Ex Parte Mueller et al

Patent Trial and Appeal Board

Oct 30, 2018

10936620 (P.T.A.B. Oct. 30, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/936,620 09/07/2004
28997 7590 11/01/2018
HARNESS, DICKEY, & PIERCE, P.L.C
7700 Bonhomme, Suite 400
ST. LOUIS, MO 63105
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Walter Mueller
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.
6102-000078/US/DVA 8245
EXAMINER
GHALI, ISIS AD
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
11/01/2018 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):
stldocket@hdp.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte WALTER MUELLER and JAMES V. PECK
Appeal2017-001048
Application 10/936,620
Technology Center 1600
Before MICHAEL FITZPATRICK, ULRIKE W. JENKS, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellants 1 appeal from the
Examiner's decision to reject claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.
1 Appellants identify the real party in interest as L TS Lohmann Therapie-
Systeme AG and UCB Manufacturing Ireland Limited. Appeal Br. 3. An
oral hearing was held on October 11, 2018.
Appeal2017-001048
Application 10/936,620
STATEMENT OF THE CASE
Claims 1-7, 12-16, and 45-51 2 are on appeal, and can be found in the
Claims Appendix of the Appeal Brief. Claim 1 is representative of the
claims on appeal, and reads as follows:
1. A method for producing a matrix layer suitable for
transdermal administration of a therapeutic effective amount of
(-)-5,6,7 ,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino ]-1-
naphthalenol free base, the method comprising:
(a) mixing a solution comprising (-)-5 ,6, 7 ,8-tetrahydro-6-
[propyl-[2-(2- thienyl)ethyl]amino ]-1-naphthalenol free
base and organic solvent with soluble
polyvinylpyrrolidone and amine-resistant silicone
adhesive to form a mass;
(b) coating the mass onto a sheet; and
( c) removing solvent in a drying process.
Appeal Br. 14 (Claims Appendix).
Appellants request review of the rejection of claims 1-7, 12-16, and
45-51 under 35 U.S.C. § 103(a) as unpatentable over Timmerman, 3 Wolter, 4
Yamanaka, 5 Hsu, 6 and Miranda. 7
Examiner finds that Timmerman recognized the advantage of
transdermal delivery ofN-0437 (rotigotine) but does not disclose a
transdermal composition comprising a silicone adhesive and
2 Claims 17--44 are withdrawn from consideration. Appeal Br. 5.
3 Wia Timmerman et al., Microdialysis and striatal dopamine release:
stereoselective actions of the enantiomers of N-0437, 163 EUROPEAN J.
PHARMA. 143-150 (1989) ("Timmerman").
4 Wolter et al., US 5,462,746, issued Oct. 31, 1995 ("Wolter").
5 Yamanaka et al., US 5,830,497, issued Nov. 3, 1998 ("Yamanaka").
6 Hsu et al., WO 94/07468, published April 14, 1994 ("Hsu").
7 Miranda, WO 95/18603, published July 13, 1995.
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Application 10/936,620
polyvinylpyrrolidone (PVP). See Final Act. 5. 8 Examiner looks to Wolter
for teaching the production of a transdermal patch. Id. Examiner also looks
to Yamanaka for teaching a transdermal device that incorporates active
agents in an acrylic-based adhesive and for suggesting silicone-rubber
adhesive as the acrylic-based adhesive. Id. at 5-6. Examiner finds that
"[t]he reference teaches that the adhesive composition comprises acidic or
basic substances." Id. at 6. Hsu teaches a rotigotine transdermal patch using
an amine-resistant silicone-based matrix. Id. Miranda teaches a transdermal
patch that includes polysiloxane adhesive such as BIO-PSA X7-4301, which
is an amine resistant silicone adhesive, and PVP. Id. at 7. Based on the
combined teachings, Examiner concludes that the method of producing a
transdermal delivery system having rotigotine imbedded in an amine-
resistant silicone adhesive containing PVP is obvious. Id.
The issue is: Has Examiner set forth a prima facie case of
obviousness based on the preponderance of the evidence of record? And if
so, have Appellants provided enough rebuttal evidence that outweighs the
prima facie case of obviousness?
Principle of Law
"After a prima facie case of obviousness has been made and rebuttal
evidence submitted, all the evidence must be considered anew." In re Eli
Lilly & Co., 902 F.2d 943, 945 (Fed. Cir. 1990) (citing In re Piasecki, 745
F.2d 1468, 1472 (Fed. Cir. 1984)).
8 Final Office Action mailed January 14, 2016 ("Office Act.").
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Application 10/936,620
Analysis
Appellants contend that the art in the field of transdermal therapeutic
systems is not sufficiently predictable to render the combination as proposed
by Examiner obvious. See generally Appeal Br. 6-13. This is the second
time this case is before us, and the rejection is similar to our prior decision
but for the inclusion of the Yamanaka reference. See Patent Board Decision
(Appeal 2012-009710) mailed April 27, 2015. In the decision, we affirmed
Examiner's prima facie case of obviousness and indicated that Appellants
had not provided sufficient rebuttal evidence to overcome the prima facie
case. Examiner's position in this appeal and the prior appeal is that absolute
predictability is not required for a finding of obviousness. See Ans. 3-19;
see Final Act. 12-14. Examiner finds the declarations insufficient to
overcome the prima facie case of obviousness. Ans. 4--5, 9 17-19. In this
appeal, Appellants have provided two declarations addressing the state of the
art at the time of the invention and addressing the lack of reasonable
expectation of Examiner's rejection. See Appeal Br. 7. 10
9 Examiner finds the declarations to be unpersuasive because they did not
provide evidence with respect to "commercial success." Ans. 5-7. We
agree with Appellants' position on this point, their arguments are not
directed at establishing commercial success, but instead address the lack of
reasonable expectation of success based on the unpredictability in the art.
See Reply Br. 2-3.
10 Examiner's position is that"[f]ailure oftransdermal delivery of lisuride,
and other drugs, is not [] evidence that rotigotine would fail, particularly in
absence of information about the formulation used to deliver lisuride. No
showing by declarations previously provided of failure of delivery of
rotigotine in a transdermal patch in order to establish a strong evidence."
Ans. 14 (emphasis removed). We do not agree with Examiner's position
that the only way to establish lack of predictability in the art is to show that
rotigotine fails in other systems. We find showing the difficulty of
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Application 10/936,620
We are not persuaded by Examiner's contentions that the declaratory
evidence is insufficient to establish a lack of reasonable expectation in the
field of formulating transdermal therapeutic systems. Claim 1 recites a
"matrix layer suitable for transdermal administration of a therapeutic
effective amount of' rotigotine, a reasonable interpretation of this limitation
is that the product made by the disclosed method must adhere to the skin, for
a sufficient length of time in order to allow the transport of sufficient active
agent (i.e. therapeutic agent) across the skin barrier to a subject so as to have
a therapeutic effect. See Spec. 5: 5-9 ( a single phase matrix: active
substance-containing self-adhesive matrix), id. at 9:3 (daily dose 1-10 mg),
id. at 11: 10-14 ( with "the free bases the active substance release is markedly
improved as compared to the use of salts .... [S]ilicone adhesive-based
plasters, although having a considerably lower active substance content,
deliver approximately the same quantity of active substance via the skin as
the systems based on polyacrylate adhesives").
In their rebuttal, Appellants provide the declarations by Dr. W olff11
and Dr. Arth, 12 in conjunction with their accompanying exhibits, to support
the position that formulating drugs into a transdermal delivery system would
not have been predictable to one of ordinary skill in the art at the time of the
invention was made. According to declarants, even if you can formulate a
formulating other amine containing drugs into a therapeutic transdermal
delivery system is sufficiently probative that a person of ordinary skill in the
art would not reasonably have expected success with rotigotine.
11 Declaration under 37 C.F.R. § 1.132 by Dr. Wolff signed June 25, 2015
("Wolff Dec 1. ").
12 Declaration under 37 C.F.R. § 1.132 by Dr. Arth signed June 26, 2015
("Arth Deel.").
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Appeal2017-001048
Application 10/936,620
product into a patch, that doesn't mean that the application of the patch to a
subject will actually provide a therapeutic effect. See Wolff Deel. ,r,r 18-19
( citing Montastruc 13), see Arth Deel. ,r,r 18-19 ( citing Montastruc ).
Montastruc teaches a "transdermal patch [that] was a 30-cm2 matrix
containing 50 mg micronized piribedil and an adhesive strip." Montastruc
337 (Study Treatment). The goal in Montastruc was to avoid hepatic first
pass effect observed for piribedil when taken orally, the study, however, did
not show clinical efficacy. Id. at 340. The lack of clinical efficacy could be
due to a too short of treatment course or not achieving sufficient plasma
concentration levels in the patch tested. Id. at 341. To achieve "improved
bioavailability of patch-delivered piribedil would require an increase in
adhesive area ( currently 30 cm2), which would be difficult to put into
practice." Id. Thus, formulating piribedil into a patch would not result in an
effective therapy because it would not deliver sufficient amount of the drug
into the plasma given the constraints of the size of the patch. This supports
the position that it would not be predicted beforehand whether a particular
combination would be reasonably successful in providing a therapeutic
effect.
Declarants further assert that the difficulty of formulating transdermal
delivery is further illustrated by the lack of a product in the field.
Rotigotine, the drug of interest in the present application, is the only
dopamine agonist commercially available for transdermal administration.
13 Jean-Louis Montastruc et al., A Randomized, Double-Blind Study of a Skin
Patch of a Dopaminergic Agonist, Piribedil, in Parkinson's Disease, 12
MOVEMENT DISORDERS 33 6-41 ( 1999) ("Montastruc"), submitted as
Exhibit 8, in both the Wolff Deel. and Arth Deel.
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Application 10/936,620
See Wolff Deel. ,r 15(citing Farlow14); see Arth Deel. ,r 15 (citing Farlow).
The commercial rotigotine system is a two-phase patch and not a single
matrix ( active agent distributed in adhesive) as presently claimed.
Farlow explains that "the use of transdermal systems of delivery is
restricted to those drugs able to penetrate the skin and enter the blood
system, although new technological developments may extend the range of
drugs appropriate for transdermal delivery." Farlow 3. Farlow explains that
the advantage of "[t]ransdermal patches [is] deliver[y ofJ drugs directly into
the circulatory system, bypassing the gastrointestinal system and avoiding
the hepatic first-pass effect." Id. "Despite recent advances in patch
technology, skin application site reactions may still occur with transdermal
medications." Id. at 6. We agree with Appellants that Farlow reasonably
provides evidence that the ability to formulate a known drug into a
transdermal delivery system is only part of the puzzle. Without more, there
is no way of predicting beforehand whether the skin will develop a site
reaction that would prevent the application of the delivery system in a
therapeutic setting.
Further to this point, Declarants attest that it could not be known
beforehand whether a particular transdermal product once formulated into
the patch will be sufficiently non-irritating to make therapy possible. Wolff
Deel. ,r 17 (citing Nenad), see Arth Deel. ,r 17 (citing Nenad). "Nenad has
been developed as matrix type transdermal patch. The active substance is
14 Martin R. Farlow and Monique Somogyi, Transdermal patches for the
treatment of neurologic conditions in elderly patients: a review, 13 PRIM.
CARE COMPANION CNS DISORD., 1-10 (2011).
(https ://www.ncbi.nlm.nih.gov/pmc/ articles/PM C3 3 04686/) ("Farlow"),
submitted as Exhibit 4, in both the Wolff Deel. and Arth Deel.
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Appeal2017-001048
Application 10/936,620
homogeneously dispersed in a self-adhesive matrix." Nenad 2.2 (Drug
Product). Specifically, Nenad 15 disclosed that the active amine containing
agent - lisuride - was homogeneously dispersed in a self-adhesive matrix
layer containing lisuride, butylated methacrylate copolymer, succinic acid,
dibutyl sebacate. Id. at2.3 (Introduction). Drug-related irritant skin
reactions and inadequate adhesiveness were contributing factors for
discontinuing the use of this patch. Id. at 45 (Conclusion). Based on the
evidence presented in the two declarations, we find that Appellants have
sufficiently established that formulating a drug into a transdermal
therapeutic system is not reasonably predicable. On this record, we agree
with Appellants' position that the method of making a rotigotine containing
adhesive silicone matrix, as recited in claim 1, is not obvious because the
combination is not reasonably predictable to produce a product that can
deliver a therapeutic amount of rotigotine without causing undesirable skin
irritation.
Appellants' presented evidence that is sufficient to support the
contention that the method of formulating a single-phase transdermal
therapeutic system involving rotigotine is not reasonably predictable.
Thereby, Appellants have overcome Examiner's rejection.
SUMMARY
We reverse all rejections.
REVERSED
15 European Medicines Agency, WITHDRAWAL ASSESSMENT REPORT FOR
NENAD, 1--44 (Feb. 18, 2010) ("Nenad").
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