Pharmaceutical Manufacturing Research Services, Inc.

Patent Trials and Appeals Board

Apr 29, 2020

15270327 - (D) (P.T.A.B. Apr. 29, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
15/270,327 09/20/2016 Edwin R. Thompson 123072-00304 7543
86738 7590 04/29/2020
MCCARTER & ENGLISH, LLP BOSTON
265 Franklin Street
Boston, MA 02110
EXAMINER
THOMAS, TIMOTHY P
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
04/29/2020 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):
docket@mccarter.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte EDWIN R. THOMPSON, ERIC R. THOMPSON,
NICHOLAS R. MYSLINSKI, and STEVEN F. KEMENY
__________

Appeal 2019-006677
Application1 15/270,327
Technology Center 1600
__________

Before ERIC B. GRIMES, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an oral,
extended release, abuse deterrent pill, which have been rejected as obvious.
We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
“FDA-approved drugs are provided in many different forms based on
the type of active substance, the indication treated and the preferred route of

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as
Pharmaceutical Manufacturing Research Services, Inc. (Appeal Br. 2.)
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administration.” (Spec. ¶ 3.) Enteral formulations include tablets, capsules
and pills. (Id.)
“[T]he idea of dissolving drugs in polymers and using extrusion to
produce a pill has been known for decades.” (Id. ¶ 4.) However, “[t]he
production of pharmaceutical drugs in pill form by hot melt extrusion is
relatively uncommon.” (Id.)
The claimed invention relates to a pill that is designed to release the
active ingredient by extended release and includes “at least one abuse
deterrent mechanism to reduce abuse by non-oral administration routes” that
is made using an extrusion process. (Id. ¶ 5.)
Claims 1–3, 5, and 7–11 are on appeal.2 Claim 1 is representative and
reads as follows:
1. An oral, extended release, abuse deterrent pill comprising a
drug and
(i) 30 wt% to 50 wt% of polyethylene oxide having an
average molecular weight between 50K Daltons and 150K
Daltons;
(ii) 8 wt% to 60 wt% of a controlled release agent;
(iii) 0.2 wt% to 20 wt% polyethylene glycol, wherein the
polyethylene glycol has an average molecular weight of 3K to
9K Daltons;
wherein the drug is not oxymorphone, and has an
extended release profile,
wherein the pill has at least 50 wt% of particles with a
particle size greater than 0.5 mm following physical or
mechanical manipulation of the pill, and

2 Claim 4 remains pending but is withdrawn from consideration as being
drawn to a non-elected species. (Final Action 2.)
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wherein the pill is a formed, uniform extrudate having a
uniform blend of the drug, the polyethylene oxide, the
controlled release agent, and the polyethylene glycol, and is
directly formed from an extrusion process.
(Appeal Br. 21.) Appellant elected hydroxypropylmethyl cellulose (HPMC)
as the controlled release agent. (Final Action 2.) Accordingly, we limit
discussion and consideration to the elected species, and take no position
respecting the patentability of the broader generic claims. See Ex parte
Ohsaka, 2 USPQ2d 1460, 1461 (BPAI 1987).

The prior art relied upon by the Examiner is:
Name Reference Date
Gower et al. US 2014/0017310 A1 Jan. 16, 2014
McGinity et al. US 6,488, 963 B1 Dec. 3, 2002
S. Schilling, Implications of Plasticization on the Properties of Hot-Melt
Extruded Oral Dosage Forms, (2009) (Dissertation, Univ. of Texas at
Austin), available at
https://repositories.lib.utexas.edu/bitstream/handle/2152/7527/schillings25
096.pdf

The following ground of rejection by the Examiner is before us on
review:
Claims 1–3, 5, and 7–11 under 35 U.S.C. § 103(a) as unpatentable
over Gower, McGinity, and Schilling.3

3 As noted in the Examiner’s Answer, the rejection of claims 1–3, 5, and 7–
11 for anticipation by Gower has been withdrawn. (Ans. 13.) Likewise, any
purported rejection of these claims as being obvious over Gower alone
(Final Action 9–11) is also withdrawn. (Ans. 18.)
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DISCUSSION
The Examiner finds that Gower teaches a pharmaceutical composition
in a tablet dosage form that provides extended release of the API, which can
be oxycodone, as well as abuse deterrent properties that include difficulty to
crush or chew and forming a viscous gel when it comes into contact with a
suitable solvent. (Final Action 6 (citing Gower abstract), 8 (“the
combination of the plasticized hydrophilic plastomers and a plasticized
hydrophilic elastomers imparts sufficient mechanical integrity (i.e., strength,
hardness, elasticity, etc.”) (citing Gower ¶ 76), 9 (citing Gower Example
(Prototype #1).) The Examiner explains that Gower teaches the composition
includes polymers that are plasticized with at least one deliquescent
plasticizer. (Id. at 6.) The polymer that is plasticized is “at least one
hydrophilic plastomer [and] optionally at least one hydrophilic elastomer,”
and the plasticizer is “at least one deliquescent plasticizer.” (Id.) The
Examiner further finds that Gower teaches plasticization occurs by “using
either of two commonly used methods that thoroughly incorporate the
plasticizers into the polymers; the most common method is hot melt
extrusion.” (Id. at 6–7 (citing Gower ¶ 6).)
The Examiner finds Gower teaches the following regarding specific
polymers and plasticizers for use in the formulation. The Examiner finds
Gower teaches the hydrophilic plastomers “include Applicant elected
hydroxypropylmethyl cellulose (HPMC), polyalkylene oxides, such as
polyethylene oxide (PEG; i.e., PEO) and polyethylene glycol (PEG;
paragraph 0019).” (Id. at 7 (citing Gower ¶¶ 8, 19).) The Examiner further
finds that Gower teaches the hydrophilic plastomer may have a molecular
weight in the range of from about 100K Da to about 400K Da, and from
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100K Da to about 200K Da. (Id. (citing Gower ¶ 20).) The Examiner
further finds that prototype #1 of Gower exemplifies using PEO as the
hydrophilic plastomer. (Id. at 13.) The Examiner concludes that “[h]igh
molecular weight polyethylene oxide (paragraph 0005), taken with the sizes
taught in paragraph 0020, are construed as teaching PEO sizes within the
ranges required” or, alternatively, that “it would clearly have been obvious
to select a size within the ranges of claims 1-2 (e.g., 150,000-200,000 from
within the range 100,000-200,000 Da taught), based on the teachings of
sizes within each of these ranges in [0020].” (Id.)
The Examiner further finds that the “deliquescent plasticizer may be a
material including an organic acid and a liquid plasticizer or combinations
thereof; [and] may be Applicant elected citric acid; . . . [and] include
Applicant elected polyethylene glycols.” (Id. at 7.) The Examiner
specifically determines that Gower’s description of liquid plasticizers
including “polyethylene glycols, e.g. PEG 300, PEG 400, PEG 600, PEG
1000, etc.” “suggests higher amounts” of PEG within the claimed range due
to the use of the term “etc.” (Id. at 7; see also id. at 14.)
In addition, the Examiner finds that Gower teaches inclusion of an
“optional modifying agent,” that may be a hydrophilic gelling polymer that
“may be Applicant elected hydroxypropylmethyl cellulose (HPMC), having
a molecular weight of about 150,000 Da [0037].” (Id. at 8 (citing Gower
¶ 37).) The Examiner finds that Gower exemplifies a prototype where the
plasticizer includes citric acid and high molecular weight hydroxypropyl
cellulose which is dry blended with HPMC and polyethylene oxide and
oxycodone hydrochloride. (Id. at 9 (citing Gower ¶ 103).)
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Regarding the specific method taught by Gower for making the abuse
deterrent, extended release pill, the Examiner notes the following. The
Examiner finds that Gower “specifically teaches steps that involve
blending . . . humidifying, forming tablets and heat . . . to cure the
hydrophilic plastomer and remove excess moisture,” which heating occurs
above the melting point of PEO and PEG, and that this process is different
from extrusion. (Final Action 10 (citing Gower ¶¶ 85–86, 93, 95, and 97).)
However, the Examiner notes that:
[i]n extrusion, simultaneous mixing and heating occurs, which
may be followed by shaping, such as pressing into a tablet; the
extrusion is conducted at similar temperatures as the curing
temperatures of Gower.
(Id.) The Examiner further finds that “[t]he two processes are very similar,
and both result in strong dosage units with mechanical structure deterrent to
abuse.” (Id.) The Examiner finds that Gower teaches, regarding the hot
melt extrusion process, that it was known that “this process can [lead to] a
sticky, non-flowable material that poses additional processing problems with
conventional manufacturing.” (Id. at 14 (citing Gower ¶ 6); but see Ans. 19
(noting that “[i]t is not taught that the formulation types taught by Gower do
or do not suffer from these two negative characteristics”).) The Examiner,
nevertheless, concludes that from Gower, one of ordinary skill in the art
“would have recognized hot melt extrusion as an art-recognized alternative
method to plasticize polymers to prepare abuse deterrent properties” and as
such “it would have been obvious to process the materials of Gower via hot
melt extrusion.” (Id. at 14–15.)
Further, regarding the obviousness of making a pill dosage form
including the Gower ingredients using a hot melt extrusion process, the
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Examiner turns to McGinity and Schilling. The Examiner finds that
McGinity teaches “pharmaceutical formulations comprising a hot-melt
extrudable mixture of a therapeutic compound and a high molecular weight
poly(ethylene oxide), that contains in some embodiments, poly(ethylene
glycol).” (Id. at 15.) The Examiner notes that McGinity teaches that PEG is
a known plasticizer. (Id.) The Examiner concludes that “McGinity
establishes that hot-melt extrusion is an alternate suitable method of
formulating controlled-release pharmaceutical compounds with formulations
similar to those taught by Gower.” (Id.)
The Examiner finds that Schilling teaches “[t]he use of processing
aids including plasticizers enlarge the temperature window for hot-melt
extrusion” and that “[l]ow molecular weight polyethylene oxide functioned
as a plasticizer and enhanced chemical stability of the parent polyethylene
oxide.” (Final Action 16.) The Examiner further finds that Schilling teaches
that solid-state plasticizers, such as powdered plasticizers, have advantages
over liquid ones in terms of handling and processing, such as that they “can
be easily dry-blended with the drug and the polymer without forming tacky
pastes with poor flow properties.” (Id.; see also Ans. 19.) In addition, the
Examiner finds that Schilling prepared “five matrix former polymers” “using
hot-melt extrusion” including “five compounds, as plasticizers, with
Eudragit S100,” where one of the plasticizers was “Applicant elected
polyethylene glycol 8000 (115, 2nd paragraph, 142, Table 5.3),” which is a
solid. (Id. at 17.) The Examiner also finds that Schilling’s teaching of the
use of solid state powdered PEG8000 as a plasticizer for hot-melt extrusion
“leads to a series of benefits, among which would have been the elimination
of the oven drying step of Gower, and the rapid production method of
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pelleting using hot-melt extrusion.” (Id. at 17–18; Ans. 18 (“Schilling
teaches PEG 8000, as a solid plasticizer, will mitigate the sticky, poor pill
forming characteristics taught by Gower, and documented by the
declaration.”).)
In light of the foregoing, the Examiner concludes that “use of PEG
8000 as a solid plasticizer (clearly within the ‘etc.’ range of PEG materials
of Gower), along with exclusion of water and other solvent materials would
have been obvious to adopt, for hot-melt extrusion, with a reasonable
expectation of formulating tablets similar to those of Gower.” (Final Action
at 18.) The Examiner states that “substitution of PEG 8000, in place of the
liquid PEGs of lower molecular weights taught by Gower (and use of dry
materials), would have reasonably been expected to mitigate the problem
discussed by Gower, i.e., that in some cases the resultant plasticized polymer
mass can be a sticky (tacky) non-flowable material.” (Ans. 20.)
We do not agree with the Examiner’s conclusion of obviousness. In
particular, first, we agree with Appellant (Appeal Br. 17–18) that Gower
does not teach that hot melt extrusion is an acceptable alternative to use in
making the pills according to its invention. The Examiner relies on Gower
paragraph 6. However, as Appellant explains (Appeal Br. 12–13), that
paragraph describes the problem in the prior art with the hot melt extrusion
process generally and subsequent processing using conventional
manufacturing equipment to make dosage forms that Appellant’s invention
seeks to solve (Gower ¶ 7).
Furthermore, we agree with Appellant (Appeal Br. 17–18; Reply Br.
3–4) that Gower specifically teaches the solid dosage forms with the
disclosed “hydrophilic plastomer, optionally at least one hydrophilic
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elastomer, and at least one deliquescent plasticizer” are made “by
humidification of the composition comprising the polymers” and that this
humidification is what allows the deliquescent plasticizer to absorb moisture
from the atmosphere thereby becoming liquid, which then allows “the
plasticizer to effectively plasticize the hydrophilic polymers.” (Gower ¶ 14.)
Hot melt extrusion, on the other hand, relies on heat and pressure for
plasticization. (Id. ¶ 6.)
Moreover, the deliquescent plasticizer, which must be able “to absorb
moisture from the air such that it forms a saturated solution,” becomes
“incorporate[d] into the hydrophilic plastomer and the hydrophilic
elastomer, thereby plasticizing” them. (Id. ¶ 27.) The subsequent addition
of heat removes the excess moisture and cures the polymers where “the
resultant composition has sufficient hardness and resiliency such that it
resists being crushed or ground into fine particles.” (Id. ¶ 14.) The
Examiner has not pointed us to persuasive evidence of record that without
humidification, the composition of Gower requiring a deliquescent
plasticizer dependent on humidification, would form.
Moreover, Appellant provided experimental evidence via a
declaration demonstrating that using the ingredients in Gower prototype 2
and 3, one could not achieve a pill using hot melt extrusion. (See, e.g.,
Appeal Br. 11–12 (referring to the Declaration of Thompson filed April 27,
2018).) The Examiner disregarded this evidence with respect to the
obviousness rejection because the rejection relies on substituting PEG8000
solid plasticizers in the Gower formulation. (Ans. 18.) We conclude that
disregarding this evidence was improper. We agree with Appellant that this
evidence establishes that hot-melt extrusion is not an acceptable alternative
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“processing method for making pills using the Gower
invention/formulation.” (Reply Br. 4.)
We turn to the non-obviousness of substituting PEG8000 in the
Gower formulation. The Examiner’s assertion that it would have been
obvious to include PEG8000 in the formulation necessarily relies on the
proposition that one of ordinary skill in the art would have understood that
this PEG could be substituted for the deliquescent plasticizer taught as
essential in the Gower composition. (Ans. 20–21.) It also relies on the
proposition that such substitution would “reasonably [be] expected to
mitigate the problems of sticky/tacky, non flowable plasticized polymer
mass.” (Ans. 21, see also id. at 20.) However, as just discussed, Gower
does not teach that its process, which depends upon including a deliquescent
plasticizer, leads to a material that has a tacky or non-flowable problem.
That is a problem arising from a hot melt extrusion process. (Gower ¶ 6.)
Also, we disagree with the Examiner that Gower’s “etc.” in the list of
PEG deliquescent plasticizers includes PEG8000. As Appellant notes
(Appeal Br. 14), Gower teaches that “suitable liquid plasticizers include . . .
polyethylene glycols (e.g., PEG 300, PEG 400, PEG 600, PEG 1000, etc.).”
(Gower ¶ 28.) Appellant submitted evidence demonstrating that PEGs with
molecular weights above 1,000 are waxy, white solids. (Appeal Br. 14.)
The Examiner does not dispute this showing; indeed, the Examiner
appreciates that “Schilling teaches PEG 8000, as a solid plasticizer.” (Ans.
18.) Gower does not teach or suggest that higher molecular weight PEGs,
that are not liquid, are deliquescent plasticizers.
While it is true that Gower does mention that solid plasticizers can be
used, it only mentions organic acid and sugar alcohols in solid forms.
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(Gower ¶ 28.) Moreover, and most importantly, whether liquid or solid, the
plasticizer required by Gower is a deliquescent plasticizer. And Gower does
not teach that higher molecular weight PEGs that are solid are suitable
deliquescent plasticizers. The Examiner has not provided sufficient
evidence to establish that PEG8000 would have been known to be a
deliquescent plasticizer, much less in a composition that includes a
hydrophilic plastomer such as required in the Gower composition. Schilling
describes the use of PEG8000 in plasticizing a non-PEO matrix, namely,
Eudragit S100 in hot melt extrusion. (See, e.g., Schilling 118 (“The
compatibility and plasticization efficiency of five plasticizers including
TEC, ATBC, PEG 8000, methylparaben and citric acid monohydrate with
Eudragit® S100 were evaluated.”).) Eudragit is a methacrylic polymer.
(See, e.g., id. at 39, 153.) Appellant argues, and the Examiner does not
dispute, that this non-PEO matrix agent is an insoluble copolymer that is
different from the soluble PEO polymers described as the hydrophilic
plastomers in Gower. (Appeal Br. 19.) Indeed, Gower does not recite
methacrylic polymers in its long list of potential hydrophilic plastomers.
(Gower ¶ 19.) It does state that the hydrophilic plastomer is one that readily
absorbs and/or dissolves in water that is also a hard rigid polymeric
substance. (Id. ¶ 18.) Eudragit is not described as a matrix agent that
readily absorbs and/or dissolves in water. (See also Reply Br. 3.)
Finally, we agree with the Appellant, without a humidification step,
even if it were known that PEG8000 would absorb moisture from the air,
one of ordinary skill in the art would not have reasonably expected the
composition including PEG8000 with a PEO as claimed to form a
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plasticized composition having the characteristics of Gower, because the
essential step of Gower would have been removed.
“A rejection based on section 103 clearly must rest on a factual basis,
and these facts must be interpreted without hindsight reconstruction of the
invention from the prior art.” In re Warner, 379 F.2d 1011, 1017 (CCPA
1967). For the reasons discussed above, we determine that the Examiner has
not set forth a factual basis sufficient to support a conclusion of obviousness
of Appellant’s claimed invention. Accordingly, we reverse the Examiner’s
rejection of claims 1–3, 5, and 7–11 under 35 U.S.C. § 103(a) as
unpatentable over Gower, McGinity, and Schilling.
DECISION SUMMARY
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–3, 5, 7–11 103(a) Gower, McGinity,
Schilling
1–3, 5, 7–11

REVERSED