Ex Parte Muller et al

Patent Trial and Appeal Board

Oct 30, 2018

11931762 (P.T.A.B. Oct. 30, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
11/931,762 10/31/2007
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 Muller
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/COC 1601
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 MULLER and JAMES V. PECK
Appeal2017-001052
Application 11/931, 7 62
Technology Center 1600
Before MICHAEL J. 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.
Appeal2017-001052
Application 11/931,762
STATEMENT OF THE CASE
Claims 30-38 and 60-692 are on appeal, and can be found in the
Claims Appendix of the Appeal Brief. Claim 30 is representative of the
claims on appeal, and reads as follows:
30. A transdermal therapeutic system (TTS) comprising a self-
adhesive matrix that comprises an acrylate-based or silicone-
based polymer adhesive system having distributed therein (-)-
5,6,7 ,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino ]-1-
naphthalenol [3J free base in an amount of about 5% to 40% by
weight of the matrix.
Appeal Br. 16 (Claims Appendix).
Appellants request review of the following grounds of rejections made
by Examiner:
I. Claims 30-38 and 61-63 under 35 U.S.C. § I03(a) as unpatentable
over Timmerman4 and Yamanaka. 5
II. Claims 60 and 64---69 under 35 U.S.C. § I03(a) as unpatentable over
Timmerman and Yamanaka in view of Miranda. 6
2 Claims 39-48 and 59 are withdrawn from consideration as being directed
to nonelected invention. Final Act. 2 (Final Office Action mailed July 27,
2015).
3 Also known as rotigotine. See PubChem,
https ://pub chem. nc bi.nlm.nih. gov/ compound/ 5 922 7 #section= Synonyms, last
accessed October 25, 2018.
4 Wia Timmerman et al., Microdialysis and striatal dopamine release:
stereoselective actions of the enantiomers of N-043 7, 163 EUROPEAN J.
PHARMA. 143-50 (1989) ("Timmerman").
5 Yamanaka et al., US 5,830,497, issued Nov. 3, 1998 ("Yamanaka").
6 Miranda, WO 95/18603 Al, published July 13, 1995.
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Appeal2017-001052
Application 11/931,762
Obviousness over Timmerman and Yamanaka
Examiner finds that "Timmerman recognized the advantage of
transdermal delivery of N-0437" (rotigotine) but does not disclose a
transdermal therapeutic system comprising an acrylic-based polymer or
silicone based adhesives polymer. Office Act. 5. 7 Examiner looks to
Yamanaka's teaching of a transdermal device that incorporates active agents
in an adhesive. Id. Examiner finds that "[t]he reference teaches that the
adhesive composition comprises acidic ... [and] basic substances." Id.
Based on these teachings, Examiner concludes that
at the time of the invention it was known to deliver N-0437 free
base transdermally with the advantage of avoiding possible first-
pass metabolism as taught by Timmerman. It was further known
at the time of the invention to deliver basic drugs transdermally
and preferably those drugs containing amino groups from
adhesive polymer composition comprising acrylic or silicone
adhesives as taught by Yamanaka. Yamanaka further teaches
that even if salts of the drug were to be included in the adhesive
composition, the presence of basic substance in the adhesive
composition serves to form free base medicine from its salt,
thereby facilitating the release of medicine.
Id. at 6.
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?
Findings of Fact
FF 1. Timmerman discloses the claimed compound rotigotine "[ fJor
transdermal administration the HCl salts or(+)- and (-)N-0437 [(2-
7 Non-Final Office Action mailed July 27, 2015 ("Office Act.").
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Application 11/931,762
(N-propyl-N.2-thienylethylamino )- 5· hydroxytetralin)] were
converted into the free base form using triethylamine." Timmerman
at 144, see id. Abstract, see id. at 148.
FF2. Yamanaka teaches pressure-sensitive adhesive layers that "serve[] to
hold a basic medicine, and/or a salt thereof and an acidic (and/or
basic) substance and to ensure adhesion of the plaster to the skin."
Yamanaka at 2:24--27. Pressure sensitive adhesive include acrylic
polymers (see id. at 2:28--41) as well as elastomeric polymers such as
silicone rubber. See id. at 4:3-5. Examples of the acrylic pressure-
sensitive adhesive, include for example butyl (meth)acrylate. Id. at
2:36.
FF3. The Specification discloses several examples of a rotigotine
containing adhesives. Spec. ,r,r 33-59. Suitable polyacrylate
adhesives include: Durotak 387-2051, Durotak 387-2287, Durotak
387-2353, Durotak 387-2516. See id. ,r,r 37, 45, 49, 57. Suitable
silicone adhesives include: BIO-PSA Q7-4301, BIO-PSA Q7-420I.
See id. ,r,r 43, 46. Of the adhesive listed in the Specification only
Durotak 387-2287 and BIO-PSA Q7-4301 were actually made and
tested. See id. ,r,r 33-59.
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)).
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Application 11/931,762
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. 6-15. This is the second
time this case is before us, and the rejections have remained the same since
our prior decision. See Patent Board Decision (Appeal 2012-012346) mailed
April 30, 2015. Examiner's position in this appeal and the prior appeal is
that absolute predictability is not required for reaching a conclusion of
obviousness. See Ans. 3-18; see Office Act. 4--9; see FF1-FF2. In the prior
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. In this appeal, Appellants have provided two
declarations addressing the state of the art at the time of the invention, as
well as addressing the lack of predictability in formulating transdermal
medicines in general. See Appeal Br. 9. Examiner finds the declarations
insufficient to overcome the prima facie case of obviousness. Ans. 4--5. 8
Specifically, Examiner contends that evidence of unsuccessful patches using
other drugs says nothing about formulating rotigotine into a patch. See Ans.
7.9
8 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 that their arguments are not directed at
establishing commercial success, but instead present arguments addressing
the lack of reasonable expectation of success based on the combination of
references. See Reply Br. 2-3.
9 "Failure of transdermal delivery of lisuride, and other drugs, is not an
evidence that rotigotine would fail, particularly in absence of information
about the formulation used to deliver lisuride." Ans. 14 ( emphasis
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Application 11/931,762
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 30 recites a
"transdermal therapeutic system," although the Specification does not
provide a definition of this term, a reasonable interpretation is that this
encompasses a patch that 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 of a subject so as to have a therapeutic effect.
See Spec. ,r 16 ( a single phase matrix: active substance-self adhesive
matrix), id. at ,r 26 (daily dose 1-10 mg), id. at ,r 31 (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. Wolff10
and Dr. Arth, 11 in conjunction with their exhibits, to support the position that
formulating drugs into a transdermal delivery system would not have been
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 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.
10 Declaration under 37 C.F.R. § 1.132 by Dr. Wolff signed June 25, 2015
("Wolff Deel.").
11 Declaration under 37 C.F.R. § 1.132 by Dr. Arth signed June 26, 2015
("Arth Deel.").
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Application 11/931,762
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 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 16 (citing
Montastruc 12), see Arth Deel. ,r 16 ( citing Montastruc ).
Montastruc teaches a "transdermal patch [that] was a 3 O-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 a 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.
12 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 336--41 (1999) ("Montastruc"), submitted as
Exhibit 7, in both the Wolff Deel. and Arth Deel.
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Application 11/931,762
Rotigotine, the drug of interest in the present application, is the only
dopamine agonist commercially available for transdermal administration.
See Wolff Deel. ,r 12 (citing Farlow13); see Arth Deel. ,r 12 (citing Farlow).
The commercial rotigotine system is a two-phase patch and not a single
matrix 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 at 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
13 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/PMC3 304686/) ("Farlow"),
submitted as Exhibit 4, in both the Wolff Deel. and Arth Deel.
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Appeal2017-001052
Application 11/931,762
Deel. ,r 14 (citing Nenad), see Arth Deel. ,r 14 (citing Nenad). Declarants
direct us to "the failure of lisuride, an amine containing compound in patch
form." See Wolff Deel. ,r 19, ,r 14; see Arth Deel. ,r 19, ,r 14. The
experience with lisuride runs counter to "any reasonable expectation of
success." See Wolff Deel. ,r 19, ,r 14; see Arth Deel. ,r 19, ,r 14. "Nenad has
been developed as matrix type transdermal patch. The active substance is
homogeneously dispersed in a self-adhesive matrix." Id. (Drug Product).
Specifically, Nenad 14 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. Nenad 2.2 (Introduction). Drug-related irritant skin reactions and
inadequate adhesiveness were contributing factors for discontinuing the use
of this patch. Id. ( conclusion). Here, lisuride, an amine containing
compound, was formulated into a methacrylate copolymer, like the one
taught in Yamanaka (FF2), but this combination was too irritating to
function as a therapeutic system. 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
formulating rotigotine into an adhesive acrylate containing matrix, as recited
in claim 30, is not obvious because the combination is not reasonably
predicable
14 European Medicines Agency, WITHDRAWAL ASSESSMENT REPORT FOR
NENAD, 1--44 (Feb. 18, 2010) ("Nenad"), submitted as Exhibit 6, in both the
Wolff Deel. and Arth Deel.
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Appeal2017-001052
Application 11/931,762
Appellants presented sufficient evidence to support the contention that
formulating a single phase transdermal therapeutic system involving
rotigotine is not reasonably predictable. Thereby, Appellants provided
sufficient evidence to overcome Examiner's rejections relying on the
combination of Timmerman and Yamanaka.
SUMMARY
We reverse all rejections.
REVERSED
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