Ex Parte Tavares et al

Patent Trial and Appeal Board

Mar 31, 2016

10945222 (P.T.A.B. Mar. 31, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/945,222 0912012004
23280 7590 04/04/2016
Davidson, Davidson & Kappel, LLC
589 8th A venue
16th Floor
New York, NY 10018
FIRST NAMED INVENTOR
Lino Tavares
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.
208.1002CON 5325
EXAMINER
COHEN, MICHAEL P
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
04/04/2016 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):
ddk@ddkpatent.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LINO TAVARES, IHOR SHEVCHUK,
MARK ALFONSO, GERALDINE MARCENY AC,
and KIR TI V ALIA 1
Appeal2013-008610
Application 10/945,222
Technology Center 1600
Before ERIC B. GRIMES, FRANCISCO C. PRATS, and
JACQUELINE T. HARLOW, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating benign prostatic hypertrophy, which have been rejected as
obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 Appellants identify the Real Party in Interest as Purdue Pharma L.P.
(Appeal Br. 2.)
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Application 10/945,222
STATEMENT OF THE CASE
Terazosin is a commercially available drug "used in the management of
mild to moderate hypertension, as well as for benign prostatic hypertrophy."2
(Spec. 1.) The Specification discloses "a method for the treatment of benign
prostatic hypertrophy in patients by utilizing a transdermal delivery system
which contains terazosin." (Id. at 4.)
The Specification states that "[t]ransdermal delivery of active agents
is measured in terms of 'relative release rate' or 'flux', i.e., the rate of
penetration of the active agent through the skin." (Id. at 14.) The
Specification also states that "first order" pharmacokinetics refers to "plasma
concentrations which increase over a specified time period," while "zero
order" pharmacokinetics refers to drug release that "substantially maintains
plasma concentrations at a relatively constant level." (Id. at 13.) "[A]
relatively constant plasma concentration is defined as a concentration which
does not decrease more than about 30% over a 48 hour time period." (Id.)
Claims 1, 5, 6, 8-10, 16, 18-20, 22, 24--26, 28, and 34--57 are on
appeal. Claims 1 and 19 are illustrative and read as follows:
Claim 1: A method of effectively treating benign prostatic
hypertrophy in a human patient, comprising:
applying a transdermal delivery system containing
terazosin or a pharmaceutically acceptable salt thereof to the
skin of the human patient, and
maintaining an effective mean relative release rate of
terazosin or a pharmaceutically acceptable salt thereof from the
transdermal delivery system such that a first order plasma level
increase of terazosin is provided from initiation of a dosing
2 The Specification also refers to benign prostatic hypertrophy as benign
prostatic hyperplasia. (See Spec. 1-2.)
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Application 10/945,222
Issue
interval until about 48 to about 72 hours after initiation of the
dosing interval and thereafter a relatively constant plasma
concentration of terazosin is maintained until the end of the
dosing interval, while providing a therapeutic plasma level of
the terazosin within 3 6 hours from the initiation of the dosing
interval, and a plasma level of terazosin at steady-state of from
about 10 to 60 ng/ml is maintained,
wherein the transdermal delivery system is maintained in
contact with the skin of the patient for at least 3 days.
Claim 19: A method for lessening the incidence of side-effects
in a patient associated with the oral administration of terazosin,
wherein the method comprises administering terazosin or a
pharmaceutically acceptable salt thereof in a transdermal
delivery system over at least twenty-four hours and thereby
maintaining an effective mean relative release rate of terazosin
or a pharmaceutically acceptable salt thereof from the
transdermal delivery system such that a first order plasma level
increase of terazosin is provided from initiation of a dosing
interval until about 48 to about 72 hours after initiation of the
dosing interval and thereafter maintaining a relatively constant
plasma concentration of terazosin until the end of the dosing
interval,
wherein said transdermal delivery system has a mean
relative release rate from about 1.0 µg/hour/cm2 to about 30
µg/hour/cm2 of said transdermal delivery system, and maintains
a plasma level of terazosin at steady-state of from about 10 to
60 ng/ml.
DISCUSSION
The Examiner has rejected claims 1, 5, 6, 8-10, 16, 18-20, 22, 24--26,
28, 34--38, 42--45, and 48-57 under 35 U.S.C. § 103(a) as obvious based on
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Application 10/945,222
Santus,3 Audett,4 and Kyncl. 5 (Ans. 4.) The Examiner has rejected claims
39--41, 46, and 47 under 35 U.S.C. § 103(a) as obvious based on Santus,
Audett, Kyncl, and Hille. 6 (Ans. 10.) Because Appellants rely on the same
arguments in response to both rejections (see Appeal Br. 22), we will
consider them together.7
The Examiner finds that Santus discloses transdermal administration
of, among other drugs, terazosin, which is used to treat benign prostatic
hypertrophy (BPH). (Ans. 4.) The Examiner also finds that Santus states
that transdermal administration reduces fluctuation in circulating drug levels,
and that using permeation enhancers allows control of the rate of delivery
(flux) through the skin. (Id. at 4--5.)
The Examiner finds that Audett discloses solubilization enhancers for
transdermal delivery of basic drugs, including terazosin. (Id. at 6.) The
Examiner also finds that Audett discloses patches that are worn for four to
seven days (id. at 7), and discloses that transdermal delivery allows control
of skin flux and "a high degree of control over blood concentrations of any
drug" (id. at 6). The Examiner finds that Kyncl discloses topical
3 US Patent No. 5,503,843 (Apr. 2, 1996).
4 US Patent No. 5,879,701 (Mar. 9, 1999).
5 US Patent No. 5,212,176 (May 18, 1993).
6 US Patent No. 5,240,711 (Aug. 31, 1993).
7 In the Reply Brief, Appellants for the first time present an argument
directed to the rejection of claim 22. (Reply Br. 9-12.) This argument is not
responsive to any points made in the Answer and is therefore untimely. See
Ex parte Borden, 93 USPQ2d 1473 (BPAI 2010). Although Appellants cite
a Board decision that was made after the Appeal Brief was filed (id. at 10),
the Board's reasoning in that case relies on a court decision that predates the
Appeal Brief. Thus, the argument presented for the first time in the Reply
Brief could have and should have been made in the Appeal Brief.
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Application 10/945,222
administration of terazosin for treating BPH, and teaches that "[d]oses of the
compound can be started at dosage levels lower than required for it to
achieve the desired therapeutic effect and gradually increased until the
desired effect is achieved ... , i.e. first-order rate." (Id. at 7.)
The Examiner concludes that it would have been obvious to modify
Santus' transdermal administration method to include the enhancing
compounds taught by Audett, which also teaches wearing a transdermal
system for 4--7 days. (Id. at 8.) The Examiner also concludes that
(Id.)
gradually raising the amount of terazosin from an amount lower
than the therapeutically effective amount up to an amount which
is therapeutic, i.e. first-order absorption, is known in the art.
Further, it would have been obvious to follow the first-order
absorption by zero-order or constant absorption motivated by the
desire[] to prevent fluctuating circulating terazosin levels with
transdermal devices as taught by Santus.
The Examiner finds that the secondary references teach adjusting
vehicle composition and drug loading in order to modify skin flux, and
concludes that "it would have been within the purview of one of ordinary
skill in the art to combine the prior art references to determine the most
effective release rate." (Id. at 9.) Finally, the Examiner finds that "[s]ince
terazosin is known in the art to treat benign prostatic hyperplasia, effective
plasma blood levels for treatment would be known in the art, and therefore it
would be within the purview of the skilled artisan to modify the device
suggested by [the references] to provide therapeutically effective levels."
(Id.)
Appellants contend that "[ t ]he cited references do not describe or
suggest any plasma levels of terazosin .... Therefore, the combined
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Application 10/945,222
teachings of the Examiner's cited references cannot possibly render obvious
the claimed plasma level of terazosin at steady-state." (Appeal Br. 13-14.)
Similarly, Appellants contend that the steady-state plasma concentration was
not recognized as a parameter affecting the results, and therefore it would
not have been obvious to optimize it. (Id. at 21.)
Appellants also contend that the cited references do not teach or
suggest providing a first-order plasma level increase over 48-72 hours,
followed by a relatively constant plasma concentration, and that Kyncl's
disclosure relates to providing a certain amount of terazosin for a period of
time, followed by a second dosage form containing more of the drug, which
is not what is recited in the claims. (Id. at 17-19.) Appellants also provide
separate arguments for claims 19, 22, and 28 as a group. (Id. at 20.)
The issue presented is whether the cited references would have made
obvious a method meeting the limitations of claims 1 and 19.
Findings of Fact
1. Santus discloses "transdermal administration of alpha-adrenoceptor
blocking compounds." (Santus 1 :4--5.)
2. Santus states that the advantages of transdermal delivery "include
reduction in dosing frequency, reduced fluctuation in circulating drug levels,
increased patient compliance and convenience, and a more uniform effect."
(Id. at 1:64--67.)
3. Santus states that "[w]hen a drug is administered intravenously or
orally, the initial level of drug in the blood rapidly rises to a maximum,
which is generally much higher than the therapeutically effective level of the
drug .... This is known as 'overdosing."' (Id. at 3:35--41.) "Eventually,
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Application 10/945,222
the blood concentration of the drug falls below the therapeutically effective
level (i.e., there is 'underdosing ')." (Id. at 3 :44--46.)
4. Santus states that "[t]he term 'therapeutically effective level' as
used herein refers to the minimal blood level of drug required to achieve a
therapeutic effect." (Id. at 3: 16-18.)
5. Santus states:
Transdermal delivery of drugs offers a means of
circumventing the problems of overdosing and underdosing that
are associated with conventional drug delivery methods. The
transdermal delivery of drugs can be designed so that the rate of
delivery of the drug closely follows the rate of the clearance of
the drug from the environment, thus keeping constant levels of
drug in the blood.
(Id. at 3:55-61.)
6. Santus' Figure 1 is reproduced below:
CONCENTRATION
IN THE
ENVtRONMENT
-····-CONVENTIONAL ORAL DRUG DELIVERY
xx x X TRANSOERMAL ORUG DELIVERY
----TOO MUCH ACTIVE AGENT
{OVERDOSING)
-~ TOXfC
______ -1~ CONCENTRATION
XXltXXltXXXJIXXX XXXXX~ll:
. x .>t x _-. MINtMUM
x _ J-C"'i EFFECTJVE
-,r- ~ ~ ~ ~ - ~ ~ - ~ - · ~. CONCENTRATION
:11 TOO U TTLE AGENT ,.
x {UNDEROOS!NGl '-
TIME Of
DOSAGE
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Figure 1 "displays the blood levels from transdermal as well as
conventional oral delivery of drugs over a period of time." (Id. at 3:62-64.)
7. Santus states that compounds that block alpha adrenoceptors (a.k.a.
alpha-adrenergic receptors; id. at 1 :30) "have been suggested to have, or
have a variety of therapeutic uses, including the treatment of prostate and
genito-urinary disorders such as benign prostatic hyperplasia (BPH)," among
other disorders. (Id. at 1 :33-36.)
8. Santus states that "[a]lpha blockers selective for the alpha1 receptor
subtype include alfuzosin, tamsulosin, prazosin, and terazosin." (Id. at 4:37-
38.)
9. Santus states that "[t]he alpha blocker terasozin [sic] has also been
suggested for the treatment of BPH .... Although oral doses of terasozin
[sic] have been suggested to be effective in the treatment of BPH, concerns
remain over potential high dose side effects." (Id. at 4:51---65.)
10. Santus states that "the development of a convenient, non-invasive
drug administration system for compounds effective in the treatment of BPH
is highly desirable. The preferred system for administration of these
compounds according to the present invention is a transdermal patch." (Id.
at 4:67 to 5:5.)
11. Santus states that "[ fJor adequate skin penetration of most drugs,
a chemical permeation enhancer is necessary .... [T]he precise
concentration of enhancer and the particular combination of enhancers must
be tailored to each drug to achieve the maximum skin flux. There are
numerous possible permeation enhancers that can be used." (Id. at 8:8-18.)
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12. Audett discloses "a drug delivery system for the transdermal
administration of a basic drug," such as terazosin. (Audett 2: 17-18, 4:26-
28.)
13. Audett states that "[t]ransdermal drug delivery ... makes possible
a high degree of control over blood concentrations of any particular drug."
(Id. at 1 :23-25.)
14. Audett states that a "method for ... obtaining a steady-state flux
profile, is to solubilize a higher percentage of the drug in the reservoir.
Doing so reduces the initial flux rate, and consequently increases the flux at
later times .... [T]he net result is improved steady state delivery." (Id. at
1 :67 to 2:6.)
15. Audett discloses a "solubilizing enhancing composition [which] is
preferably a liquid which is an isomeric acid mixture." (Id. at 5:3--4.)
16. Audett states that "[t]he solubilizing enhancing composition is
particularly advantageous when used in conjunction with skin permeation
enhancer compositions." (Id. at 5:10-12.)
17. Audett states that "[t]he targeted skin flux for delivery of a
particular drug can be achieved by adjusting vehicle composition and
vehicle loading, as well as by adjusting the surface area through which the
compositions are administered to skin." (Id. at 6:58---62.)
18. Audett states that "[t]he systems with which [its] invention is
useful are typically transdermal 'patches' worn for at least four days;
however, the invention is most useful in connection with transdermal
systems designed to be worn for on the order of seven days." (Id. at 4:65 to
5:2.)
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19. Audett states that its compositions are applied to the skin "for a
period of time sufficient to provide the desired blood level of drug for the
desired period of time." (Id. at 6:45--49.)
20. Kyncl discloses the R(+) enantiomer ofterazosin and its use in
treating BPH. (Kyncl 1: 1-15, 2:62----67.)
21. Kyncl states that "[a]ctual dosage levels of active ingredients in
the pharmaceutical compositions of this invention may be varied so as to
obtain an amount of the active compound(s) that is effective to achieve the
desired therapeutic response for a particular patient, compositions, and mode
of administration." (Id. at 8:46-51.)
22. Kyncl states that "it is within the skill of the art to start doses of
the compound at levels lower than required [ ] to achieve the desired
therapeutic effect and to gradually increase the dosage until the desired
effect is achieved." (Id. at 8:55-59.)
23. Appellants' Specification states that the "pharmacokinetic
information for terazosin is available in the literature. The adult oral dosage
for terazosin is 1, 2, 5, 10 and 20 mg/day .... The plasma concentration at
steady state for terazosin is 0.045 mcg/ml [µg/ml]." (Spec. 23.)
24. A microgram (mcg or µg) is equivalent to a 1000 nanograms (ng),
so 0.045 mcg/ml is equivalent to 45 ng/ml.
Principles of Law
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSRint'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). "If a person of
ordinary skill can implement a predictable variation [of a known work],
§ 103 likely bars its patentability." Id. at 417.
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Application 10/945,222
To show criticality of a claimed range, "'it is not inventive to discover
the optimum or workable ranges by routine experimentation.' In re Aller,
220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Only ifthe 'results
of optimizing a variable' are 'unexpectedly good' can a patent be obtained
for the claimed critical range. In re Antonie, 559 F.2d 618, 620, 195 USPQ
6, 8 (CCPA 1977)." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997).
Analysis
We agree with the Examiner that the methods of claims 1 and 19
would have been obvious to a person of ordinary skill in the art based on the
cited references. The prior art discloses that treating BPH with terazosin
was known (FF7-9), as was transdermal administration of terazosin (FF12)
and maintaining a transdermal delivery system on a patient's skin for at least
three days (FF 18). Appellants' Specification itself states that the steady
state plasma concentration for terazosin was known to be 45 ng/ml (FF23,
FF24).
Thus, the only limitations of claims 1 and 19 that are not expressly
disclosed by the cited references are the specific parameters that are recited
for delivery of terazosin. Both claim 1 and claim 19 recite a first order
plasma level increase for 48 to 72 hours after initiation followed by a
relatively constant plasma concentration. Claim 1 also recites providing a
therapeutic plasma level within 36 hours.
The Specification states that "[t]he term 'first order' pharmacokinetics
is defined as plasma concentrations which increase over a specified time
period." (Spec. 13.) The Specification also states that "a relatively constant
plasma concentration is defined as a concentration which does not decrease
more than about 30% over a 48 hour time period." (Id.)
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Thus, claims 1 and 19 require that applying a transdermal patch
results in plasma levels of terazosin that increase, at any rate, for 48-72
hours and then are maintained at a relatively constant level (i.e., they do not
decrease more than 30% over 48 hours).
Santus discloses that blood levels of a drug that is administered
transdermally increase after the time of dosage, then are maintained at a
relatively constant level for a certain period before eventually dropping
below the minimum effective dosage (FF5, FF6). Santus also states that the
minimum effective dosage is also referred to as a "therapeutically effective
level" (FF4).
In addition, Santus and Audett disclose methods of optimizing the
delivery rate (or flux) of a transdermally applied drug using permeation
enhancers (FF 11 ), a solubilizing enhancer composition (FF 14 ), vehicle
composition and loading (FF 17), or the surface area through which the drug
composition is administered (FFl 7). These teachings support the
Examiner's conclusion that
it would have been in the purview of the skilled artisan to modify
the composition and the transdermal delivery system to include
the enhancers, solvents and other additives of the prior art that
would enhance the transdermal delivery of terazosin and which
would produce desired release rates, drug flux and subsequent
absorption.
(Ans. 8.)
In other words, the prior art disclosed the general conditions of claim 1:
applying a transdermal patch that provides a release rate of terazosin that
causes an increase in plasma level of the drug over time, reaches a
therapeutically effective level after a certain time period, and then maintains a
relatively constant plasma level until the end of the dosage interval. While the
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prior art does not disclose the specific timing recited in claim 1, "where the
general conditions of a claim are disclosed in the prior art, it is not inventive
to discover the optimum or workable ranges by routine experimentation." In
re Aller, 220 F.2d 454, 456 (CCPA 1955). See also Geisler, 116 F.3d at 1469
("Only if the 'results of optimizing a variable' are 'unexpectedly good' can a
patent be obtained for the claimed critical range."). Appellants have not
provided evidence showing that the timing recited in claim 1 provides results
that are unexpectedly good.
Claim 19 also recites a mean relative release rate of 1.0-30 µg/hour/cm2.
As discussed above, however, both Santus and Audett disclose that various
methods of optimizing the delivery rate (flux) of a transdermally administered
drug were known in the art. Flux is the same parameter as relative release rate.
(Spec. 14.) For this parameter as well, therefore, the prior art taught the
general conditions of the claim and, again, Appellants have not provided
evidence of unexpected results from administration of terazosin at the recited
relative release rate.
Appellants argue that "[ t ]he cited references do not describe or
suggest any plasma levels of terazosin." (Appeal Br. 13.) Appellants argue
that "[t]herefore, the combined teachings of the Examiner's cited references
cannot possibly render obvious the claimed plasma level of terazosin at
steady-state of from about 10 to 60 ng/ml as required by claims 1, 9, 19, and
22 or the claimed plasma level of terazosin at steady-state of from about 20
to 60 ng/ml[] as required by claim 28." (Id. at 14.)
This argument is unpersuasive, for two reasons. First, Appellants'
Specification acknowledges that the plasma concentration at steady state for
terazosin was known to those in the art (FF23). Thus, the plasma levels
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recited in the claims would have been obvious to a person of ordinary skill in
the art whether or not they are specifically disclosed in the cited references.
Second, Santus discloses transdermal administration of drugs (FF 1 ),
including terazosin (FF8), and states that the therapeutically effective level is
the minimum drug level required to achieve an effect (FF4). Both Santus
and Audett disclose various methods of optimizing the rate of drug delivery
in order to achieve a desired therapeutic level (FFl 1, FF14, FFl 7). Thus,
optimizing the plasma level of transdermally applied terazosin would have
been obvious to a skilled artisan even if the steady state plasma level was not
already known.
Appellants argue, however, that optimizing the steady state plasma
level would not have been obvious because "it was not recognized in the art
that measuring a plasma level of terazosin in a patient could optimize a
treatment of a patient being administered a transdermal delivery system
containing terazosin." (Appeal Br. 21.)
This argument lacks merit. Even if it was not intuitively obvious that
the level of a drug in a patient's body will affect the efficacy of the drug,
both Santus and Audett repeatedly make it clear that plasma drug levels are a
known result-affecting variable. See, e.g., FF2 (fluctuation in circulating
drug levels are bad), FF3 ("overdosing" and "underdosing" based on blood
concentration), FF4 (blood level of a drug determines its therapeutic effect),
FF6 (blood levels range from below the minimum effective concentration to
toxic concentrations), FF 13 ("control over blood concentrations"), FF 19
("desired blood level of drug").
Appellants also argue that Kyncl does not teach a first order plasma
level increase in terazosin levels. (Appeal Br. 17-20.)
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This argument is also unpersuasive. The Specification does not define
the term "first order plasma level increase" but it uses that term
interchangeably with "first order pharmacokinetics." Compare Spec. at 6-7
(bridging paragraph), with 13 (defining "first order" and "zero order"). The
Specification defines "first order" pharmacokinetics as meaning simply
"plasma concentrations which increase over a specified time period." (Id. at
13.) Santus discloses that plasma levels of a drug increase over time after
the drug is administered transdermally (FF6). Thus, regardless of whether
Kyncl discloses administration of terazosin, specifically, in a manner that
causes a first order plasma level increase, Santus provides evidence that
transdermal administration causes that effect.
Finally, Appellants argue that "the cited references do not teach or
suggest the specific mean relative release rates recited in claims 19, 22, and
28." (Appeal Br. 20.) As discussed above, however, Santus and Audett
discloses methods of optimizing the flux, or relative release rate, of a
transdermally administered drug. Appellants have not pointed to any
evidence of unexpected results based on the recited release rates. See
Geisler, 116 F.3d at 1469 ("Only if the 'results of optimizing a variable' are
'unexpectedly good' can a patent be obtained for the claimed critical
range.").
Conclusion of Law
The cited references would have made obvious a method meeting the
limitations of claims 1and19. Claims 5, 6, 8-10, 16, 18, 20, 24--26, 34--38,
42--45, and 48-57 fall with claim 1. Claims 22 and 28 fall with claim 19.
37 C.F.R. § 41.37(c)(l)(vii).
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As noted previously, Appellants waived additional arguments directed
to the rejection of claims 39--41, 46, and 47 based on Santus, Audett, Kyncl,
and Hille. We therefore affirm that rejection as well.
SUMMARY
We affirm both of the rejections on appeal.
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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