Ex Parte Raoufinia

Patent Trial and Appeal Board

Mar 8, 2019

14034727 (P.T.A.B. Mar. 8, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/034,727 09/24/2013
58249 7590 03/12/2019
COOLEYLLP
ATTN: IP Docketing Department
1299 Pennsylvania Avenue, NW
Suite 700
Washington, DC 20004
FIRST NAMED INVENTOR
Arash Raoufinia
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.
OTSU-002/00US
310697-2007
1021
EXAMINER
FINN, MEGHAN R
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
03/12/2019 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):
zIPPatentDocketingMailbox US @cooley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ARASH RAOUFINIA 1
Appeal2017-009010
Application 14/034, 727
Technology Center 1600
Before DONALD E. ADAMS, RY ANH. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
FLAX, Administrative Patent Judge.
DECISION ON APPEAL
This is a decision under 35 U.S.C. § 134(a) involving claims directed
to a method of initiating systemic aripiprazole treatment in a patient. Claims
31-50 are on appeal as rejected under 35 U.S.C. § 103. 2 We have
jurisdiction under 35 U.S.C. § 6(b).
We reverse.
1 Appellant identifies the Real Party in Interest as "Otsuka Pharmaceutical
Co., Ltd." Appeal Br. 2.
2 Oral Argument was heard on March 5, 2019; a transcript thereof will be
made a part of the record on appeal in due course.
Appeal2017-009010
Application 14/034, 727
STATEMENT OF THE CASE
Independent claims 31, 39, and 45 are representative and are
reproduced below:
31. A method of initiating systemic aripiprazole
treatment in a patient, comprising initially intramuscularly
administering to the patient 66% to 75% of a 300 or 400 mg
weight equivalent dose of aripiprazole in the form of a long-
acting drug-containing suspension which systemically releases
aripiprazole, wherein the dose is released over a period of about
one month, and wherein the patient is CYP2D6 and CYP3A4
extensive metabolizer and is concomitantly administered a
strong CYP2D6 inhibitor or a strong CYP3A4 inhibitor.
39. A method of initiating systemic aripiprazole
treatment in a patient, comprising initially intramuscularly
administering to the patient 75% of a 300 or 400 mg weight
equivalent dose of aripiprazole in the form of a long-acting drug-
containing suspension which systemically releases aripiprazole,
wherein the dose is released over a period of about one month,
and wherein the patient is a CYP2D6 poor metabolizer not
concomitantly administered a strong CYP3A4 inhibitor or a
strong CYP2D6 inhibitor.
45. A method of initiating systemic aripiprazole
treatment in a patient, comprising initially intramuscularly
administering to the patient 53% of a 300 mg or 50% of a 400
mg weight equivalent dose of aripiprazole in the form of a long-
acting drug- containing suspension which systemically releases
aripiprazole, wherein the dose is released over a period of about
one month, and wherein the patient is a CYP2D6 and CYP3A4
extensive metabolizer and is concomitantly administered a
strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor.
Appeal Br. 37, 38-39 (Claims Appendix).
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The following rejections are appealed:
Claims 31-35, 37, 39--41, 43, 45--47, and 49 stand rejected under 35
U.S.C. § 103 over Park, 3 Fleischhacker, 4 Sparshatt, 5 Abilify, 6 Azuma,7
Hendset, 8 and Kane. 9 Final Action 3.
Claims 36, 38, 42, 44, 48, and 50 stand rejected under 35 U.S.C. § 103
over Park, Fleischhacker, Sparshatt, Abilify, Azuma, Hendset, Kane, and
Remenar. 10 Id. at 48.
3 M. Park et al., Aripiprazole treatment for patients with schizophrenia:
from acute treatment to maintenance treatment, 11(11) EXPERT REV.
NEUROTHER. 1541-52 (2011) ("Park").
4 W. Fleischhacker, M.D., et al., A Pharmacokinetic Study of Once-Monthly
Aripiprazole Extended-Release Injectable Suspension (ERIS) in Adult
Patients with Schizophrenia, AMERICAN PSYCHIATRIC ASSOCIATION, NEW
RESEARCH BOOK 247--48 (2011) ("Fleischhacker").
5 A. Sparshatt et al., A Systemic Review of Aripiprazole-Dose, Plasma
Concentration, Receptor Occupancy, and Response: Implications for
Therapeutic Drug Monitoring, 71(11) J. CLIN. PSYCHIATRY 1447-56 (2010)
("S parshatt").
6 Otsuka America Pharmaceutical, Inc., Abilify Prescribing Information
Label 1-85 (2012) ("Abilify").
7 J. Azuma et al., The relationship between clinical pharmacokinetics of
aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme
inhibition by coadministration of paroxetine or fluvoxamine, 68 EUR. J.
CLIN. PHARMACOL. 29-37 (2012) ("Azuma").
8 Magnhild Hendset et al., Impact of the CYP2D6 genotype on steady-state
serum concentrations of aripiprazole and dehydroaripiprazole, 63 EUR. J.
CLIN. PHARMACOL. 1147-51 (2007) ("Hendset").
9 J. Kane, M.D., et al., Aripiprazole Intramuscular Depot as Maintenance
Treatment in Patients With Schizophrenia: A 52-Week, Multicenter,
Randomized, Double-Blind, Placebo-Controlled Study, 73(5) J. CLIN.
PSYCHIATRY 617-24 ("Kane").
10 US 8,431,576 B2 (issued Apr. 30, 2013) ("Remenar").
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Application 14/034, 727
Claims 31-50 stand rejected under 35 U.S.C. § 103 over Park,
Kostanski 11 or Ehrich, 12 Sparshatt, Abilify, Azuma, Hendset, Kane, and
Remenar. Id. at 52.
DISCUSSION
"[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting aprimafacie case ofunpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
Arguments made by Appellant in the Appeal Brief and properly presented in
the Reply Brief have been considered in this Decision; arguments not so-
presented in the Briefs are waived. See 37 C.F.R. § 4I.37(c)(l)(iv) (2015);
see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010)
(informative) ("Any bases for asserting error, whether factual or legal, that
are not raised in the principal brief are waived."); and Ex parte Nakashima,
93 USPQ2d 1834 (BP AI 2010) (informative) ( arguments and evidence not
timely presented in the principal Brief will not be considered when filed in a
Reply Brief, absent a showing of good cause explaining why the argument
could not have been presented in the Principal Brief).
As applicable to the rejections on appeal and Appellant's arguments
there-over, "[t]he combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield predictable
results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007). "[T]he
question is whether there is something in the prior art as a whole to suggest
11 US 7,807,680 B2 (issued Oct. 5, 2010) ("Kostanski").
12 US 2009/0022823 Al (published Jan. 22, 2009) ("Ehrich").
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the desirability, and thus the obviousness, of making the combination, not
whether there is something in the prior art as a whole to suggest that the
combination is the most desirable combination available." In re Fulton, 391
F.3d 1195, 1200 (Fed. Cir. 2004) (citation omitted). However, "[i]t is well-
established that before a conclusion of obviousness may be made based on a
combination of references, there must have been a reason, suggestion, or
motivation to lead an inventor to combine [the teachings and suggestions of]
those references." Pro-Mold and Tool Co. v. Great Lakes Plastics Inc., 75
F.3d 1568, 1573 (Fed. Cir. 1996). "Obviousness requires more than a mere
showing that the prior art includes separate references covering each
separate limitation in a claim under examination." Unigene Labs., Inc. v.
Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir. 2011). "Rather, obviousness
requires the additional showing that a person of ordinary skill at the time of
the invention would have selected and combined those prior art elements in
the normal course of research and development to yield the claimed
invention." Id.
The Examiner determined that the claimed methods directed to
reducing a 300 mg or 400 mg dosage of aripiprazole by 50%, 53%, 66%, or
75% when initially intramuscularly (IM) administering a long-acting
formulation to a patient with diminished aripiprazole-metabolizing activity
( due to the patient being a poor metabolizer or to the effects of an inhibiting
drug) would have been obvious over the prior art combination of Park,
Fleischhacker, Sparshatt, Ability, Azuma, Hendset, and Kane, optionally
substituting either Kostanski or Ehrich for Fleischhacker. Final Action 3-
58; Answer 2-60. With respect to the claims reciting that a pro-drug is
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included in the formulation rather than aripiprazole, the Examiner adds
Remenar to the combination. See, e.g., Final Action at 48---68. The
Examiner's rationale on obviousness is extensive, but a well-articulated
summary of the Examiner's position is provided in the Final Action at pages
44--47.
The Examiner's rationale on obviousness indicates that the prior art
taught that the drug aripiprazole was well-known and had been used to treat
schizophrenia for many years in fast-acting oral and IM daily-administered
formulations, that the way the drug acts within the body and how it effects
the body (pharmacokinetics, or PK, and pharmacodynamics, or PD,
respectively) were also well-known characteristics of the daily formulations,
that these PK and PD characteristics were also known for the long-acting IM
depot (once-monthly) formulation ( also called an extended-release injectable
suspension or ERIS), and that, generally, the variously formulated
aripiprazole compositions were similar in this regard. See, e.g., Park 1541,
1542, 1547--49; Fleischhacker 248; Sparshatt 1447, 1453; Abilify 1, 9, 62;
Kane 617, 618, 623. Furthermore, the Examiner determined that it was
well-known and taught by the cited prior art that the enzymes CYP2D6 and
CYP3A4 were responsible for metabolizing aripiprazole and that the
impaired function of one or both of these enzymes in patients (based on
genetics or pharmaceutical inhibition) caused an undesirable increase in
systemic concentration of the drug, which required a reduction in the dose
administered. See, e.g., Park 1542; Abilify 2, 10; Azuma 29, 35; Hendset
1147, 1150.
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As identified by the Examiner, various cited prior art indicated
potential reduced dosages from normal aripiprazole dosages, as follows:
Abilify indicated reducing aripiprazole to 50% of a normal dose (tablets,
oral disintegrating tablets, oral solution, or IM formulations) if the patient
was co-administered a CYP2D6 or CYP3A4 inhibitor or reducing to a 25%
dose if both inhibitors were co-administered or the patient was a CYP2D6
poor metabolizer; Hendset suggested that CYP2D6 poor metabolizing
patients should typically receive 60o/o-70% of the normal (unspecified
formulation, daily administered) aripiprazole dose; and Azuma taught that
patients being co-administered a CYP2D6 and/or CYP3A4 inhibitor with a
daily oral dose of aripiprazole would experience an 18o/o-62% decrease in
systemic clearance of aripiprazole (i.e., such patients had 18o/o-62% more
drug in their systems than desired). Abilify 1-2, 10; Hendset 1147, 1148,
1150; Azuma 29.
The Examiner also determined that it was well-known to adjust the
dose of aripiprazole during the initial stages of introducing an IM depot,
long-acting formulation of the drug so as to stabilize the systemic
concentration of the drug to a desired level in a normal CYP2D6/CYP3A4
extensive metabolizing patient by supplementing the dose with an oral
formulation of the drug. See, e.g., Park 1549--49; Kane 618. The Examiner
also noted that there were three commercially available IM depot
formulations available ( 400 mg, 300 mg, and 200 mg) and that the 300 mg
and 200 mg doses fit, generally, into the claimed dose reductions, using the
400 mg dose as a foundation. See Park 1548; Fleischacker 248; Kane 617.
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Based on such findings, the Examiner determined that it would have
been obvious to administer an IM depot formulation having a dosage
reduced to the claimed dosages based on a patient's CYP2D6 and/ or
CYP3A4 metabolism, in part, because such adjustment was no more than an
obvious optimization as instructed by the prior art. See Abilify 1 O; Hendset
1147; Azuma 29.
"If a prima facie case is made in the first instance, and if the applicant
comes forward with reasonable rebuttal, whether buttressed by experiment,
prior art references, or argument, the entire merits of the matter are to be
reweighed." In re Hedges, 783 F.2d 1038, 1039 (Fed. Cir. 1986). We find
the Examiner's rationale to be well-reasoned and convincing of a prima facie
case for obviousness. However, Appellant presents a persuasive rebuttal
argument for non-obviousness.
Appellant presented several arguments on non-obviousness for the
appealed claims, generally. See generally Appeal Br. 8-34. Appellant seeks
to drive a wedge between the prior arts' teachings regarding the fast-acting
( daily) oral and IM aripiprazole formulations and the long-acting (monthly)
IM depot formulation claimed such that the knowledge with respect to
reducing dose in the fast-acting formulations would not be applicable to the
long-acting IM depot formulation. For the most part, Appellant's arguments
amount to mere attorney argument, which is generally unconvincing in the
face of the logically-arranged factual foundation supporting the Examiner's
prior art rejection. However, Appellant cites to and submits as evidence the
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Declaration of Arash Raoufinia, 13 which makes a persuasive point, echoed
by Appellant's oral argument at the hearing for this appeal. See, e.g.,
Appeal Br. 11. That point is as follows:
While it is not uncommon to adjust ("titrate'~ short-acting
dosage forms to optimize efficacy and minimize side effects,
physicians would not normally [have] considered doing so for
psychiatric medications in the form of long-acting dosage
forms which release aripiprazole over a period of at least about
a month. As a practical matter, psychiatric patients in need of
treatment with aripiprazole and administered as a long-acting
dosage form are invariably outpatients who are not under close
(i.e. daily) supervision of a physician. Furthermore, because of
the long duration of drug release inherent in long-acting
dosage forms, the dose cannot be adjusted frequently.
Accordingly, ethically and medically, titration of long-acting
dosage forms (e.g. based on the much lower dose adjustments
provided by the Abilify Label) is not considered safe and is not
done as a practical matter because of the risk of prolonged,
unsupervised under-dosing of the patient.
Raoufinia Declaration ,r 19 ( emphasis added). Declaratory evidence as to
issues of fact is entitled to substantial weight. In re Alton, 7 6 F .3 d 1168
(Fed. Cir. 1996). Although we are uncertain whether a schizophrenic out-
patient would not be closely supervised by a physician when being
introduced to a new therapy, as suggested in the declaration, we agree that
once a long-acting IM depot injection is administered (and intended to last a
month), there is no way to reduce the amount of the drug that the patient is
subject to over the period for which the IM depot is to last, and too high a
dose could present serious disadvantages. See, e.g., Abilify 1, 12-17
13 Declaration of Arash Raoufinia, Pharm.D. Under 37 C.F.R. § 1.132 dated
April 2, 2014 ("Raoufinia Declaration").
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( discussing adverse/side effects); Hendset 1150 ("the increased
concentration in PMs actually trigger psychotic symptoms").
Moreover, at oral argument, although Appellant acknowledged that
the prior art taught optimizing an aripiprazole dosage when initiating
administration of the long-acting IM formulation, the optimization was only
as to supplementing with oral aripiprazole on a daily basis where it was
established that the patient was not receiving enough drug to be effective
initially (to reach desired systemic levels), Appellant argued that this was the
extent of the prior arts' suggestion for optimization because there is an
inability to lower the dosage administered when the formulation is an IM
depot injection. Appellant's point is that the prior art teaches, at most,
administering a 50% dose for CYP2D6/CYP3A4 impaired patients, e.g. a
200 mg IM depot instead of a 400 mg IM depot, and that if such a dose were
determined to not be providing sufficient efficacy to the patient, it could be
increased during the initial stages of treatment, not by increasing the IM
depot dose, but by supplementing with oral ( or at least a fast-acting, daily
formulation of) aripiprazole, as taught by the prior art.
Appellant's argument and evidence, considered along with the
findings of fact by the Examiner, support the conclusion that the skilled
artisan would not have found the claimed long-acting aripiprazole, reduced-
percentage IM depot formulations to have been obvious over the cited prior
art. Therefore, we reverse the Examiner's obviousness rejections, each of
which relies on the same rationale and relevant evidence in the prior art.
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SUMMARY
The obviousness rejections are each reversed.
REVERSED
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