Ex Parte Lauterbach et al

Patent Trial and Appeal Board

May 31, 2016

10140096 (P.T.A.B. May. 31, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/140,096 0510712002
28997 7590 06/02/2016
HARNESS, DICKEY, & PIERCE, PLC
7700 Bonhomme, Suite 400
ST. LOUIS, MO 63105
FIRST NAMED INVENTOR
Thomas Lauterbach
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.
6102-000064/US 5664
EXAMINER
YOUNG, MICAH PAUL
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
06/02/2016 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
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 THOMAS LAUTERBACH, WALTER MULLER,
DIETRICH WILHELM SCHACHT, and HANS-MICHAEL WOLFF 1
Appeal2014-000987
Application 10/140,096
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS, and
ROBERT A. POLLOCK, Administrative Patent Judges.
PERCURIAM
DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) from the
Examiner's rejection of claims 12, 30, 32 and 33. We have jurisdiction
under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
The Specification discloses "the use of a Transdermal Therapeutic
System (TTS) for delivering the dopamine receptor agonist rotigotine ... to
1 Appellants identify the Real Parties in Interest as L TS Lohmann Therapie-
Systeme AG and UCB Pharma GMBH (App. Br. 3).
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Application 10/140,096
provide therapeutically effective treatment or alleviation of symptoms of
Parkinson's disease." Spec. 1:12-16. "[A] silicone-based TTS containing
rotigotine in the free base form provides mean maximum drug plasma levels
in the range of almost 0.5 ng/ml for a 20 cm2 silicone patch containing 9 mg
ofrotigotine." Id. at 6:17-21.
Claim 12, the only independent claim before us, recites:
12. A method for treating a subject suffering from
Parkinson's disease, comprising administering to the subject
once daily a transdermal therapeutic system having an area of
10 to 40 cm2, comprising a matrix that comprises at least one
high tack and at least one medium tack pressure sensitive
silicone adhesive, said matrix having dispersed therein 0.1 to
3.15 mg/cm2 of rotigotine free base as an active ingredient and
a solubilizer, wherein the system induces a mean plasma
concentration of rotigotine in the subject in the range of 0.4 to 2
ng/ml 24 hours after administration.
App. Br. 11 (Claims Appendix).
Issue
The Examiner has rejected claims 12, 30, 32 and 33 under 35 U.S.C.
§ 103(a) as obvious in view of Muller. 2'3 Ans. 4---6.
The issue presented is: Does the evidence of record support the
Examiner's conclusion that Muller would have made obvious a method for
treating Parkinson's disease comprising administering to a subject, once
daily, a transdermal therapeutic system comprising a matrix with at least one
2 Walter Muller et al., WO 99/49852 Al, published Oct. 7, 1999.
3 Citations to Muller are to the English language equivalent, Walter Muller
1 U-.-, 6- R·-4 4'~4B)1 . -d \ ,)<- '),f10'1 et a ., -- S ,c.o ) · _1 · , issue i-\pr. LO) LA. ~-.
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Application 10/140,096
high tack and at least one medium tack pressure sensitive silicone adhesive,
a solubilizer, and 0.1 to 3 .15 mg/cm2 of rotigotine free base, and comprising
an area of 10 to 40 cm, 2 "wherein the system induces a mean plasma
concentration of rotigotine in the subject in the range of 0.4 to 2 ng/ml 24
hours after administration," as required by claim 12?
Analysis
We have reviewed Appellants' contentions that the Examiner erred in
rejecting claims 12, 30, 32, and 33 as obvious over the cited art. App. Br. 6-
10. We disagree with Appellants' contentions and adopt the findings
concerning the scope and content of the prior art set forth in the Examiner's
Answer and the Non-Final Rejection dated December 18, 2012. For
emphasis, we highlight and address the following:
1. The Specification discloses that preferred solubilizers for use in
the TTS patch system include soluble polyvinylpyrrolidone, which is
commercially available as Kollidon®. Spec. 8:16-20. Preferred adhesives
are "BIO-PSA silicone pressure sensitive adhesives manufactured by Dow
Coming, particularly the Q7-4201 and Q7-4301 qualities. A mixture of ...
Q7-4201 (medium tack) and Q7-4301 (high tack) amine resistant silicone
pressure sensitive adhesives in about equal amounts" was particularly
useful." Id. at 7:29-31 and 8: 16-20.
2. "Rotigotine is the International Non-Proprietary Name (INN) of
the compound (-)-5,6,7 ,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino ]-
1-naphthalenol." Id. at 3:36-4:1.
3. Muller discloses a "transdermal therapeutic system comprising
a self-adhesive matrix layer containing the free base (-)-5,6, 7 ,8-tetrahydro-6-
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[propyl-1 [2-(2-thienyl)ethyl]amino ]-1-naphthalenol [(i.e., free base
rotigotine)] in an amount effective for the treatment of the symptoms of
Parkinson's syndrome, wherein the matrix is ... [a] silicone-based polymer
adhesive system." Muller, Claim 1. "[I]n connection with silicone
adhesives only the active substance base is suitable." Id. at 3:60-63.
4. Muller discloses that "[a]bout 1.5-5% (w/w) of
polyvinylpyrrolidone in an amine-resistant silicone adhesive increase the
solubility of [rotigotine] to about 10-15% (w/w)." Id. at 4:6-9. "This is
sufficient to dissolve 10 mg active substance in a 20 cm2 large patch having
a coat weight of the matrix of 50 g/m2." Id. at 4:9-11. "[O]nly about 50%
of the active substance employed will be available during the period of
application ... [and] given a daily dose in the range of 1-10 mg of the active
substance[,] a plaster size of between 2 and 40 cm2 can be expected ... to
achieve therapeutic plasma levels." Id. at 4: 11-17; see also, id. at 5: 14--18
(The disclosed systems "make it possible to administer the necessary daily
dose of the dopamine agonist ... transdermally through the skin by means of
a patch having a size of approximately 20 cm2").
5. Muller Example 2 discloses a silicon system in which 18 grams
of rotigotine "dissolved in 40 g ethanol are added to 24 g of a 25% solution
of Kollidon 90F and the mass is homogenized ... 251 g of a solution of an
amine[-]resistant silicone adhesive ... are added to this mass, and the mass
is homogenized." Id. at 5:56-61. "[T]he mass is coated ... onto a polyester
film ... [at a dry] coat weight of 50 g/m2." Id. at 5:65---6:2. "The
concentration of [rotigotine] base in the patch matrix is 9%." Muller, 6:7-9.
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Application 10/140,096
"Suitable amine-resistant silicone adhesives are, for example, BIO-PSA Q7-
4301 and BIO-PSA Q7-4201." Id. at 6:10-11.
6. Figure 1 of Muller is shown below:
Figure 1 shows a plot of "permeation rates through human epidermis
achieved under in-vitro conditions." Id. at 6:13-14; see id. at 2:44--46 and
5:3---6.
7. Muller describes the transdermal system of Hsu4 as containing
rotigotine "as hydrochloride in a two-phase matrix which is formed
substantially by a hydrophobe polymer material ... with hydrated silicate
dispersed therein for taking up the hydrophile drug salt." Id. at 2:5-13.
"This system has the disadvantage that the active substance salt must be
mixed with the silicate in aqueous solution, and that an additional emulsifier
is necessary to emulsify this aqueous solution with the lipophile polymer."
Muller 2: 14--17. "Due to coating problems, it is much more difficult to
manufacture transdermal systems using this emulsion. In addition ... only
4 Tsung-Min Hsu et al., WO 94/07468 Al, published April 14, 1994
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the salt can be used, since only the salt is sufficiently hydrophil[ic] to be
soluble in water." Muller 2: 19-23. "It is thus the object of the invention to
develop systems for [ rotigotine] avoiding the disadvantages of the system
described in WO 94-07468." Muller, 2:24--30.
8. Appellants have provided a declaration under 37 C.F.R. § 1.132
(Declaration of Michael Wolff, filed Dec. 16, 2005, cited at App. Br. 7). Dr.
Wolff quotes the following paragraphs, among others, from WO 96/40139 5
The failure of the transdermal route to fulfill the initial
expectations of its potential as an administrative portal was
primarily due to the incredible variety of properties with which
nature has endowed the skin to permit it to perform its function
as the primary barrier to prevent the ingress of foreign substances
into the body. See Transdermal Drug De[l]ivery: Problems and
Possibilities, B. M. Knepp, et al, CRC Critical Reviews and
Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987).
Thus, the transdermal route of administration, rather than being
available to every short half-life agent of high potency and skin
permeability, was found to be available only to those few agents
that possess the proper combination of a host of characteristics,
most of which are unpredictable, required to render the agent
suitable for safe and effective transdermal administration.
Wolff Declaration, i-f 8.
9. Dr. Wolff declares that the "lack of predictability and
difficulties associated with transdermal formulation were well documented
at the time the ... [instant] application was filed." Id. i-f 10. "[O]ne skilled
in the art of transdermal formulation would not expect that determining
5 Su II Yum, et al., WO 96/40139, published Dec. 19, 1996
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specific dosage regimens and specific concentrations of excipients could be
readily ascertained for a transdermal system." Id. i-f 10.
10. Bondi,6 a reference cited by Appellants (App. Br. 8), discloses
"a transdermal delivery system suitable for the administration of ( 4aR-
trans)-3,4,4a,5,6, 1Ob-hexahydro-4-propyl-2H-naphth[1,2-b] 1,4-oxazin-9-ol
over an extended period of time." Bondi, 1:4--8. The compound "is useful
in the treatment of Parkinson's disease." Id. at 1:10-27.
The Examiner finds that Muller discloses a transdermal patch
"identical to those of the instant claims." Ans. 6 ("[Muller's] formulation is
of the same size, shape and is applied for the same purposes" as the patch of
claim 12.). In particular, Muller's transdermal patches are useful in treating
Parkinson's disease, have an area of 2 to 40 cm2, and comprise from 10-
15%, about 0.5 mg/cm2 rotigotine free base as an active ingredient; "a
matrix that comprises at least one high tack and medium tack silicone
pressure sensitive adhesive;" and a solubilizer such as polyvinylpyrrolidone.
Ans. 4--5. In some embodiments, "[t]he patch is free of hydrochloride
impurities[, ]can measure in size about 20 cm2" and, as shown in Example 2,
comprise "about 4.5 mg of rotigotine." Id. at 5.
The Examiner further finds that, although Muller does not specify the
resulting blood plasma levels of rotigotine, "blood plasma concentration is a
structural feature of the transdermal patch and is dependent on the
compositional components of the formulation." Ans. 5. Because Muller's
patch "combines the same components, in the same concentrations in the
6 Joseph V. Bondi et al., US 4,942,037, July 17, 1990.
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same way as the instant claims .... the blood plasma concentrations must
also have the same compositional properties." Id., citing In re Spada, 911
F.2d 705, 709 (Fed. Cir. 1990). Accordingly, it would have been obvious to
use Muller's transdermal patch "to treat Parkinson's Disease ... in order to
produce a safe and effective method of treating Parkinson's disease." Ans.
5; see also id. at 5---6 (obvious "to optimize and develop a treatment regimen
for the transdermal patches of Muller").
Appellants argue that the Examiner errs in finding that once-daily
administration of Muller's patch would have inherently resulted in "a mean
plasma concentration of rotigotine in the subject in the range of 0.4 to 2
ng/ml 24 hours after administration" as set forth in claim 12. App. Br. 6-9;
see id. at 8 ("Muller does not teach or suggest the administration interval in
connection with the plasma concentration element."). In particular,
Appellants argue that the Examiner's reasoning is flawed because there
would have been no predictability in the art that the claimed plasma levels of
rotigotine could be obtained after twenty-four hours. App. Br. 7.
In support of this position, Appellants argue that because rotigotine
has a short half-life in plasma, "maintaining a therapeutically effective
plasma level for a full 24 hours after once daily administration is in-and-of-
itself highly unpredictable." App. Br. 8. Appellants further rely on the
Wolff Declaration as providing evidence for the unpredictability of
transdermal therapy (id. at 7-8, see FFs 8-9) and argue that the transdermal
systems of Hsu and Bondi were known to provide sub-therapeutic plasma
levels of anti-Parkinsonian drugs, including rotigotine. See App. Br. 8; FFs
7 and 10. Accordingly, Appellants contend that given "the general difficulty
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and unpredictably [sic] of transdermal administration combined with
rotigotine' s short half-life ... [and] the poor results of the Hsu and Bondi
... , an ordinary artisan would have no reasonable expectation that once
daily administration of a rotigotine TTS would maintain an effective plasma
concentration at even 24 hours after administration." App. Br. 8-9.
The Examiner responds that although difficulties with transdermal
patches were known in the art, Muller solves the difficulties "by providing a
functioning transdermal patch comprising rotigotine." Ans. 7. And in
contrast to Muller's disclosure, the "patches of Hsu and Bondi do not
comprise the mixture of high and medium tack silicone adhesives." Id.
Accordingly, the difficulties cited by Appellants "would not be applicable
since the patches [of Muller] are identical to the instant claims. The silicone
matrix solves the problem of short half-life and stability for the dosage
form." Ans. 7. Moreover, "Example 2 of Muller comprises the exact
silicone adhesive of the instant claims," such that Muller's silicone patches
"have the same drug, combined with the same silicone adhesives, in the
same concentration for the purpose of treating the same disease." Ans. 7.
"Products of identical chemical composition can not have mutually
exclusive properties." In re Spada, 911 F.2d 705, 709 (Fed. Cir. 1990).
Accordingly, because Muller's patches are identical to those of the instant
claims they "would predictabl[y] perform the same way." Ans. 7.
We agree with the Examiner that Muller would have made obvious a
method for treating a subject suffering from Parkinson's disease as recited in
claim 12. Claim 12 requires a transdermal therapeutic system or patch with
an area of 10 to 40 cm2 that comprises 0.1to3.15 mg/cm2, i.e. 2 to 63 mg
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for patch that is 20 cm2. Muller discloses a silicone-based polymer adhesive
patch that comprises rotigotine for the treatment of Parkinson's disease. FF
3. Muller discloses that a 20 cm2 silicone-based patch can contain 10 mg of
rotigotine, and that a patch size of between 10 to 40 cm2 can be expected to
achieve a daily dose of therapeutic plasma levels. FFs 3--4. Consistent with
this teaching, Muller discloses in vitro test results demonstrating human
epidermis permeation of rotigotine from the patch of Example 2 through and
beyond 24 hours. FF 6. Muller discloses that rotigotine free base can be
used in the silicone-based patch, and that the patch comprises a mixture of a
high tack and a medium tack silicone adhesive. See FFs 1-3. Thus, Muller
discloses a patch with the same composition, the same size, and the same
active ingredient as recited in claim 12.
Although Muller does not disclose the exact rotigotine plasma levels
recited in claim 12, we agree with the Examiner that it would have been
obvious to one of ordinary skill in the art to optimize a patch for the desired
plasma level of rotigotine. "[T]he discovery of an optimum value of a
variable in a known process is normally obvious." Exceptions to this 1u1e
include ( l) the results of optimizing a variable were unexpectedly good and
(2) the parameter optimized was not recognized in the prior mi as one which
would affect the results. In re Antonie, 559 F.2d 618, 620 (CCPA 1977).
Appe11ants do not argue that either exception applies. As in the present case,
"where the general conditions of a claim are disclosed in the prior mi, it is
not inventive to discover the optimum or workable ranges by routine
experimentation.'' In re Aller, 220 F.2d 454, 456 (CCPA 1955). Given that
the "discovery of an optimum value of a result effective variable in a known
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process is ordinarily within the skill of the art," ln re Boesch, 617 F.2d 272,
276 (CCPA 1980), we agree with the Examiner's conclusion that the method
of claim 12 with the claimed range for the mean plasma concentration of
rotigotine after 24 hours would have been obvious in view of Nluller.
<....-
Appellants' arguments with regard to the \Volff Declaration and the
Hsu and Bondi transdermal therapeutic systems are not persuasive because
none of thern discuss or disclose rotigotine base in a silicone-based patch as
claimed and as disclosed in 1\t1uller. See FFs 7----10.
Thus, we affirm the rejection of claim 12 as being obvious in view of
Muller.
Appellants also argue the rejection of dependent claims 30, 32 and 33,
which read as follows:
30. The method of claim 12, wherein the transdermal system
further comprises rotigotine hydrochloride in not more than a
trace amount.
32. The method of claim 30, wherein the trace amount of
rotigotine hydrochloride does not exceed 5 wt %, based on the
amount of the free base.
33. The method of claim 30, wherein the trace amount of
rotigotine hydrochloride does not exceed 2 wt %, based on the
amount of the free base.
Appellants argue that the Examiner has not advanced a "basis in fact
or technical reasoning" with regard to how claims 30, 32, and 33 would have
been obvious in view of Muller (App. Br. 9). In addressing Appellants'
arguments, we note the following additional facts of Muller:
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11. Muller discloses that the solubility of rotigotine base in silicone
adhesives is about 5% w/w, while "the corresponding salts are practically
insoluble therein." Muller, 3:56-61. "Thus, in connection with silicone
adhesives only the active substance base is suitable." Muller, 3:61---63.
12. Muller discloses that, "[t]o produce the patches according to
this invention, [rotigotine] or the hydrochloride is dissolved or suspended in
ethanol ... and is then added to the adhesive solution." Muller, 4:28-32.
"An auxiliary substance which advantageously is added to the active
substance solution directly is, for example, an alkaline substance which is
suit able [sic] of converting the active substance hydrochloride into the free
active substance base." Muller, 4:36-40. "[I]t is preferred to use alkali
metal hydroxide such as sodium or potassium hydroxide, or an alkali metal
silicate such as sodium or potassium trisilicate or sodium or potassium
metasilicate as the alkaline substance." Muller, 4: 41--44. "After the
reaction, the solution may optionally be filtered, whereby the reactants, with
the exception of the active substance base, are quantitatively practically
eliminated." Muller, 4: 44--47. "Said reactants are sodium chloride or
potassium chloride in the case that sodium hydroxide or potassium
hydroxide, respectively, are used, and sodium chloride or potassium chloride
and polymeric silicon dioxide in the case that sodium or potassium silicates,
respectively, are used." Muller, 4: 47-52.
13. Muller discloses, in Example 4, that "20 g [rotigotine]
hydrochloride are stirred, together with 8.0 g sodium metasilicate or 9.1 g
sodium trisilicate, in 35 ml ethanol for 48 hours, at room temperature."
Muller, 6:33-36. "Optionally, the active substance solution is now filtered
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and 6.0 g polyvinylpyrrolidone ... in [] a 25% (w/w) solution in ethanol,
and 25 g of a 70% solution of an amine-resistant silicone adhesive ... are
added and the mass is subsequently homogenized." Muller, 6:37--42.
"[T]he mass is subsequently coated onto a suitable film ... [and] [t]he dried
matrix film is laminated with a 23-µm-thick polyester film." Muller, 6:43-
49. "The individual patches are punched out of the so complete laminate. If
the active substance solution is filtered, the composition of the finished
patch corresponds to that of the patch according to Example 2." Muller,
6:49-52.
We are not persuaded by Appellants' arguments. Muller discloses
that for silicone-based systems, only the rotigotine free base is suitable, and
that rotigotine hydrochloride is practically insoluble in such a system.
FF 11. Muller also discloses that when rotigotine hydrochloride is used as a
starting material, it can be converted to the free base with an alkaline
substance and then filtered to remove essentially remove all reactants other
than the free base. FFs 12-13. Thus, Muller suggests that the patches are
essentially free of hydrochloride, and thus would have made obvious the
methods of claims 30, 32, and 33.
Thus, we affirm the rejection of claims 30, 32 and 33 as being obvious
in view of Muller.
Conclusion of Law
The evidence of record supports the Examiner's conclusion that
Muller would have made obvious a method for treating Parkinson's disease
comprising administering to a subject, once daily, a transdermal therapeutic
system comprising a matrix with at least one high tack and at least one
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medium tack pressure sensitive silicone adhesive, a solubilizer, and 0.1 to
3.15 mg/cm2 of rotigotine free base, and comprising an area of 10 to 40 cm,2
"wherein the system induces a mean plasma concentration of rotigotine in
the subject in the range of 0.4 to 2 ng/ml 24 hours after administration," as
required by claim 12.
SUMMARY
We affirm the rejection of claims 12, 30, 32, and 33 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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