Ex Parte Babul

Patent Trial and Appeal Board

Jan 17, 2019

13320989 (P.T.A.B. Jan. 17, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/320,989 11/17/2011
207 7590 01/22/2019
PRETI FLAHERTY BELIVEAU & PACHIOS LLP
60 State Street
Suite 1100
BOSTON, MA 02109
UNITED ST A TES OF AMERICA
Najib Babu!
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.
Re1Th004US 4273
EXAMINER
WEST, THEODORE R
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
01/22/2019 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):
patents@preti.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte NAJIB BABUL
Appeal2017-011082
Application 13/320,989
Technology Center 1600
Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1,2 under 35 U.S.C. § 134(a) involving claims to a
dosage form for orally administering levorphanol to a human. The
Examiner rejected the claims as obvious. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.
1 Appellant identifies the Real Party in Interest as Relmada Therapeutics,
Inc. (see App. Br. 1 ).
2 We have considered and herein refer to the Specification of Nov. 17, 2011
("Spec."); Final Office Action of July 5, 2016 ("Final Act."); Appeal Brief
of May 5, 2017 ("App. Br."); Examiner's Answer of June 27, 2017 ("Ans.");
and Reply Brief of Aug. 28, 2017 ("Reply Br.").
Appeal2017-011082
Application 13/320,989
Statement of the Case
Background
"Extended release opioid formulations have now become the standard
of care for the management of chronic pain" (Spec. ,r 4). However, the
Specification identifies "a need for new therapeutic alternatives for the
management of pain, including alternative extended release opioids that are
bioavailable, therapeutically effective and pharmacologically differentiated
from existing extended release opioids" (id.).
"Levorphanol ... is a potent opioid analgesic ... levorphanol is
purported to have a long half life and a long duration of analgesic action"
(Spec. ,r,r 5, 7). "[L]evorphanol has significant greater activity than
morphine at the kappa and delta opioid receptor, and robust activity as an
NMDA antagonist, the latter being important in modulating pain and opioid
tolerance. Levorphanol has also been shown to substantially reverse
analgesic tolerance to morphine" (Spec. ,r 6).
The Claims
Claims 4--9 and 53---68 are on appeal. Claim 4 is representative and
reads as follows:
4. A dosage form for orally administering levorphanol to a
human patient, the dosage form comprising
a therapeutically effective amount of levorphanol or a
pharmaceutically acceptable salt thereof, combined with
a controlled release material comprising
a) at least one of a wax, a vegetable oil, a vegetable oil
ester, and a combination of these;
b) a cellulose-based release rate modifier; and
c) a thixotrope and
being formulated such that the in-vitro fractional release
of levorphanol therefrom, when measured by the USP Paddle
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Appeal2017-011082
Application 13/320,989
Method at 100 rpm in 900 mL aqueous phosphate buffer at pH
6.8 and at 37 °C is:
not greater than 47.5% at 1 hour,
from 10% to 65% at 2 hours,
from 15% to 70% at 4 hours,
from 25% to 77 .5% at 6 hours,
from 35% to 87.5% at 9 hours, and
greater than 65% at 12 hours.
The Issues
A. The Examiner rejected claims 4--9 and 53----67 under 35 U.S.C.
§ I03(a) as obvious over Chasin3 and Anderson4 (Final Act. 3-5).
B. The Examiner rejected claims 7 and 68 under 35 U.S.C. § I03(a) as
obvious over Chasin, Anderson, and Katzung5 (Final Act. 8-9).
A. 35 U.S.C. § 103(a) over Chasin and Anderson
The Examiner finds Chasin teaches "controlled-release oral dosage
forms comprising a controlled-release matrix ( col. 2, 11. 49-53) and
levorphanol ( col. 3, 1. 4)" (Final Act. 3). The Examiner finds that Chasin
further teaches that the controlled release "matrix includes vegetable oils or
waxes ( col. 10, 1. 66 - col. 11, 1. 2)" as well as "HPMC ( col. 11, 11. 11-17)"
(id.). The Examiner finds that Chasin teaches the "properties of the dosage
form may be modified by including a gastrointestinal or time-release
coating" (id.).
3 Chasin et al., US 6,103,261, issued Aug. 15, 2000.
4 Anderson et al., US 2003/0125347 Al, published July 3, 2003.
5 Katzung, Basic & Clinical Pharmacology, Appleton & Lange 513
(7th ed. 1998).
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Appeal2017-011082
Application 13/320,989
The Examiner acknowledges that Chasin does not teach inclusion of
fumed silica as well as "the various functional (i.e., pharmacological)
limitations" (Final Act. 4). The Examiner finds Anderson teaches the use of
fumed silica (see id.).
The Examiner finds the functional limitations obvious because Chasin
"discloses compositions that have similar (if not identical) release profiles as
asserted by applicant ... [so] a composition prepared according to the
combined teachings of the cited references would meet the [pharmacokinetic
parameter] limitations of the instant claims" (Final Act. 5).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner's conclusion that Chasin and
Anderson render the claims obvious?
Findings of Fact
1. Chasin teaches "a solid controlled-release oral dosage form, the
dosage form comprising a therapeutically effective amount of analgesic,
preferably an opioid analgesic" (Chasin 2:49-53).
2. Chasin teaches that "[p ]referred opioids include mu-agonist
opioid analgesics such as ... levorphanol" (Chasin 3:2--4).
3. Chasin teaches "a controlled-release matrix that affords in-vitro
dissolution rates of the opioid within the narrow ranges required and that
releases the opioid in a pH-independent manner. Suitable materials for
inclusion in a controlled-release matrix are ... vegetable oils and waxes"
(Chasin 10:54 to 11:2).
4. Chasin teaches a "suitable matrix comprises at least one water
soluble hydroxyalkyl cellulose . . . The at least one hydroxyalkyl cellulose
is preferably ... hydroxypropylmethylcellulose" (Chasin 11: 11-17). Chasin
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Appeal2017-011082
Application 13/320,989
further teaches that "a controlled-release matrix may also contain suitable
quantities of other materials, e.g., ... glidants that are conventional in the
pharmaceutical art" (Chasin 11 :53-57).
5. Chasin teaches a
dissolution rate in-vitro of the dosage form, when measured by
the USP Paddle or Basket Method at 100 rpm in 900 ml
aqueous buffer (pH between 1.6 and 7 .2) at 37° C. is from
about 12.5 to about 42.5% (by wt) opioid released after 1 hour,
from about 25 to about 65% (by wt) opioid released after 2
hours, from about 45 to about 85% (by wt) opioid released after
4 hours, and greater than about 60% (by wt) opioid released
after 8 hours, the in-vitro release rate being substantially
independent of pH, such that the peak plasma level of opioid
obtained in-vivo occurs from about 2 to about 8 hours after
administration of the dosage form. The oral dosage forms of the
present invention provide pain relief for about 24 hours, and
therefore may be administered on a once-a-day basis.
(Chasin 2:54---67).
6. Anderson teaches a "composition comprises as the analgesic
only one or more opiates" (Anderson ,r 15) where the opiate may include
levorphanol (id. ,r 13).
7. Anderson teaches "[ e ]xamples of suitable glidants ( or anti-
adherents) include ... fumed silica" (Anderson ,r 38).
8. Anderson also teaches inclusion of excipients including
hydroxypropylmethyl cellulose (Anderson ,r 35), hydrogenated vegetable
oils (id. ,r 37) and waxes (id. ,r 37).
9. Anderson teaches "an absorption profile which is capable of
providing in the user a sustained release of opiate, for example, at least about
1 hour up to about 30 hours ... the coating is designed to achieve optimal
release" (Anderson ,r 46).
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Appeal2017-011082
Application 13/320,989
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."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007).
Analysis
We adopt the Examiner's findings of fact and conclusions of law (see
Final Act. 3-5; FF 1-9) and agree that the combination of Chasin and
Anderson renders the claims obvious.
In particular, we agree that Chasin teaches controlled release oral
dosage opioid compositions (FF 1) and specifically identifies levorphanol as
a preferred opioid (FF 2). Chasin teaches to include in the formulation
materials to provide for controlled release including waxes and vegetable
oils (FF 3) as well as celluloses such as HPMC (FF 4). Anderson teaches a
sustained release composition (FF 9) that may include levorphanol (FF 6) as
well as excipients such as the thixotrope fumed silica (FF 7) along with
HPMC, vegetable oils and waxes (FF 8). Finally, Chasin teaches desirable
delayed release profiles that provide pain relief for up to 24 hours (FF 5).
Thus, we agree with the Examiner that Chasin and Anderson reasonably
support a prima facie case of obviousness because the references use known
opioids with known excipients to obtain known controlled release profiles
(FF 1-9). An "[e]xpress suggestion to substitute one equivalent for another
need not be present to render such substitution obvious." In re Fout, 675
F.2d 297,301 (CCPA 1982) (citation omitted). Moreover, the flexible
analysis set out by the Supreme Court in KSR recognizes the obviousness of
pursuing known options within the technical grasp of the skilled artisan, e.g.,
known equivalents. See KSR, 550 U.S. at 421.
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Appeal2017-011082
Application 13/320,989
We address Appellant's arguments below.
Appellant contends
A POSA reading CHASIN and ANDERSON would conclude
that CHASIN and ANDERSON simply failed to appreciate the
unsuitability of LEV in ER dosage forms - not that CHASIN or
ANDERSON had discovered any way of overcoming that
unsuitability. The Applicant's specification is the first
disclosure of compositions that overcome the accepted
unsuitability of LEV for ER dosage forms.
(App. Br. 10). Appellant states they "provided three references (Argoff,[6J
[Du PenJ,[7J and Zichterman[8J) to the Examiner which demonstrate that a
POSA considered LEV unsuitable for use in ER dosage forms and also
explained to the Examiner what a POSA would infer from those references"
(id. at 11; original citations replaced).
Appellant concludes that Argoff "illustrates the crucial interplay
between DoE[9J (leading to 'good;' i.e., the beneficial effects of the drug)
and pHL[lOJ (leading to 'bad;' i.e., the adverse effects of the drug) for
assessing the suitability of a drug for multiple-sequential or extended release
administration" (App. Br. 13). Appellant contends that Argoff demonstrates
"it was recognized that opioid analgesics having DoE>pHL (like HYD[,
6 Argoff et al., A Comparison of Long- and Short-Acting Opioids for the
Treatment of Chronic Noncancer Pain: Tailoring Therapy to Meet Patient
Needs, 84 MAYO CLIN. PROC. 602-12 (2009).
7 Du Pen et al., US 2003/0178031 Al, published Sept. 25, 2003.
8 Zichterman, Opioid Pharmacology and Considerations in Pain
Management, U.S. Pharmacist (2007);
http://www.uspharmacist.com/ continuing_education/
ceviewtest/lessonid/105473 (accessed Mar. 27, 2014).
9 DoE stands for duration of effect. (App. Br. 13.)
10 pHL stands for plasma half-life. (App. Br. 13.)
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Appeal2017-011082
Application 13/320,989
hydromorphone,] and MOR[, morphine,]) could be effectively used in ER
formulations, while opioid analgesics having DoE