Ex Parte Babul

Patent Trials and Appeals Board

Mar 7, 2019

12223327 - (D) (P.T.A.B. Mar. 7, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/223,327 07/29/2008
207 7590 03/11/2019
PRETI FLAHERTY BELIVEAU & PACHIOS LLP
Suite 1100
60 State Street
Suite 1100
BOSTON, MA 02109
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.
RelTHOOlUS 7615
EXAMINER
COUGHLIN, DANIEL F
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
03/11/2019 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
Appeal2018-003814
Application 12/223,327
Technology Center 1600
Before JAMES A. WORTH, ROBERT A. POLLOCK, and
ELIZABETH A. LA VIER, Administrative Patent Judges.
POLLOCK, Administrative Patent Judge.
DECISION ON APPEAL
Appellant1 appeals the Examiner's Final rejection of claims 181, 187,
191, 196-200, 203, and 211-218 under 35 U.S.C. § 134(a). We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
The Specification, discloses "pharmaceutical compositions of opioids2
that provide simultaneous abuse deterrence properties and extended release
1 Appellant identifies Relmada Therapeutics, Inc. as the real party in interest.
App. Br. 1.
2 As Appellant points out, the Specification uses the terms opioid, opioid
agonist, and opioid analgesic interchangeably. See App. Br. 2, n. l ( citing
Spec. ,r,r 4, 336, 341).
Appeal2018-003814
Application 12/223,327
properties." Spec. ,r 52. According to Appellant, these properties are
achieved by combing the opioid with a base excipient, thixotrope, and
HPMC recited in claim 181, such that the "base excipient ... slows and
extends release of the opioid agonist," "[t]he thixotrope ... prevents abusers
from abusing the melted dosage form," and "[t]he HPMC ... also modulates
the rate of release of the opioid agonist, effecting both extended release and
deterrence against abuse." App. Br. 3 (emphasis omitted).
Claims 181, 187, 191, 196-200, 203, and 211-218 are pending. Of
these, the sole independent claim, claim 181, recites:
181. An abuse-resistant pharmaceutical dosage form for orally
administering an opioid agonist to a human, the dosage form
including a substantially homogenous matrix that comprises:
a) from 0.1-1000 milligrams of the opioid agonist;
b) a base excipient in an amount from 7-90% (based on
the dry weight of the matrix), the base excipient being
selected from the group consisting of
i) hydrogenated vegetable oils,
ii) polyoxyethylene stearates,
iii) glycerol monostearate,
iv) waxes that are poorly soluble in water and
that have a melting point in the range from 40
to 100 degrees Celsius, and
v) combinations of these,
the base excipient being selected such that release
of substantially all of the opioid agonist from a
reference capsule occurs not sooner than about
18 hours after the reference capsule is subjected
to the USP Paddle Method at 7 5 rotations per
minute in 600 milliliters of USP Simulated
Intestinal Fluid without enzyme at 3 7 degrees
Celsius,
2
Appeal2018-003814
Application 12/223,327
the reference capsule consisting of a size 1
gelatin capsule containing a uniform mixture
of 7 5 milligrams of the opioid agonist and
325 milligrams of the base excipient;
c) a thixotrope selected from the group consisting of
silicon dioxide and a mixture of silicon dioxide and
aluminum oxide in a thixotropically-effective amount not
less than 2.0% but not greater than 4.3% (based on the
dry weight of the matrix); and
d) from 10-25% (based on the dry weight of the matrix)
of a hydroxypropyl methylcellulose, wherein a 2% (w/v)
aqueous suspension of the hydroxypropyl
methylcellulose at 20 degrees Celsius exhibits a viscosity
in the range from 6 to 100,000 Centipoise.
The Examiner rejects claims 181, 187, 197, 198, and 203 under pre-
AIA 35 U.S.C. § 103(a) as unpatentable over Oshlack3 and Vergnault4 as
evidenced by DrugBank5 and Dynamic Viscosity6 (Rejection 1 ).
The Examiner rejects claims 191, 196, 212-216, and 218 under pre-
AIA 35 U.S.C. § 103(a) as unpatentable over Oshlack, Vergnault, and
Chen. 7, 8 (Rejection 2). 9
3 Oshlack et al., US 2003/0124185 Al, published July 3, 2003.
4 Vergnault et al., US 2003/0180359 Al, published Sept. 25, 2003.
5 DrugBank entry for "Levorphanol," accessed Feb. 6, 2015 from
http://www.drugbank.ca.drugs/DB00854.
6 "Dynamic Viscosity," accessed March 15, 2016 from
http://www. calculator. org/property. aspx?name=dynamic+viscosity
7 Chen et al., US 2003/0077297 Al, published April 24, 2003.
8 As noted by Appellant, the Examiner appears to have inadvertently listed
claim 212 among the rejections in view of the first, rather than the second
rejection. See App. Br. 5. We consider it here.
9 Depending from claim 196, claim 217 further requires that the matrix
comprises an aversive agent (as do claims 199 and 200). Although the
Examiner does not list claim 217 among the stated rejections, it is unclear to
3
Appeal2018-003814
Application 12/223,327
The Examiner rejects claims 199 and 200 under pre-AIA
35 U.S.C. § 103(a) as unpatentable over Oshlack, Vergnault, and Emigh 10
(Rejection 3).
We have reviewed Appellant's contentions that the Examiner erred in
rejecting claims 181, 187, 191, 196-200, 203, and 211-218 as obvious over
the cited art. App. Br. 6-25; Reply Br. 1-7. Appellant directs its arguments
largely to the rejection of claim 181, rejection 1. App. Br. 6. Although
Appellant separately argues claims 191 and 196 under Rejection 2, and
claim 200 under Rejection 3, such arguments "closely mirror those presented
in connection [with Rejection 1]." 11 Id. Accordingly, we focus on the
rejection of claim 181 over Oshlack and Vergnault as evidenced by
DrugBank and Dynamic Viscosity (Rejection 1 ).
We disagree with Appellant's contentions and adopt the findings of
fact and reasoning set forth in the Examiner's Answer and the Final
Rejection dated October 12, 2016. For emphasis, we highlight and address
the following:
us why claim 217 was not rejected in light of Oshlack' s extensive teaching
to use aversive agents in oral pharmaceutic formulations for the delivery of
opioids. See FF 1. Out of an abundance of caution, and in the interests of
fairness, we designate our affirmance of the Examiner's rejection of claim
217 as a new ground of rejection.
10 Emigh et al., US 2006/0177380 Al, published Aug. 10, 2006.
11 Claim 191 specifies that the base excipient is a hydrogenated vegetable
oil; claim 196 specifies that the matrix comprises a coconut oil product; and
claims 199 and 200 further recite an aversive agent. Relevant to the
Examiner's explanation of Rejection 1, claims 187 and 212 specify that the
opioid includes levorphanol.
4
Appeal2018-003814
Application 12/223,327
FINDINGS OF FACT
FF 1. Oshlack discloses opioid formulations, including oral controlled 12
release dosage forms, designed to reduce the potential for opioid abuse.
Oshlack, Abstract, ,r,r 2-33, 28. The disclosed formulations include one
or more aversive agents ( e.g., a bittering agent, an irritant, and/or a
gelling agent) to deter abuse. Id. ,r,r 26-28. The "gelling agent [ e.g.,
silicon dioxide] may be added to the formulation in a ratio of gelling
agent to opioid agonist of from about 1 :40 to about 40: 1 by weight." Id.
,r,r 53-54; (see id. ,r 225, Example 2A (dosage form comprising 2.3%
gelling agent (i.e., 3 mg xanthan gum in a 126 mg dosage form)). 13
FF2. Oshlack further discloses adjusting the composition of controlled
release matrices to provide in vitro dissolution rates within desired
ranges. Id. ,r,r 119-124. Representative matrices comprise one or more
hydrophilic and/or hydrophobic materials including hydrogenated
vegetable oils, and at least one sustained-release polymer such as a water-
soluble hydroxyalkyl cellulose, preferably HPMC. Id. ,r,r 120-121. "The
amount of the at least one hydroxyalkyl cellulose in the present oral
12 For the purpose of this Opinion we view the terms "controlled release,"
"extended release," and "sustained release" as interchangeable.
13 The Examiner finds, and Appellant does not contest, that silicon dioxide is
a thixotrope. See Ans. 3.
5
Appeal2018-003814
Application 12/223,327
dosage form may be determined, inter alia, by the precise rate of opioid
analgesic release required." Id. ,r 124.
FF3. Vergnault discloses oral controlled release pharmaceutical
compositions having preferred release profiles. In particular, Vergnault
discloses:
An oral dosage form comprising a pharmaceutical tablet
of one or more layers, one of which carries a biologically active
substance; the formulation of said tablet includes different
percentages of hydrophilic and lipophilic polymeric materials,
and adjuvant substances. The tablets of the present invention
show a release rate which is independent from the amounts of
active substance present in the tablet.
Vergnault, Abstract. The disclosed dosage forms may contain an opioid
analgesic such as levorphanol as the active substance. Id. ,r,r 32-33, 80.
Controlled release of the active substance is preferably achieved by
including HPMC in the active layer, and release rates may be controlled by
selecting the viscosity of the HPMC. Id. ,r,r 48-50. "[T]o obtain a faster
release rate, the viscosity range for the hydroxypropylmethylcellulose
polymers in the active and/or barrier layer(s) may be in the range of from 50
to 25,000 mPa.sec ... preferably, HPMC polymers having a viscosity in the
range of from 1000 to 25,000 mPa.sec are present in the active or barrier
layer in a percentage of from 5 to 50% by weight of the active or barrier
layer." Id. ,r 50.
FF4. Dynamic Viscosity depicts an online calculator for converting Pa.sec
to cP where 1.0 Pa-sis equal to 1000 cP. The Examiner calculates, and
Appellant does not contest, that the 1000 to 25,000 mPa.sec recited in
Vergnault corresponds to 1,000 to 25,000 cP. See Final Act. 3--4.
6
Appeal2018-003814
Application 12/223,327
ANALYSIS
According to the Examiner, one of ordinary skill in the art would have
found it obvious
to prepare an abuse-resistant levorphanol formulation
comprising hydrogenated vegetable oil, and hydroxypropyl
methylcellulose, and silicon dioxide, as disclosed by [Oshlack],
wherein the HPMC is present at a range of from 5 to 50% wgt,
as expressly taught by [V ergnault]. One of ordinary skill in the
art would be motivated to do so, with a reasonable expectation
of success in so doing, by the express teachings of [Oshlack] as
to the effect of the loading level matrix components, such as
HPMC, on release rates.
Final Act. 5. The Examiner, thus, relies on Vergnault for its teaching to
create controlled release oral dosage forms using HPMC, including HPMC
having the claimed solution viscosities, wherein the release characteristics of
the dosage form may be modified by varying the viscosities of the HPMC.
See Final Act. 5; Ans. 5---6.
In response, Appellant argues that the Examiner identifies no reason
that an ordinarily skilled artisan would combine the teachings of Oshlack
and Vergnault. App. Br. 9, 13-14. We do not find Appellant's argument
persuasive. Oshlack discloses oral controlled release opioid formulations
with reduced potential for abuse, whereas V ergnault discloses oral
controlled release formulations that may beneficially be used to deliver
opioids and further discloses means to adjust in vitro dissolution rates of
those formulations ( and, thus, the rate of opioid release in vivo) to desired
ranges. See FFl-3. That both references address the delivery of opioids in
extended release oral formulations provides sufficient motivation to combine
their teachings for the further development of oral controlled release opioid
formulations.
7
Appeal2018-003814
Application 12/223,327
Appellant also argues that it "has discovered and claims a 'sweet spot'
among the myriad possible formulations of opioid agonists - oral dosage
forms of opioid agonists which deliver 'enough,' but not 'too much' drug."
App. Br. 9; see Reply Br. 3. In that respect, Appellant contends that the
Examiner identifies "no motivation why a POSA would select the particular
excipients or the particular amounts of' the claimed excipients and that the
Examiner ignores that the "base excipient" recited in part 'b' of independent
claim 181 must satisfy the Extended-Release Recitation. Id. at. 9, 12-13;
Reply Br. 1-7. We do not find Appellant's arguments persuasive for the
reasons set forth in the Examiner's Answer and as further set forth below.
As an initial matter, we note that Appellant provides no evidence that
this broadly claimed "sweet spot"-i.e., "release of substantially all of the
opioid agonist ... not sooner that about 18 hours" under defined test
conditions-is itself novel or unexpected, or provides any unexpected
results.
Moreover, with respect to Appellant's contention that the Examiner
ignores the relationship between these release parameters and the base
excipient, we note that although claim 181 states that "the base excipient [is]
selected such that" the dosage form has the claimed release rate, Oshlack
and Vergnault make clear that the addition of hydrophobic materials such as
hydrogenated vegetable oils, as well as the amount and viscosity of HPMC
affect the release rate. See FF2-3. Appellant appears to concede that both
the base excipient and the HPMC contribute to the claimed release profile.
See App. Br. 3 (stating that the "base excipient ... slows and extends release
of the opioid agonist ... [and] [t]he HPMC ... also modulates the rate of
release of the opioid agonist") ( emphasis omitted). Thus, as we understand
8
Appeal2018-003814
Application 12/223,327
claim 181, both the base excipient and the HPMC recited in parts (b) and
(d), respectively, are art-recognized result effective variables for solid
dosage form release rates. Insofar as Appellant has not set forth any unusual
or unexpected properties to the claimed release profile, we agree with the
Examiner that the claimed combination is obvious. See In re Antonie, 559
F .2d 618, 620 (CCP A 1977) ("[T]he discovery of an optimum value of a
variable in a known process is normally obvious."); see also In re Aller, 220
F.2d 454, 456 (CCPA 1955) ("[W]here 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").
Further, with respect to the selection of the particular excipients set
forth in the appealed claims, we agree with the Examiner that the "references
are relevant as prior art for all they contain." Ans. 4--5. It is well settled that
it is obvious for one of ordinary skill in the art to select a particular
component from among many disclosed by the prior art as long as the prior
art teaches that the selection will result in the disclosed effect. See Merck &
Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) ("That the
'813 patent discloses a multitude of effective combinations does not render
any particular formulation less obvious."). As explained by the Examiner,
Oshlack teaches
matrix dosage forms compris[ing] "sustained release
formulation[ s]," the sustained release materials in the
formulations comprising hydrophilic and hydrophobic materials,
such as hydrogenated vegetable oil as a hydrophobic material ( cf
claim 181.b )i) ), and hydroxypropyl methylcellulose as a
preferred hydrophilic material (cf claim 181d)) (see fl:0120]).
The reference further teaches that the disclosed formulations can
comprise "aversive agents" in the form of gelling agents, and that
these gelling agents can comprise hydroxypropyl
9
Appeal2018-003814
Application 12/223,327
methylcellulose, silicon dioxide, and "mixtures thereof' (see
i-f[0053]). Thus, in addition to expressly teaching that the
disclosed dosage forms can be formulated with sustained release
matrices ... the formulations disclosed in Oshlack '185 ( same
active [levorphanol], same "thixotrope" [ silicon dioxide], same
"base material" [hydrogenated vegetable oil], and HPMC, all at
loadings at least significantly overlapping the limitations of the
claims), the dosage forms of the reference would necessarily
display in vitro release profiles reading on the functional
limitation recited in claim 181.b) and characterized by Applicant
as being encompassed by the "sweet spot" of the invention.
Ans. 3--4.
For the reasons above, we affirm the rejection of claim 181 over
Oshlack and Vergnault as evidenced by DrugBank and Dynamic Viscosity
(Rejection 1). Claims 187, 197, 198, and 203 fall with claim 181. See 37
C.F.R. § 4I.37(c)(l)(iv). Because Appellant's arguments regarding
Rejections 2 and 3 are substantially the same as those regarding Rejection 1,
we affirm the rejections of claims 191, 196, 197, 199, 200, and 211-218 for
the same reasons. For the reasons set forth in footnote 9, we further
designate the rejection of claim 217 a new ground.
SUMMARY
We affirm the Examiner's decision rejecting claims 181, 187, 191,
196-200, 203, and 211-218.
TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 4I.50(b). Section 4I.50(b) provides "[a] new ground of rejection
10
Appeal2018-003814
Application 12/223,327
pursuant to this paragraph shall not be considered final for judicial review."
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating to
the claims so rejected, or both, and have the matter reconsidered
by the examiner, in which event the prosecution will be
remanded to the examiner. The new ground of rejection is
binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the opinion
of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the claims,
appellant may again appeal to the Board pursuant to this subpart.
(2) Request rehearing. Request that the proceeding be
reheard under§ 41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure§ 1214.01.
AFFIRMED; NEW GROUND
11