Kyle Bass IPR Against Insys Therapeutics, Part 2

U.S. Patent No.
US 8,486,972
UNITED STATES PATENT AND TRADEMARK OFFICE

__________________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________________
Coalition For Affordable Drugs XI LLC,
Petitioner
v.
Insys Pharma, Inc.,
Patent Owner
U.S. Patent 8,486,972
__________________
PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
8,486,972 AND
MANDATORY NOTICES UNDER 37 C.F.R. 42.8
Mailed August 24, 2015
U.S. Patent No. 8,486,972

TABLE OF CONTENTS
NOTICE OF RELATED MATTERS...........................................................................................3
NOTICE OF SERVICE INFORMATION ..................................................................................3
GROUNDS FOR STANDING ......................................................................................................3
STATEMENT OF PRECISE RELIEF REQUESTED...............................................................3
STATEMENT OF REASONS FOR RELIEF REQUESTED....................................................6
II. THE CLAIMS UNDER CONSIDERATION.......................................................................8
III. THE 972 PATENT AND PROSECUTION HISTORY OF THE '972 PATENT ............9
IV. CLAIM CONSTRUCTION .................................................................................................23
A. MEAN TIME TO MAXIMUM PLASMA CONCENTRATION (TMAX) OF
FENTANYL OF FROM ABOUT 5 TO ABOUT 120 MINUTES ......................................23
B. DISCRETE LIQUID DROPLETS .....................................................................................25
V. LEVEL OF SKILL IN THE ART .......................................................................................26
VI. CLAIMS 1-3 ARE OBVIOUS .............................................................................................26
A.
GROUND 1 -- CLAIMS 1 AND 3 ARE UNPATENTABLE AS OBVIOUS

OVER ROSS_GB, IN VIEW OF ROSS_US2006, AND THE 862 PATENT ..................27
1.
INDEPENDENT CLAIM 1 .................................................................................................27
A. UNIT DOSE ...........................................................................................................................28

B. NON-PROPELLANT ............................................................................................................28
C. SUBLINGUAL FENTANYL FORMULATION COMPRISING DISCRETE
LIQUID DROPLETS.............................................................................................................28
D. AN EFFECTIVE AMOUNT OF FENTANYL .....................................................................29
E. A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER .......................................29
F. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION COMPRISES:
FROM ABOUT 0.1% TO ABOUT 0.8% BY WEIGHT OF FENTANYL OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF .............................................30
G. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES FROM
ABOUT 20% TO ABOUT 60% BY WEIGHT OF ETHANOL ............................................31
ii

H. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES FROM
ABOUT 4% TO ABOUT 6% BY WEIGHT OF PROPYLENE GLYCOL ...........................31
I.
SUBLINGUAL ADMINISTRATION TO A HUMAN..........................................................34
J.
SAID SUBLINGUAL FENTANYL FORMULATION PROVIDES A MEAN TIME

TO MAXIMUM PLASMA CONCENTRATION (TMAX) OF FENTANYL OF
FROM ABOUT 5 TO ABOUT 120 MINUTES .....................................................................34
3.
DEPENDENT CLAIM 3 ......................................................................................................37
A. AFTER SUBLINGUAL ADMINISTRATION TO A HUMAN, THE

SUBLINGUAL FENTANYL FORMULATION PROVIDES A MEAN TIME TO
MAXIMUM PLASMA CONCENTRATION (TMAX) OF FENTANYL OF FROM
ABOUT 10 TO ABOUT 60 MINUTES. ................................................................................38
B.
GROUND 2 -- CLAIM 2 IS UNPATENTABLE AS OBVIOUS OVER

ROSS_GB, IN VIEW OF ROSS_US2006, THE 862 PATENT, AND THE 496
PUBLICATION ....................................................................................................................40
1.
DEPENDENT CLAIM 2......................................................................................................40
2.
THE PRIOR ART AND ITS COMPARISON TO CLAIM 2 ..........................................40
A. SAID DISCRETE LIQUID DROPLETS HAVE A SIZE DISTRIBUTION OF

FROM ABOUT 10 M TO ABOUT 200 M. .......................................................................41
C.
THE PATENT OWNERS ARGUMENT FOR SECONDARY

CONSIDERATIONS SET FORTH IN THE PROSECUTION FILE HISTORY
ARE MISLEADING AND WRONG ..................................................................................43
1.
PATENT OWNERS ARGUMENT FOR SECONDARY CONSIDERATIONS

IS NOT COMMENSURATE WITH THE SCOPE OF THE CLAIMS ........................44
2.
A FAST ONSET OF FIVE MINUTES WAS NOT UNEXPECTED BECAUSE

A COMMERCIAL FENTANYL NASAL SPRAY ACHIEVED A FIVE
MINUTES ONSET EFFECT ..............................................................................................47
3.
A FAST ONSET OF FIVE MINUTES WAS NOT UNEXPECTED BECAUSE

OTHER PRIOR ART REFERENCES REPORTED EFFICACIOUS PAIN
RELIEF AT FIVE MINUTES OR LESS ...........................................................................50
4.
A PRIOR ART FENTANYL NASAL SPRAY ACHIEVED A BLOOD

CONCENTRATION FIVE MINUTES POST ADMINISTRATION THAT
WAS HIGHER THAN THE CONCENTRATION OF THE CLAIMED
INVENTION WITH THE SAME DOSAGE .....................................................................53
VII. CONCLUSION ......................................................................................................................55
iii
TABLE OF AUTHORITIES
CASES
KSR Intl Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) .................................... 26, 27
In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 U.S. App. LEXIS 1699,
Slip. Op. at 21 (Fed. Cir. Feb. 4, 2015). ................................................................. 23
Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012),
cert denied, 133 S. Ct. 1736 (2013)). ..................................................................... 27
RULES
37 C.F.R 42.8(b)(1) ................................................................................................... 1
37 C.F.R. 42.100(b) ................................................................................................ 23
iv
Coalition For Affordable Drugs XI LLC ("CFAD" or "Petitioner") requests

inter partes review of claims 1 - 3 of U.S. Patent No. 8,486,972 ("the '972 Patent")
(Exhibit 1001) assigned to Insys Pharma, Inc. (Insys).
NOTICE OF LEAD AND BACKUP COUNSEL

Lead Counsel:
Dr. Gregory J. Gonsalves
Reg. No. 43,639
2216 Beacon Lane
Falls Church, VA 22043
(571) 419-7252
gonsalves@gonsalveslawfirm.com
Backup Counsel:
Christopher Casieri
McNeely, Hare & War LLP
12 Roszel Road, Suite C104
Princeton, NJ 08540
Phone: 609 731 3668
chris@miplaw.com
NOTICE OF EACH REAL-PARTY-IN-INTEREST

Pursuant to 37 C.F.R. 42.8(b)(1), Petitioner certifies that Coalition For
Affordable Drugs XI LLC (CFAD), Hayman Credes Master Fund, L.P.
(Credes), Hayman Orange Fund SPC Portfolio A (HOF), Hayman Capital
Master Fund, L.P. (HCMF), Hayman Capital Management, L.P. (HCM),
Hayman Offshore Management, Inc. (HOM), Hayman Investments, L.L.C.
(HI), nXn Partners, LLC (nXnP), IP Navigation Group, LLC (IPNav), J Kyle
Bass, and Erich Spangenberg are the real parties in interest (collectively, RPI).
The RPI hereby certify the following information: CFAD is a wholly owned
1
subsidiary of Credes. Credes is a limited partnership. HOF is a segregated portfolio

company. HCMF is a limited partnership. HCM is the general partner and
investment manager of Credes and HCMF. HCM is the investment manager of
HOF. HOM is the administrative general partner of Credes and HCMF. HI is the
general partner of HCM. J Kyle Bass is the sole member of HI and sole shareholder
of HOM. CFAD, Credes, HOF and HCMF act, directly or indirectly, through HCM
as the general partner and/or investment manager of Credes, HOF and HCMF. nXnP
is a paid consultant to HCM. Erich Spangenberg is the Manager and majority
member of nXnP. IPNav is a paid consultant to nXnP. Erich Spangenberg is the
Manager and majority member of IPNav. Other than HCM and J Kyle Bass in his
capacity as the Chief Investment Officer of HCM and nXnP and Erich Spangenberg
in his capacity as the Manager/CEO of nXnP, no other person (including any
investor, limited partner, or member or any other person in any of CFAD, Credes,
HOF, HCMF, HCM, HOM, HI, nXnP or IPNav) has authority to direct or control (i)
the timing of, filing of, content of, or any decisions or other activities relating to this
Petition or (ii) any timing, future filings, content of, or any decisions or other
activities relating to the future proceedings related to this Petition. All of the costs
associated with this Petition will be borne by HCM, CFAD, Credes, HOF and/or
HCMF.
NOTICE OF RELATED MATTERS

Petitioner is aware of a concurrently filed Petition for inter partes review
(IPR) of U.S. Patent No. 8,835,459 (Case No. Unassigned); and a concurrently
filed Petition for IPR of U.S. Patent No. 8,835,460 (Case No. Unassigned). To
the best of Petitioners knowledge, there are no pending litigations or other
related matters related to the 972 patent that would affect, or be affected by, a
decision in this proceeding.
NOTICE OF SERVICE INFORMATION

Please address all correspondence to the lead and backup counsel at the
address shown above. Petitioner also consents to electronic service by e-mail at:
gonsalves@gonsalveslawfirm.com and chris@miplaw.com.
GROUNDS FOR STANDING

Petitioner certifies that the patent for which review is sought is available for
inter partes review, and that Petitioner is not barred or estopped from requesting an
inter partes review on the grounds identified in the petition.
STATEMENT OF PRECISE RELIEF REQUESTED

Petitioner relies on the following patents and printed publications to support
its grounds of challenge to claims 1-3 of the 972 patent in this Petition:
1. Great Britain patent publication GB2399286A by Calvin John Ross et
al, entitled Sub-lingual fentanyl formulation. published September
15, 2004 (Ross_GB, Exhibit 1003). Ross_GB is prior art to the
972 patent under at least 35 U.S.C. 102(b) (pre-AIA) because it
was published on September 15, 2004, more than one year prior to
January 25, 2006, the earliest effective filing date for the claims of
the 972 patent.
2. United States Patent 5,370,862 by Karin Klokkers-Bethke et al.,
entitled Pharmaceutical hydrophilic spray containing nitroglycerin for
treating angina, issued December 6, 1994 (the 862 patent, Exhibit
1004). The 862 patent is prior art to the 972 patent under at least 35
U.S.C. 102(b) (pre-AIA) because it issued on December 6, 1994,
more than one year prior to January 25, 2006, the earliest effective
filing date for the claims of the 972 patent.
3. United States Patent Application Publication 2006/0062812 by Calvin
John Ross et al. entitled Novel compositions, published March 23,
2006 (Ross_US2006, Exhibit 1005). Ross_US2006 is prior art to
the 972 patent under at least 35 U.S.C. 102(e) (pre-AIA) because it
was filed on September 12, 2005, prior to January 25, 2006, the
4
earliest effective filing date for the claims of the 972 patent.
4. United States Patent Publication 2002/0055496 by Randall McCoy et
al. entitled Formulation and System For Intra-oral Delivery Of
Pharmaceutical Agents, published May 9, 2002 (the 496
publication, Exhibit 1006). The 496 publication is prior art to the
972 patent under at least 35 U.S.C. 102(b) (pre-AIA) because it
was published on May 9, 2002, more than one year prior to January
25, 2006, the earliest effective filing date for the claims of the 972
patent.
Petitioner requests that claims 1-3 of the '972 patent be held unpatentable
based on the following grounds:
Ground 1. Claims 1 and 3 are unpatentable as obvious over Ross_GB, in
view of Ross_US2006, and the 862 patent. See 35 U.S.C. 103(a).1 The 862
patent was not before the Examiner during the prosecution of the application that
led to the 972 patent.
The pre-AIA version of 103 applies in this proceeding, because the 972 Patent
has an effective filing and issue date before March 16, 2013. The 972 patent
claims a priority date of January 25, 2006.
Ground 2. Claim 2 is unpatentable as obvious over Ross_GB, in view of

Ross_US2006, the 862 patent, and the 496 publication. The 496 publication was
not cited by the Examiner as basis for rejection during the prosecution of the
application that led to the 972 patent. See 35 U.S.C. 103(a).
THRESHOLD REQUIREMENT FOR INT ER PAR T ES REVIEW
A petition for inter partes review must demonstrate "a reasonable
likelihood that the petitioner would prevail with respect to at least one of the
claims challenged in the petition." 35 U.S.C. 314(a). This Petition meets that
threshold. All of the elements of claims 1-3 of the '972 Patent are taught or
suggested in the prior art, as explained below in the proposed grounds of
unpatentability. The reasons to combine the cited references, where applicable,
are established under 35 U.S.C. 103(a).
This Petition is supported by the
Declaration of Dr. Park (Exhibit 1002).

Therefore, in accordance with 37 C.F.R. 42.22, Petitioner respectfully
requests cancellation of claims 1-3 of the 972 patent.
STATEMENT OF REASONS FOR RELIEF REQUESTED
I.
INTRODUCTION AND SUMMARY OF ARGUMENT

The 972 patent is directed to a sublingual liquid fentanyl formulation. As
described herein each element of the claims is clearly taught by the prior art.
6
During the prosecution of the 972 patent, after several rejections of obviousness,
the patentee argued that unexpected advantages rebutted the prima facie case of
obviousness made by the Examiner. The Applicants submitted a Declaration
allegedly showing unexpected results (rapid onset of effect) over the prior art. The
Examiner accepted the conclusion of the Declaration and allowed the claims.
However, as described below, there were no unexpected results so the claims
are obvious. The Applicants Declaration was not consistent with the scope of the
claims, it misinterpreted data from prior art references, and failed to consider a
number of more relevant references that contradict the notion that rapid onset of
effect was unexpected or surprising.
Accordingly, the claims of the 972 patent are obvious over the prior art and
there is no objective evidence of non-obviousness.
The public has a significant interest in ensuring monopoly privileges are not
granted by an invalid patent particularly where, as here, Subsys (the drug
corresponding to the 972 patent) can cost up to $300 per day per patient.2 The
2
See e.g., Exhibit 1030, Fallon community Health Plan, Prior Authorization
Approval Criteria, Subsys (fentanyl sublingual spray), 3/14/2012; Exhibit 1031,

Subsys Manufacturing/Pricing Good RX, 2015; and Exhibit 1032, Subsys
Manufacture/Pricing Epocrates Online, 2015.
patent owner can attempt to secure such high prices through FDA regulatory
exclusivity but should not be allowed to extend these privileges with an obvious
972 patent.
II.
THE CLAIMS UNDER CONSIDERATION

1.
A unit dose of a non-propellant sublingual fentanyl formulation
comprising discrete liquid droplets of an effective amount of fentanyl and a

pharmaceutically acceptable liquid carrier, wherein the sublingual fentanyl
formulation comprises:
from about 0.1% to about 0.8% by weight of fentanyl or a pharmaceutically
acceptable salt thereof;
from about 20% to about 60% by weight of ethanol; and from about 4% to
about 6% by weight of propylene glycol;
wherein after sublingual administration to a human, said sublingual fentanyl
formulation provides a mean time to maximum plasma concentration (Tmax)
of fentanyl of from about 5 to about 120 minutes.
2.
The unit dose of claim 1, wherein said discrete liquid droplets have a
size distribution of from about 10 m to about 200 m.
3.
The unit dose of claim 1 wherein after sublingual administration to a
human, the sublingual fentanyl formulation provides a mean time to

maximum plasma concentration (Tmax) of fentanyl of from about 10 to about
60 minutes.
III.
THE 972 PATENT AND PROSECUTION HISTORY OF THE '972

PATENT
A.
The '972 Patent
The 972 patent is directed to non-propellant sublingual fentanyl

formulations, which include discrete liquid droplets. The claimed formulations
recite specific amounts by weight of fentanyl, ethanol and propylene glycol. The
claims also recite that when administered sublingually to a human, the formulation
provides a mean time to maximum plasma concentration of fentanyl (Tmax) within
a certain range.3 Claim 1 is as follows:
1. A unit dose of a non-propellant sublingual fentanyl formulation
comprising discrete liquid droplets of an effective amount of fentanyl
and a pharmaceutically acceptable liquid carrier, wherein the
sublingual fentanyl formulation comprises:
from about 0.1% to about 0.8% by weight of fentanyl or a
pharmaceutically acceptable salt thereof;
from about 20% to about 60% by weight of ethanol; and from about
4% to about 6% by weight of propylene glycol;
Exhibit 1001, the 972 patent, claim 1.
wherein after sublingual administration to a human, said sublingual

fentanyl formulation provides a mean time to maximum plasma
concentration (Tmax) of fentanyl from about 5 to about 120 minutes.
The formulation of claim 1 contains three recited components: fentanyl;

ethanol; and propylene glycol. Fentanyl is a -opioid receptor agonist with
analgesic potency approximately 80-100 times that of morphine.4 Ethanol and
propylene glycol are both identified as organic solvents which are used to enhance
the solubility of fentanyl.5
In the prior art, fentanyl is administered by way of a number of different
routes including oral, parenteral, buccal, transdermal6 and intranasal.7 Orally
administered fentanyl is subject to first pass effect metabolism, which leaves 50%
or more of the fentanyl unabsorbed.8 The other forms of administration avoid or
decrease the first pass effect for fentanyl.9
4
Exhibit 1001, 972 patent, col. 1, ll. 12-13.
Id. at col. 1, ll. 29-33.
Exhibit 1013, US Patent 8,889,176, col 2, ll. 10-16.
Id. at col. 1, ll. 29-33.
10
Transdermal administration of fentanyl is reportedly not suitable for severe

pain or breakthrough pain.10 According to the Patentee, buccal administration of
fentanyl via transmucosal lozenge is reported to have relatively slow absorption
times.11 However, sublingual spray administration of fentanyl that is free of
propellant is reported to provide rapid onset of therapeutic effect.12 In addition,
oral transmucosal administration of fentanyl is reported as providing rapid onset of
effect in as low as five minutes after dosing.13
B.
The Prosecution History Of The '972 Patent
The 972 patent has a lengthy and involved prosecution history. The 972 patent
was filed on January 25, 2007 and claims benefit of U.S. provisional application
No. 60/763,057 filed on January 25, 2006. The original claims were amended a
number of times during the prosecution and ultimately cancelled in favor of a new
10
Exhibit 1013 US Patent 8,889,176, col 1, ll. 50-55.
11
Id. at col 1, ll. 58-64.
12
Exhibit 1003, GB2399286A, Ross_GB, page 3, ll. 29-33.
13
See e.g. Exhibit 1010, Peng_1999, page 587, left column, 3; Exhibit 1011,
Mercadante_1999, page 2, 5; Exhibit 1012, Lichtor_1999, page 736, right

column, 1.
11
set of claims introduced by way of an RCE. For the sake of completeness a

summary of the history of the first set of claims is as follows.
First, in response to a Restriction dated March 10, 2010, claim 1 was
amended to recite the limitation of claim 9 which introduced a plasma
concentration range into claim 1 (the only independent claim not withdrawn).14 A
Non-Final Office Action issued on June 9, 2010 provisionally rejecting the claims
on the ground of nonstatutory obviousness-type double patenting.15 In response,
Applicants argued that the rejection should be withdrawn since it was the only
rejection pending.16
A second Non-Final Office Action issued on September 15, 2010 rejecting
the claims as anticipated by US20030190290 to Ross17 (Ross_US 2003).18
Applicants argued that Ross US 2003 did not necessarily teach droplets having a
14
Exhibit 1017, Response to Restriction dated April 12, 2010.
15
Exhibit 1018, Non-Final Rejection dated June 9, 2010
16
Exhibit 1019, Response to Non-Final Office Action dated June 21, 2010.
17
Exhibit 1020, US Application No. 20030190290 (Ross_US 2003)
18
Exhibit 1021, Non-Final Office Action dated September 15, 2010
12
mean diameter of at least 10 microns as recited in the claims.19 Applicants further

argued that the functional limitations were actual limitations and not an intended
use.20
A third Non-Final Office Action issued on May 2, 2011 rejecting the claims
as obvious over US2006006281221 (Ross_US2006).22 In response, Applicants
argued that the claims were not obvious over Ross_US2006 without amending the
claims.23 A Final Rejection issued on November 17, 2011 maintaining the
obviousness rejection of the claims over Ross_US2006.24
Thereafter Applicants filed an RCE on February 17, 2012 cancelling all the
claims and introducing new claims 144-147.25 Claim 144, the only independent
claim, eventually issued as claim 1 in the 972 patent and is reproduced below:
19
Exhibit1022, Response to Non-Final Office Action dated February 15, 2011,
page 20-21.
20
Id. at p. 22.
21
Exhibit 1005, US Application No 20060062812 (Ross_US2006)
22
Exhibit 1023, Non-Final Rejection dated May 2, 2011
23
Exhibit 1024, Response to Non-final Rejection dated August 2, 2011.
24
Exhibit 1025, Final Rejection dated November 17, 2011.
25
Exhibit 1026, Amendment dated February 17, 2012.
13
144. (New) A unit dose of a non-propellant sublingual fentanyl

formulation comprising discrete liquid droplets of an effective amount
of fentanyl and a pharmaceutically acceptable liquid carrier, wherein
the sublingual fentanyl formulation comprises:
from about 0.1 % to about 0.8% by weight of fentanyl or a
pharmaceutically acceptable salt thereof;
from about 20% to about 60% by weight of ethanol; and
from about 4% to about 6% by weight of propylene glycol;
wherein said discrete liquid droplets have a size distribution of
from about 5 m to about 500 m, and a mean diameter of about 20
m to about 200 m;
wherein after sublingual administration to a human, said
sublingual fentanyl formulation provides:
a mean maximum plasma concentration (Cmax) of
fentanyl of from about 158 pg/mL to about 177 pg/mL per 100 g
fentanyl;
a mean time to maximum plasma concentration (Tmax) of
fentanyl of fromabout 10 to about 60 minutes; and
a mean area under the plasma concentration time curve to
infinity (AUC)of fentanyl of from about 715 pghour/mL to about
1061 pghour/mL per 100 g fentanyl.26
A Non-Final Office Action issued on June 8, 2012 again rejecting the claims as
obvious over Ross_US2006.27 The rejection indicated that Ross_US2006 did not
26
Id.
14
specifically teach the recited droplet size, the specific weight of propylene glycol,
or mean Cmax, but concluded that the broad teaching of Ross_US2006 cured the
deficiencies.28
Applicants responded by amending the claim to delete the droplet size
limitation, the Cmax limitation, and AUC limitations from the claim. 29 This
amendment left the mean time to plasma concentration (Tmax) as the only so-called
functional limitation in the claim. The claim was, after the amendment, in the
form that it would ultimately be allowed. Applicants argued that Ross_US2006
failed to recognize propylene glycol as a result-effective variable.30 Applicants
further argued unexpected results of the claimed formulation and submitted the
Dillaha Declaration Exh.1015 in support of the argument.31 Of particular
relevance, the Dillaha Declaration offered the following statements:
Continued from previous page

27
Exhibit 1027, Non-Final Rejection dated June 8, 2012.
28
Id. at p. 5
29
Exhibit 1014, Amendment and Response dated October 8, 2012, pp 2, 3.
30
Id. at p. 6
31
Id. at pp. 4, 6.
15
1) [E]ffective treatment for pain in 5 minutes compared to 10 or 15

minutes or longer is significant.32
2) No marketed, competitive fentanyl product has been able to show
statistically significant pain relief any earlier than 10 minutes.33
3) These publications, Exhibits 1-7 described above, demonstrate
that the presently claimed unit dose provides effective pain relief at
significantly faster times than placebo or competitive fentanyl
products.34
Dillaha ultimately concludes:
4) Accordingly the presently claimed unit dose provides efficacious
pain relief at significantly faster times relative to other transmucosal
immediate release fentanyl formulations, which is both unexpected
and, more importantly, a distinct clinical benefit.35
The Dillaha Declaration provided no new data but instead relied entirely on
Dillahas interpretation of seven publications that purportedly correspond to
32
Exhibit 1015, Dillaha Declaration at 4.
33
Id at 8.
34
Id. at 9.
35
Id. at 10
16
marketed, competitive products.36 Further, the Dillaha Declaration did not

compare the respective Tmax values of the products but instead compared what is
referred to as 1st Positive Efficacy Timepoint (minutes)37 The only reference
related to plasma concentration in the Dillaha Declaration is the following:
Patients having breakthrough cancer pain [On SUBSYS] begin to
experience statistically significant pain relief as early as 5 minutes
after dosing. This is consistent with the notion that the claimed dose
needs to have a meaningful blood concentration at about 5 minutes.38
No other explanation is provided to connect or correlate the Tmax to the
results in the publication in Exhibit B of the Dillaha Declaration. The Examiner
seemingly accepted the time to experience pain relief as a proxy for Tmax.
A Notice of Allowance issued on April 15, 2013, which provided reasons for
Allowance.39 First, the Examiner rejected the argument that propylene glycol was
established as a result-effective variable.40 Second, the Examiner stated, the fact
36
Id. at 9 and Exhibit B.
37
Id. at Exhibit B
38
Id. at 7.
39
Exhibit 1028, Notice of Allowance dated April 15, 2013.
40
Id. at p. 3.
17
that Applicants formulation is effective (onset of action) 5 minutes after

administration, which is more rapid than any other formulation on the market (10
to 15 minutes at best), provides evidence that the formulation was not appreciated
by Ross.41 Further, the Examiner stated, Due to the nature of the pain being
treated, there was a need in the art at the time of the instant invention for a fastacting pain reliever. Until the Applicants invention, it does not appear that any
other formulations were able to act as quickly.42
Applicants made Amendments after Notice of Allowance changing the Tmax
time range in claim 144 from 10 to about 60 minutes to 5 to about 120 minutes and
the opposite amendment to claim 148. The amendments were entered. The 972
patent issued on July 16, 2013.
During the prosecution of the 972 patent, Applicants argued unexpected
advantages to overcome a prima facie obviousness rejection. In particular,
Applicants argued that clinical efficacy of the claimed formulation provided
unexpected advantages over placebo and all commercial transmucosal immediate
release fentanyl formulations . . .:43 Applicants submitted the Declaration of Dr.
41
Id.
42
Id.
43
Exhibit 1014, Amendment dated 2012-10-08, p.4.
18
Larry Dillaha (the Dillaha Declaration)44 in support of such argument. While the
Dillaha Declaration was accepted by the Examiner to rebut a prima facie case of
obviousness, the Dillaha Declaration was deficient for such purpose for several
reasons.
First, the conclusion provided in the Dillaha Declaration was not
commensurate with the scope of the claimed invention and is therefore ineffective
at rebutting obviousness. Second, the Dillaha Declaration incorrectly interpreted a
key reference, specifically Portenoy R K et al, A multicenter, placebo-controlled,
double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in
the treatment of breakthrough cancer pain, 151 Pain 617 (2010)(Portenoy).45
Third, the Dillaha Declaration failed to consider a number of relevant references
that contradict the conclusion provided therein.
With regard to the first deficiency, Claim 1 recites said sublingual fentanyl
formulation provides a mean time to maximum plasma concentration (Tmax) of
44
Exhibit 1015, Declaration Of Dr. Larry Dillaha To 37 CFR 1.132 dated
September 17, 2012.

45
Exhibit 1008, Portenoy R K et al, A multicenter, placebo-controlled, double-
blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the

treatment of breakthrough cancer pain, 151 Pain 617 (2010).
19
fentanyl from about 5 to about 120 minutes. The Dillaha Declaration failed to
establish a nexus between the claimed Tmax values over the complete time range
recited in the claim and the so called rapid onset of therapeutic effect describe in
the Declaration. The Dillaha Declaration failed to consider or compare Tmax values
of the claimed invention to Tmax values of the other commercial fentanyl
formulations at all. Instead, as explained below, the Dillaha Declaration purports
to compare the time for onset of therapeutic effect of the fentanyl upon
administration. In this regard, the Specification does not quantify or apply any
metric as to what constitutes rapid onset of therapeutic effect of the fentanyl.
More importantly, the Specification does not correlate therapeutic effect with
Tmax generally, nor does the specification correlate rapid onset of therapeutic
effect with a specific Tmax time or time range.
Further, to the extent it equates the Tmax with onset of action, the Dillaha
Declaration considered only the low end of the claimed time range (5-10 minutes),
but did not consider the entire recited time range, i.e. about 5 to about 120
minutes. The data contained in the Dillaha Declaration establishes significant
overlap between the time range of the references examined therein and the claimed
20
Tmax range. In particular, the Dillaha Declaration identifies references with a range
of 10 minutes to 120 minutes for onset of efficacy.46
With regard to the second deficiency, the Dillaha Declaration erroneously
concludes that the Portenoy47 reference shows first positive efficacy at 10
minutes.48 Dillaha does not explain how the 10 minute time point was determined
from the text of Portenoy. In contrast to Dillahas conclusion, Portenoy and coworkers concluded that "[a] rapid onset of effect was observed, with FPNS
achieving statistically significant differences in PI 5 min after dosing."49
Finally, the Dillaha Declaration considered only commercial formulations
and not the closest prior art. In this regard, numerous reports in the prior art refute
46
Exhibit 1015, Dillaha Declaration at Exhibit B.
47
Portenoy was included in the Dillaha Declaration however it does not appear to
be prior art to the 972 patent. An analysis of Portenoy is included herein because
it was included in the Dillaha Declaration and illustrates the inaccuracies in the
Declaration.
48
Id.
49

treatment of breakthrough cancer pain, 151 Pain 617 (2010) at p. 623.
21
the conclusion that efficacious pain relief at 5 minutes for transmucosal fentanyl
formulations was unexpected at the time of the invention.
One example is U.S. Patent No. 8,889,176 (The 176 patent), which
describes a nasal spray of fentanyl solutions that achieves higher blood
concentration at 5 minutes post administration than Subsys. Other examples
include the following references, each of which report onset of therapeutic effect
within 5 minutes: 1) P. W. H. Peng et al., A Review of the Use of Fentanyl
Analgesia in the Management of Acute Pain in Adults, Anesthesiology. 1999 Feb;
90(2):576-99; 50 2) Sebastiano Mercadante and Fabio Fulfaro, Alternatives to Oral
Opioids for Cancer Pain, Oncology, February 01, 1999;51 3) J. Lance Lichtor et
al., The Relative Potency of Oral Transmucosal Fentanyl Citrate Compared with
Intravenous Morphine in the Treatment of Moderate to Severe Postoperative Pain,
50
Exhibit 1010, P. W. H. Peng et al., A Review of the Use of Fentanyl Analgesia in
the Management of Acute Pain in Adults, Anesthesiology. 1999 Feb; 90(2):576-99

at p. 587.
51
Exhibit 1011, Sebastiano Mercadante and Fabio Fulfaro, Alternatives to Oral
Opioids for Cancer Pain, Oncology, February 01, 1999 at p.2.
22
Anesth Analg 1999; 89:7328;52 and, 4) US Patent Application No.

2003017803153.
IV.
CLAIM CONSTRUCTION
In inter partes review, a claim term is given its "broadest reasonable
construction in light of the specification." See 37 C.F.R. 42.100(b); see also

In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 U.S. App. LEXIS 1699,
Slip. Op. at 21 (Fed. Cir. Feb. 4, 2015).
A.
mean time to maximum plasma concentration (Tmax) of fentanyl of

from about 5 to about 120 minutes
Claim 1 recites: A unit dose of a non-propellant sublingual fentanyl

formulation comprising discrete liquid droplets of an effective amount of
fentanyl and a pharmaceutically acceptable liquid carrier, wherein the
sublingual fentanyl formulation comprises:
52
Exhibit 1012, J. Lance Lichtor et al., The Relative Potency of Oral Transmucosal
Fentanyl Citrate Compared with Intravenous Morphine in the Treatment of

Moderate to Severe Postoperative Pain, Anesth Analg 1999; 89:7328 at p. 736.
53
Exhibit 1016, US Patent Application No. 20030178031 at paragraph [0360].
23
from about 0.1% to about 0.8% by weight of fentanyl or a pharmaceutically

acceptable salt thereof;
from about 20% to about 60% by weight of ethanol; and from about 4% to
about 6% by weight of propylene glycol;
wherein after sublingual administration to a human, said sublingual fentanyl
formulation provides a mean time to maximum plasma concentration (Tmax) of
fentanyl of from about 5 to about 120 minutes.
One phrase requiring construction is mean time to maximum plasma
concentration (Tmax) of fentanyl of from about 5 to about 120 minutes. The
phrases broadest reasonable construction must be construed as meaning the
average time to achieve the maximum concentration of fentanyl in a patients
plasma is from about 5 to about 120 minutes.
The phrase mean time to maximum plasma concentration (Tmax) is not
explicitly defined in the specification. The term Tmax by itself is identified in the
specification as a Pharmacokinetic Parameter54 and defined in the specification as
the Time to reach Cmax55. Cmax is defined as Peak plasma concentration.56 The
54
55
Id. at col. 25, ll. 62.
56
Id.
24
term mean is not defined but the plain and ordinary meaning of the term mean
is average.57
B.
discrete liquid droplets
A second term requiring construction is discrete liquid droplets which is

recited in claims 1 and 2. The phrase is not explicitly defined in the 972
specification, but is closely associated with the term spray throughout the 972
specification. For one example, the specification states, [I]n certain embodiments,
the present invention is directed to a method of treating pain comprising
sublingually administering a liquid spray formulation in the form of discrete liquid
droplets having a mean diameter of at least about 10 microns, . . .58
The term spray was defined prior to the alleged effective filing date of the
972 patent as water or other liquid broken up into minute droplets and blown,
ejected into, or falling through the air.59 The phrase discrete liquid droplet
broadest reasonable construction must be construed as meaning, water or other
liquid broken up into minute droplets and blown, ejected into, or falling through the
57
Exhibit 1029, Random House Websters Dictionary, p. 821, mean3 definition 4a.
58
59
Exhibit 1007, Random House Websters College Dictionary, Random House,
Inc., April, 2000, p. 1270.
25
air.
V.
LEVEL OF SKILL IN THE ART

A person of ordinary skill in the art at the time of filing of these patents
would be someone who holds a B.S. degree in pharmacy, chemistry, engineering, or

related fields with several years of experience, or a Ph.D. degree in the same fields,
and is a highly trained formulation chemist, well-versed in developing formulations
from experience with drug formulations in an industrial or academic environment.60
VI.
CLAIMS 1-3 ARE OBVIOUS

The obviousness inquiry is a question of law based on four factual
predicates: (1) "the scope and content of the prior art," (2) the "differences between
the prior art and the claims at issue," (3) "the level of ordinary skill in the pertinent
art," and (4) "secondary considerations" such as "commercial success, long felt but
unsolved needs, failure of others, etc." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398,
406-07 (2007) (citing Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)); 35
U.S.C. 103(a). KSR reaffirmed that "[t]he combination of familiar elements
according to known methods is likely to be obvious when it does no more than
60
Exhibit 1002, Dr. Parks Declaration, 9.
26
yield predictable results." KSR, 550 U.S. at 416.

"Motivation to combine may be found in many different places and forms."
Par Pharm. Inc. v. TWI Pharms., Inc., 773 F.3d 1186, No. 2014-1391, 2014 U.S.
App. LEXIS 22737, at *24 (Fed. Cir. Dec. 3, 2014) (citations omitted). Thus, for
example, a challenger is not limited to the same motivation that the patentee had.
Id. (citing Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir.
2012), cert denied, 133 S. Ct. 1736 (2013)).
A. Ground 1 -- Claims 1 And 3 Are Unpatentable As Obvious Over
Ross_GB, In View Of Ross_US2006, And The 862 Patent
1.
Independent Claim 1
Claim 1 is the only independent claim at issue in this petition. It is directed

to a unit dose of a fentanyl formulation comprising discrete liquid droplets of an
effective amount of fentanyl and a pharmaceutically acceptable liquid carrier.
The unit dose of the fentanyl formulation is non-propellant and sublingual. The
fentanyl formulation comprises: from about 0.1% to about 0.8% by weight of
fentanyl or a pharmaceutically acceptable salt thereof; from about 20% to about
60% by weight of ethanol; and from about 4% to about 6% by weight of
propylene glycol. After sublingual administration to a human, the sublingual
fentanyl formulation provides a mean time to maximum plasma concentration
(Tmax) of fentanyl of from about 5 to about 120 minutes.
2.
The Prior Art And Its Comparison To Claim 1

27
As explained in detail below, claim 1 would have been obvious to one of

ordinary skill in the art in light of the teachings of Ross_GB, the 862 patent, and
Ross_US2006.61
a.
unit dose
Ross_GB teaches a unit dose of the fentanyl formulation: single or multiple
use devices comprising a single or multiple dose of the formulation of the invention
is envisaged.62
b.
non-propellant
Ross_GB teaches that [t]he [fentanyl] formulations of the present invention
are also preferably free of any propellant.63

c.
sublingual fentanyl formulation comprising discrete liquid droplets

Ross_GB teaches a pharmaceutical formulation comprising (i) fentanyl.64
Ross_GB further teaches that its fentanyl formulation is preferably administered

sublingually as a spray. The formulations are well tolerated when administered to
the sensitive sublingual mucosa and the sublingual spray administration will result in
61
Id. at 15.
62
Exhibit 1003, Ross_GB, page 8, ll. 25-26.
63
Exhibit 1003, Ross_GB, page 4, l 1.
64
Exhibit 1003, Ross_GB, Abstract.
28
rapid onset of the therapeutic effect of the fentanyl.65 Moreover, as explained by

Dr. Park, one of ordinary skill in the art as of the alleged effective filing date of the
972 patent (i.e., January 25, 2006) would have understood that the spray disclosed
in Ross_GB comprises discrete liquid droplets.66 For example, a spray was defined
prior to the alleged effecting filing date of the 972 patent as having discrete liquid
droplets: water or other liquid broken up into minute droplets and blown, ejected
into, or falling through the air.67
Accordingly, the claimed sublingual fentanyl formulation comprising
discrete liquid droplets would have been obvious over the teachings of Ross_GB.68
d.
an effective amount of fentanyl

Ross_GB teaches that a therapeutically effective amount of a [fentanyl]
formulation for the treatment of pain according to the invention is used.69

e.
a pharmaceutically acceptable liquid carrier
65
Id. at page 3, ll. 29-33 (emphasis added).
66
67
Exhibit 1007, Random House Websters College Dictionary, Random House,
Inc., April, 2000, p. 1270.

68
69
Exhibit 1003, Ross_GB, page 8, ll. 10-11 (emphasis added).
29
Ross_GB teaches that the dose of the fentanyl formulation includes water as
a pharmaceutically acceptable liquid carrier:
(a) fentanyl or a pharmaceutically acceptable salt thereof;
(b) water as carrier; and
(c) a polar organic solvent in sufficient amount to enhance the
solubility of the fentanyl or pharmaceutically acceptable salt thereof in
the water.70
f.
wherein the sublingual fentanyl formulation comprises: from about 0.1% to

about 0.8% by weight of fentanyl or a pharmaceutically acceptable salt
thereof
Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g fentanyl,
0.0177g saccharin, 2.8336 g ethanol, 0.0531g menthol, and 4.1516g citrate

buffer.71 As explained by Dr. Park, [b]ased on this disclosure, the fentanyl
concentration is calculated to be 0.028g fentanyl / (0.028g + 0.0177g + 2.8336g +
0.0531g + 4.1516g) x 100 % = .395% by weight of fentanyl, which is within the
claimed range of 0.1 % to 0.8 % by weight of fentanyl.72
70
71
Id. at page 11, ll. 1-9.
72
30

g.
the sublingual fentanyl formulation comprises from about 20% to about

60% by weight of ethanol
Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g fentanyl,
0.0177g saccharin, 2.8336g ethanol, 0.0531g menthol, and 4.1516g citrate buffer.73
As explained by Dr. Park, [b]ased on this disclosure, the ethanol concentration is
calculated to be 2.8336g fentanyl / (0.028g + 0.0177g + 2.8336g + 0.0531g +
4.1516g) x 100% = 40% by weight of ethanol, which is within the claimed range of
20 % to 60 % by weight of ethanol.74
h. the sublingual fentanyl formulation comprises from about 4% to about
6% by weight of propylene glycol

Ross_GB teaches that its sublingual fentanyl formulation comprises
propylene glycol:
Examples of polar organic solvents that may be used to enhance the
solubility of fentanyl, or the physiologically acceptable salt thereof in
the water, include: lower alcohols (e.g. C24 alcohols) such as ethanol;
lower polyols (e.g. C2-4 polyols) such as glycerol and propylene
glycol.75
Moreover, Ross_GB mentions a second time that its fentanyl formulation includes
propylene glycol: [s]uitable moisturizing agents include, for example, the polar
73
74
75
Exhibit 1003, Ross_GB, page 5, ll. 1-4 (emphasis added).
31
organic solvents such as glycols, especially propylene glycol.76

In addition, the 862 patent teaches a buccal spray comprising propylene
glycol in a broad range of 2% to 30% by weight.77 As explained by Dr. Park, [t]he
range of propylene glycol taught by the 862 patent encompasses the claimed range
of about 4% to about 6% by weight of propylene glycol.78 Moreover, the 862
patent also teaches a buccal spray comprising propylene glycol of 7.28% by
weight.79 As also explained by Dr. Park, [t]his percentage of propylene glycol
meets the upper bound of the range recited in claim 1 of the 972 patent as about 6%
of propylene glycol.80
As further explained by Dr. Park, [i]t would have been obvious to use the
range of propylene glycol by weight that is taught by the 862 patent in the fentanyl
formulation taught by Ross_GB.81 Ross_GB specifically calls for an amount of
76
77
Exhibit 1004, the 862 patent, col. 4, l. 63.
78
79
Exhibit 1004, the 862 patent, col. 4, l. 47.
80
81
Id. at 24.
32
polar organic solvent to enhance the solubility of fentanyl . . .82 Ross_GB

indicates that the formulations are well tolerated when administered to sensitive
sublingual mucosa and the sublingual spray administration will result in rapid onset
of the therapeutic effect of fentanyl83 and specifically identifies propylene glycol.
Thus, as explained by Dr. Park, [o]ne skilled in the art would look to the teaching
of the 862 patent as it is a buccal spray for the administration of a medication that is
used in emergencies when the medication should be fast acting.84 As further
explained by Dr. Park, [o]ne skilled in the art would adjust and optimize the
amount of propylene glycol to account for the solubility of the drug substance as a
matter of routine.85
The identification of the claimed range of about 4% to 6% by weight of
propylene glycol is nothing more than the optimization of a range or other variable
within the claims that flows from the normal desire of scientists or artisans to
improve upon what is already generally known. Pfizer, Inc. v Apotex, 480 F.3d
82
83
Id. at ll. 30-32
84
Exhibit 1002, Dr. Parks Declaration, 24 quoting Exhibit 1004, the 862 patent,
col. 1 ll. 19-20.

85
Exhibit 1002, Dr. Parks Declaration, 24
33
1348, 1369 (Fed. Cir. 2007) citing In re Peterson, 315 F.3d 1325, 1330
(Fed.Cir.2003) (determining where in a disclosed set of percentage ranges the
optimum combination of percentages lies is prima facie obvious). As concluded by
Dr. Park, Accordingly it would be obvious to arrive at the claimed range based on
the teachings of Ross_GB in combination with the 862 patent.86
i.
sublingual administration to a human

Ross_GB teaches administration of formulations of fentanyl, especially
pump spray formulations suitable for sublingual delivery87 and the formulations of
the invention are preferably administered sublingually as a spray.88 Ross_GB
further teaches monitor[ing] patients for evidence of self medication.89 As
explained by Dr. Park, [b]ecause only people can self-medicate, the sublingual
administration taught by Ross_GB is to a human, as required by this claim
limitation.90
j.
said sublingual fentanyl formulation provides a mean time to maximum

plasma concentration (Tmax) of fentanyl of from about 5 to about 120
86
Exhibit 1002, Dr. Parks Declaration, 24
87
88
Id. at page 3, ll. 29-30
89
Id. at page 1, l. 15.
90
34
minutes
As explained by Dr. Park, Ross_US2006 teaches in Table 2 a median time to
maximum plasma concentration (Tmax) of 0.5 hours (30 minutes) with a range
between 0.333 and 0.833 hours (20 minutes and 50 minutes, respectively) following
sublingual administration of 200 microgram (mcg or g) of fentanyl with a nonpressurized pump spray device to 12 patients.91 As also explained by Dr. Park,
Table 2 of Ross_US2006 also teaches a mean time to maximum plasma
concentration (Tmax) of 0.486 hours (about 29 minutes) following sublingual
administration of 200 microgram of fentanyl with a non-pressurized pump spray
device to 12 patients.92 A mean (Tmax) of 29 minutes is within the claimed range of
about 5 minutes to about 120 minutes.
Accordingly, as explained by Dr. Park, [i]t would have been obvious to have
a sublingual fentanyl formulation providing a mean time to maximum plasma
concentration (Tmax) of fentanyl of from about 5 to about 120 minutes in light of the
teachings of Ross_US2006 and Ross_GB. The fentanyl formulations taught by
91
Exhibit 1002, Dr. Parks Declaration, 26, citing Exhibit 1005, ROSS_US2006,
page 8, Table 2.
92
Id.
35
Ross_US2006 and Ross_GB are very similar.93 The data in Table 2 of

Ross_US2006 was obtained from Formulation 2 in which the Fentanyl Base is
0.011g, Ethanol is 2.2319g, Menthol is 0.0417g, Citrate buffer is 3.2675g, and
Saccharin is 0.0139g.94 As explained by Dr. Park, [t]his gives a composition by
weight of 0.2% fentanyl, 40.1% ethanol, 0.75% menthol, 58.7% citrate buffer, and
0.25% saccharin.95
The formulation of Example 1 of Ross-GB includes 0.028g fentanyl,
0.0177g saccharin, 2.8336 g ethanol, 0.0531g menthol, and 4.1516g citrate
buffer.96 As explained by Dr. Park, [t]his gives a composition by weight of 0.4%
fentanyl, 40% ethanol, 0.75% menthol, and 58.6% citrate buffer.97
As further explained by Dr. Park, [i]n light of the similarities between the
fentanyl formulations taught by Ross_US2006 and Ross_GB, one of ordinary skill
in the art would have been motivated to combine the teachings of Ross_US2006
93
94
Exhibit 1005, ROSS_US2006, Formulation 2, page 7, [0115].
95
96
Exhibit 1003, Ross_GB, Example 1, page 11, ll. 1-9.
97
36
and Ross_GB.98 Moreover, as also explained by Dr. Park, [o]ne important

aspect of the administration of a drug is how long it takes to achieve the maximum
(or peak) drug concentration in the plasma within the patients body (Tmax).99 As
further explained by Dr. Park, both Ross_GB and ROSS_US2006 teach fentanyl
formulations that are similar to each other as well as the claimed formulation of the
972 patent.100 Accordingly, one of ordinary skill in the art would have been
motivated to combine the fentanyl teachings of Ross_US2006 and Ross_GB to
achieve a shorter Tmax for the administration of a drug so that the patient would
more quickly experience the effects of the drug.101
3.
Dependent Claim 3
Claim 3 depends from independent claim 1 and is directed to the dose

of the fentanyl formulation of claim 1 which provides, after sublingual
administration to a human, a mean time to maximum plasma concentration
(Tmax) of fentanyl of from about 10 to about 60 minutes. That is, claim 3 recites
98
Id. at 28.
99
Id.
100
Id.
101
Id.
37
the same sublingual fentanyl formulation as claim 1 except that the value of Tmax
varies from about 10 to about 60 minutes in, a range that is narrower than the range
of about 5 minutes to about 120 minutes in claim 1. However, a mean Tmax of 29
minutes disclosed in Ross_US2006 is within the claimed range of about 10
minutes to about 60 minutes.102
4.
As explained in detail below, claim 3 would have been obvious to one of

ordinary skill in the art in light of the teachings of Ross_GB, the 862 patent, and
Ross_US2006.103
a.
after sublingual administration to a human, the sublingual fentanyl

formulation provides a mean time to maximum plasma concentration (Tmax)
of fentanyl of from about 10 to about 60 minutes.
As explained by Dr. Park, Ross_US2006 teaches in Table 2 a median time to
maximum plasma concentration (Tmax) of 0.5 hours (30 minutes) with a range
between 0.333 and 0.833 hours (20 minutes and 50 minutes, respectively) following
sublingual administration of 200 microgram of fentanyl with a non-pressurized
102
Exhibit 1002, Dr. Parks Declaration, 30, citing Exhibit 1005, ROSS_US2006,
page 8, Table 2.
103
Id. at 29.
38
pump spray device to 12 patients.104 As also explained by Dr. Park, Table 2 of

Ross_US2006 also teaches a mean time to maximum plasma concentration (Tmax) of
0.486 hours (about 29 minutes) following sublingual administration of 200
microgram of fentanyl with a non-pressurized pump spray device to 12 patients.105
A mean time to Tmax of 29 minutes is within the range recited in claim 3 of about
10 minutes to about 60 minutes.
Accordingly, as explained by Dr. Park, [i]t would have been obvious to have
a sublingual fentanyl formulation providing a mean time to maximum plasma
concentration (Tmax) of fentanyl of from about 10 to about 60 minutes in light of the
teachings of Ross_US2006 and Ross_GB.106 The fentanyl formulations taught by
Ross_US2006 and Ross_GB are very similar.107 As explained by Dr. Park, [i]n
light of the similarities between the fentanyl formulations taught by Ross_US2006
and Ross_GB, one of ordinary skill in the art would have been motivated to
104
Exhibit 1002, Dr. Parks Declaration, 30 citing Exhibit 1005, ROSS_US2006,
page 8, Table 2.
105
Id.
106
107
Id. Supra, V.A.2.j.
39
combine the teachings of Ross_US2006 and Ross_GB.108

Moreover, one of ordinary skill in the art would have been motivated to
combine the fentanyl teachings of Ross_US2006 and Ross_GB to achieve a shorter
Tmax for the administration of a drug so that the patient would more quickly
experience the effects of the drug.109
B. Ground 2 -- Claim 2 Is Unpatentable As Obvious Over Ross_GB, In

View Of Ross_US2006, The 862 Patent, And The 496 Publication
1.
Dependent Claim 2
Claim 2 depends from independent claim 1 and is directed to the dose of the
discrete liquid droplets of the fentanyl formulation of claim 1 in which the droplets
have a size distribution of from about 10 m to about 200 m.
2.
As explained by Dr. Park, Claim 2 would have been obvious to one of

ordinary skill in the art in light of the teachings of Ross_GB, Ross_US2006, the
862 patent and the 496 publication.110 As explained above, the dose of the
108
109
Id. Supra, V.A.2.j.
110
40
fentanyl formulation of claim 1 is obvious in light of the combination of Ross_GB,

Ross_US2006, and the 862 patent.111 Moreover, the 496 publication teaches the
additional limitation recited in claim 2 as explained in detail below.
a. said discrete liquid droplets have a size distribution of from about 10 m to

about 200 m.
Like Ross_GB and Ross_US2006, the 496 publication teaches a fentanyl
formulation: [t]wo formulations containing fentanyl citrate were prepared...112
The 496 publication also teaches that its fentanyl formulation is administered in
liquid droplets sized within the range of about 1 to 200 microns, more preferably
within the range of 10-100 microns.113 As explained by Dr. Park, [a] droplet
within the preferred range of 10 to 100 microns is clearly with the range of about 10
microns to about 200 microns recited in claim 2 of the 972 patent.114
As further explained by Dr. Park, [i]t would have been obvious to have a
fentanyl formulation with a discrete liquid droplet size of about 10 microns to about
111
Supra, V.A.
112
Exhibit 1006, 496 Publication, [0041].
113
Id. at [0019].
114
41
200 microns in light of the teachings of Ross_US2006, Ross_GB, the 862 patent
and the 496 publication. The 496 publication, like Ross_US2006 and Ross_GB,
teaches a fentanyl formulation.115 The 496 publication also teaches a decreased
droplet size translates to a higher surface area to be absorbed by the mucosa of the
intra-oral cavity.116 Accordingly, as indicated by Dr. Park, one of ordinary skill in
the art would have been motivated to combine the teachings of the 496 publication
with the teachings of Ross_US2006 and Ross_GB.117
Moreover, as explained by Dr. Park, [o]ne aspect of the administration of a
drug is to achieve a small droplet size so as to eliminate or decrease the discomfort
felt by a patient in receiving the drug.118 Accordingly, one of ordinary skill in
the art would have been motivated to combine the fentanyl teachings of
Ross_US2006 and Ross_GB with the small droplet size of the 496 publication to
eliminate or decrease any discomfort to the patient from administration of the
drug.119
115
116
Exhibit 1006, 496 Publication, [0031].
117
118
119
Id.
42
C. The Patent Owners Argument For Secondary Considerations Set Forth

In The Prosecution File History Are Misleading And Wrong
The 972 patent issued because of a misleading and incorrect argument set
forth by the Applicant Insys (now the Patent Owner) regarding an allegedly
unexpected property of a fast onset of effect of 5 minutes. More particularly, the
Patent Owner Insys submitted a declaration by its Chief Medical Officer, Dr.
Dillaha, alleging that patients having breakthrough cancer pain began to
experience statistically significant pain relief as early as 5 minutes after dosing
and that no other marketed, competitive fentanyl product has been able to show
statistically significant pain relief any earlier than 10 minutes, in an attempt to
overcome a prima facie case of obviousness established by the Examiner.120 Dr.
Dillaha then concluded that the presently claimed unit dose provides efficacious
pain relief at significantly faster times relative to other transmucosal immediate
release fentanyl formulations, which is both unexpected and, more importantly, a
distinct clinical benefit.121
The Patent Owners analysis and conclusion, however, are misleading and
120
Exhibit 1015, Dillaha Declaration at 7-8.
121
Id. at 10.
43
wrong for four groups of reasons, as explained by Dr. Park.122 First, Insyss
argument is not commensurate with the scope of the claims because Insys failed to
establish a nexus between the alleged unexpected results and the claimed
invention. None of the claims recite an onset of therapuetic effect of five minutes;
and Insys failed to establish that an onset of therepeutic effect of five minutes
corresponds to both 1) the broad ranges of Tmax recited in the claims and 2) the
concentrations of fentanyl, ethanol, and PEG recited in the claims of the 972
patent. Second, the purported rapid onset therepuetic effect of five minutes was
not unexpected because another marketed, competitive fentanyl product,
fentanyl nasal spray, achieved a statistically significant differences in pain intensity
(PI) scores compared with placebo within 5 min of dosing (even with an average
dosage much lower than the claimed invention of the 972 patent). Third, the
Dillaha Declaration considered only commercial formulations and not the closest
prior art. Fourth, the rapid onset was not unexpected for the additional reason that
the competing fentanyl nasal spray was able to achieve a blood concentration 5
minutes after dosing that is higher than the blood concentration of the claimed
invention using the same dosage.
1.
122
Patent Owners Argument For Secondary Considerations

Is Not Commensurate With The Scope Of the Claims
44
To be considered in a determination of obviousness, evidence of

secondary considerations must be relevant to the subject matter as claimed,
and therefore, the evidence of secondary considerations must have a nexus to
the merits of the claimed invention. Ashland Oil, Inc. v. Delta Resins &
Refractories, Inc., 776 F.2d 281, 305 n.42, 227 USPQ 657, 673-674 n. 42 (Fed.
Cir. 1985), cert. denied, 475 U.S. 1017 (1986). The term nexus indicates a
factually and legally sufficient relation between the objective evidence of
secondary considerations and the claimed invention so that the evidence is of
probative value in the determination of obviousness. Demaco Corp. v. F. Von
Langsdorff Licensing Ltd., 851 F.2d 1387, 7 USPQ2d 1222 (Fed. Cir.), cert.
denied, 488 U.S. 956 (1988).
As explained by Dr. Park, Patent Owners argument of an unexpected
result of time of onset of therapuetic effect of five minutes as a secondary
consideration of nonobviousness is not commensurate with the scope of the claims.
First, none of the claims recite a time for onset of therepuetic effect of five
minutes.123 Even though the terms are not interchangeable, the Patent Owner
seemingly equates Tmax with onset of therepeutic effect; however the actual
relationship between the two concepts is not contemplated by the Dillaha
123
45
Declaration or the Patent Owner. With regard to the alleged unexpected results,
Patent Owner failed to establish that an onset of therepeutic effect of five minutes
corresponds to a mean time to maximum plasma concentration (Tmax), which is
the actual limitation recited in claims 1 and 3 of the 972 patent. Further, the
Patent Owner failed to establish that the alleged onset of therepeutic effect of five
minutes occurs across the entire range of the recited concentrations of fentanyl,
ethanol, and propylene glycol in the claims. Accordingly, there is no nexus of a
factually and legally sufficient relation between the evidence of a five minute onset
of therepuetic effect and the claimed ranges of Tmax or recited components of the
claim.
As also explained by Dr. Park, the Dillaha Declaration considered only the
low end of the recited Tmax time range (5-10 minutes); it did not consider the entire
claimed time range, i.e. about 5 to about 120 minutes. For example, there is
nothing in the Dillaha Declaration to establish that the alleged five minute onset of
therapeutic effect would occur if the Tmax was 120 minutes or even close to it.124
As further explained by Dr. Park, contrary to the argument set forth in the Dillaha
declaration, the data contained in the declaration shows a significant overlap
between the time range of the references examined therein and the claimed Tmax
124
46
range.125
Accordingly, any evidence of onset should be given no weight by the Patent
Trial and Appeal Board in its obviouness analysis.
2.
A Fast Onset Of Five Minutes Was Not Unexpected Because

A Commercial Fentanyl Nasal Spray Achieved A Five
Minutes Onset Effect
Contrary to Patent Owners argument and as explained by Dr. Park, one

competing fentanyl pectin nasal spray (FPNS), Lazanda, achieved a first onset of
effect at 5 minutes post administration. This rapid effect was achieved even with an
average dosage much lower than Patent Owners fentanyl formulation called
Subsys.126 Lazandas result was reported in a publication by Portenoy R K et al,127
entitled A multicenter, placebo-controlled, double-blind, multiple-crossover study
of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer
125
Id.
126
Id. at 39.
127
Portenoy was included in the Dillaha Declaration however it does not appear to
be prior art to the 972 patent. An analysis of Portenoy is included herein because
it was included in the Dillaha Declaration and illustrates the inaccuracies in the
Declaration.
47
pain, 151 Pain 617 (2010) (Portenoy, Exhibit 1008). In particular, Portenoy
reported that [t]he mean PI (pain intensity) score for patient-averaged FPNS-treated
episodes was significantly different from that for placebo-treated episodes at the 5min time point (P = 0.03).128 The analysis of patient-averaged PID (pain
intensity difference) scores showed a trend in favor of Lazanda at 5 min (P = 0.07)
and statistical significance from 10 min (P< 0.01) onward.129 Based on this data,
Portenoy concluded that "[a] rapid onset of effect was observed, with FPNS
achieving statistically significant differences in PI 5 min after dosing."130
As explained by Dr. Park, Dr. Dillaha cited Portenoy in his Declaration but
failed to mention that Portenoy taught an onset of therapeutic effect of five minutes
with Lazanda, or explain how he arrived at his conclusion concerning Portenoy. Dr.
Dillaha also failed to mention or otherwise address the fact that Lazanda achieves
the five minute onset of effect using a significantly lower average dose than the dose
128

treatment of breakthrough cancer pain. 151 Pain 617, 620 (2010).
129
Id.
130
Id at 620-21.
48
used in the study of Patent Owners Subsys.131

According to Portenoy and co-workers, a total of 73 patients completed the
study with four different dose levels between 100 mcg and 800 mcg: i) 8 patients
received a dose level of 100 mcg, ii) 7 patients received a dose level of 200 mcg, iii)
24 patients received a dose level of 400 mcg, and iv) 34 patients received a dose
level of 800 mcg).132 As explained by Dr. Park, the average dose given to all 73
patients [in Portenoy] is 534 mcg (8 patients x 100 mcg + 7 patients x 200 mcg + 24
patients x 400 mcg + 34 patients x 800 mcg).133
As explained by Dr. Park, the average dose in the Subsys trial was much
higher.134 According to the New Drug Application (NDA) package on the FDA
website, a total of 92 patients completed the Subsys clinical study with seven
different dose levels between 100 mcg and 1600 mcg: i) 4 patients received a dose
level of 100 mcg, ii) 6 patients received a dose level of 200 mcg, iii) 14 patients
received a dose level of 400 mcg, iv) 14 patients received a dose level of 600 mcg,
v) 22 patients received a dose level of 800 mcg, vi) 20 patients received a dose level
131
132
Exhibit 1008, Portenoy, p. 619, Figure 1.
133
134
Id. at 41.
49
of 1200 mcg, and vii) 12 patients received a does level of 1600 mcg.135 As
explained by Dr. Park, the data in the Subsys NDA indicates that the average dose
given to all 92 patients was 830 mcg, which is 55.4% higher than the average dose
given to the patients in the Lazanda study.136
Therefore, it was not unexpected for Subsys to achieve an onset of
therapeutic effect at 5 minutes because another spray fentanyl, Lazanda, had
achieved statistically significant differences in PI 5 min after dosing, even though
the average dosage used in the Subsys study was 55% higher than the one used in
the Lazanda study.137
3.
A Fast Onset Of Five Minutes Was Not Unexpected Because

Other Prior Art References Reported Efficacious Pain Relief
At Five Minutes Or Less
As explained by Dr. Park, [t]he Dillaha Declaration considered only

commercial formulations and not the closest prior art. Several prior art references
show that an onset of therapeutic effect of 5 minutes for fentanyl transmucosal
formulations was not unexpected.138 Specifically, the Dillaha Declaration did not
135
Exhibit 1009, NDA_Subsys, Clinical review, pages 62-3, Table 19.
136
137
Id. at 42.
138
Id. at 43.
50
consider the following prior art references that contradict the conclusion therein:
i.
P. W. H. Peng et al., A Review of the Use of Fentanyl Analgesia in the
Management of Acute Pain in Adults, Anesthesiology. 1999 Feb; 90(2):576-99.

Peng (Exhibit 1010) describes an oral transmucosal fentanyl citrate (OTFC) that
incorporates fentanyl citrate in a candy mixture shaped into a lozenge on a stick.
With oral transmucosal administration, fentanyl can be absorbed directly into
systemic circulation through the oral mucosa or swallowed in saliva and absorbed
through the gastrointestinal tract. The median time to onset of analgesia with
OTFC is approximately 4 min.139
ii.
Sebastiano Mercadante and Fabio Fulfaro, Alternatives to Oral
Opioids for Cancer Pain, Oncology, February 01, 1999 (Exhibit 1011).
Mercandante reports, Sublingual fentanyl has been used as a rescue medication in
doses of 25 mg (0.5 mL). The effect was achieved within 1 minute and lasted 20 to
30 minutes.140 Oral transmucosal fentanyl citrate (Actiq) is a fentanyl-containing
matrix that dissolves when rubbed against the buccal mucosa. When the matrix
dissolves, approximately 25% of the total fentanyl is absorbed almost immediately
through the buccal mucosa and enters the bloodstream with no first pass
139
Exhibit 1010, Peng_1999, page 587, left column, 3.
140
Exhibit 1011, Mercadante_1999, page 2, 5.
51
metabolism, producing a rapid effect.141

iii.
J. Lance Lichtor et al., The Relative Potency of Oral Transmucosal
Fentanyl Citrate Compared with Intravenous Morphine in the Treatment of

Moderate to Severe Postoperative Pain, Anesth Analg 1999; 89:7328 (Exhibit
1012), reports a study to determine the relative potency of oral transmucosal
fentanyl citrate (OTFC) compared to IV morphine. OTFC produced an onset of
meaningful relief similar to the onset reported with IV morphine, with at least 50%
of patients in each group receiving relief by approximately 5 minutes and almost
all patients receiving relief by 10 minutes.142 Some patients reported onset of
meaningful relief as early as 12 seconds after the start of consumption of OTFC, at
which time only a fraction of the dose of drug would have been absorbed into
systemic circulation.143
iv.
US20030178031 (Exhibit 1016) describes a rapid onset Oral
Transmucosal Fentanyl Citrate (OTFC) with an onset as quick as one minute.

The Actiq preparation is initiated in opioid tolerant patients at the 200 g dose
over 15 minutes. A dose may be consumed 15 minutes after the previous unit is
141
Id. at page 2, 6.
142
Exhibit 1012, Lichtor_1999, page 736, right column, 1.
143
Id.
52
consumed. Use no more than two units per episode. Effective dosing achieved
when adequate relief is achieved with a single OTFC unit. Its onset is very fast,
within one to five minutes, but the duration is shorter (2-3 hours) by an hour than
morphine.144
4.
A Prior Art Fentanyl Nasal Spray Achieved A Blood

Concentration Five Minutes Post Administration That Was
Higher Than The Concentration Of The Claimed Invention
With The Same Dosage
As explained by Dr. Park, [t]he fast onset of the claimed invention is not
unexpected because of the additional reason that the nasal spray of prior art
fentanyl solutions achieved higher blood concentration at 5 minutes post
administration than the Patent Owners Subsys.145
Subsys NDA package disclosed plasma concentrations from 5 minutes to 36
hours post administration for dose levels of 100 mcg to 800 mcg in Figure 5.146
According to the figure in the NDA package, fentanyl plasma concentrations at 5minutes are approximately 0.03 ng/mL, 0.08 ng/mL, 0.19 ng/mL, 0.34 ng/mL, and
144
Exhibit 1016, U.S. Patent Publication 20030178031, page 17, 3 (emphasis
added).
145
146
Exhibit 1009, Subsys NDA Package, Clinical Review, page 23, Figure 5.
53
0.42 ng/mL, for Subsys dose levels of 100 mcg, 200 mcg, 400 mcg, 600 mcg, and
800 mcg, respectively.147
Similar studies were carried out for fentanyl nasal spray at the dose level of
100 mcg.148 For example, Figure 2 of U.S. Patent 8,889,176 disclosed fentanyl
plasma concentrations from 5 minutes to 6 hours.149 According to this figure,
fentanyl concentrations at 5 minutes post administration are approximately 80
pg/mL (0.08 ng/mL), 120 pg/mL (0.12 ng/mL), and 450 pg/mL (0.45 ng/mL), for
fentanyl chitosan/poloxamer solution, fentanyl pectin solution, and fentanyl
chitosan solution, respectively.150 Based on their earlier studies as explained by
Dr. Park, the pharmacokinetic properties of the chitosan solution can be
considered to be representative of a simple aqueous solution of fentanyl.
Therefore, at 5 minutes post administration, nasal spray of 100 mcg fentanyl
147
Id.
148
Exhibit 1013, U.S. Patent No. 8,889,176 (the 176 Patent). The 176 Patent is
prior art to the 972 patent under at least 35 U.S.C. 102(e) (pre-AIA) because it
was filed on July 3, 2012, claiming priority to Application 10/753628 filed on
January 8, 2004.
149
Id., Figure 2.
150
Id.
54
aqueous solution can achieve a blood concentration of 0.45 ng/mL, which is higher
than the blood concentration achieved by 800 mcg Subsys (0.42 ng/mL). In fact, at
the 5-min time point, two other 100 mcg fentanyl solutions in the same nasal spray
study achieved a blood concentration level at least equivalent to what was achieved
by 200 mcg Subsys. 151
Therefore, it is not unexpected for the claimed invention to have an onset of
effect at 5 minutes after dosing because nasal spray of aqueous fentanyl solutions
was able to achieve higher blood concentration than Subsys could with the same
dosage.152
VII. CONCLUSION
For the foregoing reasons, Petitioner requests that inter partes review be
instituted for claims 1 - 3 of the '972 Patent.
Date: August 24, 2015
Respectfully Submitted,
By: /Gregory Gonsalves/
Dr. Gregory Gonsalves
151
Exhibit 1002, Dr. Parks Declaration, 45, citing Exhibit 1013, the 176 Patent,
col 11, ll. 15-7.

152
55
Reg. No. 43,639

2216 Beacon Lane
Falls Church, Virginia 22043
(571) 419-7252
Christopher Casieri
Reg. No. 50,919
MCNEELY, HARE & WAR, LLP
12 Roszel Road, Suite C104
Princeton, NJ 08540
Phone: (609) 731-3668
Fax: (202) 478-1813
chris@miplaw.com
56
Table of Exhibits For Petition For Inter Partes Review Of U.S.

Patent No. 8,486,972
Exhibit
1001
1002
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
Description
Declaration of Dr. Park
GB2399286A (Ross_GB)
U.S. Patent No. 5,370,862 (the 862 patent)
U.S. Patent Application Publication 2006/0062812 (Ross_US2006)
U.S. Patent Application Publication 2002/0055496 (the 496
publication)
Random House Websters College Dictionary, Random House, Inc.,
April, 2000, p. 1270.
Portenoy R K et al, A multicenter, placebo-controlled, double-blind,
multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in
the treatment of breakthrough cancer pain, 151 Pain 617 (2010)
(Portenoy)
Subsys Clinical Review New Drug Application
P. W. H. Peng et al., A Review of the Use of Fentanyl Analgesia in
the Management of Acute Pain in Adults, Anesthesiology. 1999 Feb;
90(2):576-99 (Peng_1999)
Sebastiano Mercadante and Fabio Fulfaro, Alternatives to Oral
Opioids for Cancer Pain, Oncology, February 01, 1999
(Mercandante_1999)
J. Lance Lichtor et al., The Relative Potency of Oral Transmucosal
Fentanyl Citrate Compared with Intravenous Morphine in the
Treatment of Moderate to Severe Postoperative Pain, Anesth Analg
1999; 89:7328 (Lichtor_1999)
US Patent No. 8,889,176 (the 176 patent)
Amendment dated October 8, 2012
Declaration Of Dr. Larry Dillaha To 37 CFR 1.132, dated
September 17, 2012.
US Patent Application No. 20030178031
Response to Restriction dated April 12, 2010.
Non-Final Rejection dated June 9, 2010
Response to Non-Final Office Action dated June 21, 2010
U.S. Application No. 20030190290 (Ross_US 2003)
Non-Final Office Action dated September 15, 2010
Response to Non-Final Office Action dated February 15, 2011
57
1023
1024
1025
1026
1027
1028
1029
1030
1031
1032
Non-Final Rejection dated May 2, 2011

Response to Non-final Rejection dated August 2, 2011
Final Rejection dated November 17, 2011
Amendment dated February 17, 2012
Non-Final Rejection dated June 8, 2012
Notice of Allowance dated April 15, 2013
Random House Websters Dictionary, p. 821, mean3 definition 4a.
Fallon community Health Plan, Prior Authorization Approval
Criteria, Subsys (fentanyl sublingual spray), 3/14/2012
Subsys Manufacturing/Pricing Good RX, 2015
Subsys Manufacture/Pricing Epocrates Online, 2015
58
CERTIFICATE OF SERVICE
Under 37 C.F.R. 42.6(e), this is to certify that I caused a true and correct
copy of the foregoing materials:
Petition for Inter Partes Review of U.S. Patent No. 8,486,972 Under 35
U.S.C. 312 and 37 C.F.R. 42.104
Exhibits 1001-1032
Power of Attorney
to be served via Express Mail on the following attorneys of record as listed
in PAIR:
WOOD, PHILLIPS, KATZ, CLARK & MORTIMER
500 W. MADISON STREET
SUITE 1130
CHICAGO IL 60661
Date: August 24, 2015
Respectfully Submitted,
By: _/Gregory Gonsalves_____
Dr. Gregory Gonsalves
Reg. No. 43,639
2216 Beacon Lane
Falls Church, Virginia 22043
(571) 419-7252
59

Kyle Bass IPR Against Insys Therapeutics, Part 2

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U.S. Patent No.

UNITED STATES PATENT AND TRADEMARK OFFICE

U.S. Patent 8,486,972

U.S. Patent No. 8,486,972

GROUND 1 -- CLAIMS 1 AND 3 ARE UNPATENTABLE AS OBVIOUS

INDEPENDENT CLAIM 1 .................................................................................................27

A. UNIT DOSE ...........................................................................................................................28

U.S. Patent No. 8,486,972

SUBLINGUAL ADMINISTRATION TO A HUMAN..........................................................34

SAID SUBLINGUAL FENTANYL FORMULATION PROVIDES A MEAN TIME

DEPENDENT CLAIM 3 ......................................................................................................37

A. AFTER SUBLINGUAL ADMINISTRATION TO A HUMAN, THE

GROUND 2 -- CLAIM 2 IS UNPATENTABLE AS OBVIOUS OVER

DEPENDENT CLAIM 2......................................................................................................40

THE PRIOR ART AND ITS COMPARISON TO CLAIM 2 ..........................................40

A. SAID DISCRETE LIQUID DROPLETS HAVE A SIZE DISTRIBUTION OF

THE PATENT OWNERS ARGUMENT FOR SECONDARY

PATENT OWNERS ARGUMENT FOR SECONDARY CONSIDERATIONS

A FAST ONSET OF FIVE MINUTES WAS NOT UNEXPECTED BECAUSE

A FAST ONSET OF FIVE MINUTES WAS NOT UNEXPECTED BECAUSE

A PRIOR ART FENTANYL NASAL SPRAY ACHIEVED A BLOOD

VII. CONCLUSION ......................................................................................................................55

U.S. Patent No. 8,486,972

U.S. Patent No. 8,486,972

Coalition For Affordable Drugs XI LLC ("CFAD" or "Petitioner") requests

NOTICE OF LEAD AND BACKUP COUNSEL

NOTICE OF EACH REAL-PARTY-IN-INTEREST

U.S. Patent No. 8,486,972

subsidiary of Credes. Credes is a limited partnership. HOF is a segregated portfolio

U.S. Patent No. 8,486,972

NOTICE OF RELATED MATTERS

NOTICE OF SERVICE INFORMATION

GROUNDS FOR STANDING

STATEMENT OF PRECISE RELIEF REQUESTED

U.S. Patent No. 8,486,972

U.S. Patent No. 8,486,972

U.S. Patent No. 8,486,972

Ground 2. Claim 2 is unpatentable as obvious over Ross_GB, in view of

This Petition is supported by the

Declaration of Dr. Park (Exhibit 1002).

INTRODUCTION AND SUMMARY OF ARGUMENT

U.S. Patent No. 8,486,972

Approval Criteria, Subsys (fentanyl sublingual spray), 3/14/2012; Exhibit 1031,

U.S. Patent No. 8,486,972

THE CLAIMS UNDER CONSIDERATION

A unit dose of a non-propellant sublingual fentanyl formulation

comprising discrete liquid droplets of an effective amount of fentanyl and a

size distribution of from about 10 m to about 200 m.

The unit dose of claim 1 wherein after sublingual administration to a

human, the sublingual fentanyl formulation provides a mean time to

U.S. Patent No. 8,486,972

THE 972 PATENT AND PROSECUTION HISTORY OF THE '972

The '972 Patent

The 972 patent is directed to non-propellant sublingual fentanyl

Exhibit 1001, the 972 patent, claim 1.

U.S. Patent No. 8,486,972

wherein after sublingual administration to a human, said sublingual

The formulation of claim 1 contains three recited components: fentanyl;

Exhibit 1001, 972 patent, col. 1, ll. 12-13.

Exhibit 1001, 972 patent, col. 11, ll. 19-26.

Id. at col. 1, ll. 29-33.

Exhibit 1013, US Patent 8,889,176, col 2, ll. 10-16.

Exhibit 1001, 972 patent, col. 1, ll. 29-30.