboxyl group-containing compound, and a
separate polymer matrix that includes the free base from of a tertiary amine
drug. An additional structural requirement of the TDS required by claim 22
is that the rate-controlling membrane be disposed between the polymer
matrix and the face adhesive layer. Unlike claim 1, claim 22 does not have a
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salification limitation. Claim 22, like claim 1 however, does require that the
TDS structure with the claimed elements “is effective to deliver a
therapeutically effective amount of the tertiary amine drug through skin for
at least 3 days.”
The Examiner finds that the claim does not provide for any
“particularly limiting definition or configuration of ‘rate controlling
membrane’.” (Final Action 4.) The Examiner concludes that “any
membrane which is described as contributing to the effective delivery of
active agent from a polymeric matrix will be considered a ‘rate controlling
membrane.’” (Id.)
The Examiner finds that Kanios teaches
that rate controlling membranes and drug permeable adhesive
layers are known to be usefully employed in reservoir-type
transdermal drug delivery devices, where the active agent is
isolated from the adhesive used to affix the device to the user
such as those disclosed by Gargiulo, as means to effectively
control the delivery rate of the active agent and attachment of
the device to the user. (Col.1, L.37-65).
(Final Action 13.)
The Examiner finds that Yum teaches a TDS where the polymeric
matrix is separated from the face adhesive by a rate controlling membrane.
(Id.)
We again disagree with the Examiner’s conclusion of obviousness.
Our conclusion rests on the fact that, contrary to the Examiner’s position
(Ans. 18), Gargiulo describes a TDS that is not designed to include a rate
controlling membrane.
As indicated in Chan “there are two types of transdermal delivery
systems: a drug reservoir-in-adhesive system and a drug matrix-in-adhesive
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system. (Chan 770; see also Kanios 1:38–39.) Each of the structures are
illustrated in the figures below.

Figures 1 and 2 above, reproduced from Chan (Chan 770), depict the two
structurally different transdermal patches. Chan explains that in the drug
matrix-in-adhesive TDS, the drug is dissolved in a semisolid matrix,
whereas in the drug reservoir-in-adhesive TDS, there is a liquid
compartment containing a drug solution or suspension, that is separate from
the adhesive layer, where the liquid compartment is separated from the
adhesive layer by a semi-permeable membrane. (Id.; see also Kanios 1:50–
2:5; Yum ¶ 76.)
The TDS described in Gargiulo is the structure described in Figure 2,
where the drug is not separated from the adhesive layer with a rate-
controlling membrane, but is rather part of the adhesive reservoir matrix.
(Gargiulo ¶ 17 (noting that the adhesive properties of a “poorly adhesive
reservoir matrix” was increased by the addition of a line of silicone
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adhesive, but “without reducing the release of active ingredient from the
matrix and its permeation through the skin.”); see generally id. ¶¶ 12–16,
18.) Consequently, we disagree with the Examiner’s finding that Gargiulo
teaches a “reservoir-type transdermal drug delivery devices, where the active
agent is isolated from the adhesive used to affix the device to the user”
(Final Action 13).
We do not find the Examiner has established on this record that a
person of ordinary skill in the art would have included a rate controlling
membrane such as described in Kanios or Yum for use in a drug reservoir-
in-adhesive TDS in the drug matrix-in-adhesive TDS described in Gargiulo.
Indeed, Yum describes inclusion of a separate rate controlling membrane in
the devices set forth in Figure 1, “where the reservoir is either a liquid or gel
reservoir, or a non-adhesive matrix.” (Yum ¶ 76.) Yum further explains
that an adhesive layer in such reservoir systems itself may be a rate-
controlling layer, but that in some such systems, “a further rate controlling
membrane” is included. (Id. ¶ 96.) On the other hand, Yum does not ever
describe including a rate controlling membrane in devices where the
reservoir that includes the drug is “a matrix-type reservoir” where the matrix
is an adhesive. (See, e.g., id. ¶¶ 81–85, 88.)
Consequently, we do not affirm the Examiner’s rejection of claim 22–
28, and 32 as being obvious from Gargiulo, Duro-Tak, Chan, Audett,
Kochinke, Kanios, and Yum.
Furthermore, the Examiner does not rely on Kanios or Yum to address
the deficiency of the rejection of claim 1 as being obvious over Gargiulo,
Duro-Tak, Chan, Audett, and Kochinke. Consequently, we do not affirm the
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Examiner’s rejection of claims 1–14, 16–19, and 31 as being obvious from
Gargiulo, Duro-Tak, Chan, Audett, Kochinke, Kanios, and Yum.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–14, 16–19 103 Gargiulo, Duro-
Tak, Chan, Audett,
Kochinke
1–14, 16–19
1–19, 31 103 Gargiulo, Duro-
Tak, Chan, Audett,
Kochinke,
Breitenbach
1–19, 31
1–14, 16–
19, 22–28,
31, 32
103 Gargiulo, Duro-
Tak, Chan, Audett,
Kochinke, Kanios,
Yum
1–14, 16–
19, 22–28,
31, 32
Overall
Outcome
1–19, 22–
28, 31, 32

REVERSED