Kyle Bass IPR Against Insys Therapeutics, part 2

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

i

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

ii

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


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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 µM TO ABOUT 200 µM. .......................................................................41

C. THE PATENT OWNER’S ARGUMENT FOR SECONDARY

CONSIDERATIONS SET FORTH IN THE PROSECUTION FILE HISTORY

ARE MISLEADING AND WRONG ..................................................................................43

1. PATENT OWNER’S 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


iv

TABLE OF AUTHORITIES

CASES

KSR Int’l 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


1

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: Backup Counsel:

Dr. Gregory J. Gonsalves

Reg. No. 43,639

2216 Beacon Lane

Falls Church, VA 22043

(571) 419-7252 [email protected]

Christopher Casieri

McNeely, Hare & War LLP

12 Roszel Road, Suite C104

Princeton, NJ 08540

Phone: 609 731 3668

[email protected]

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

mailto:[email protected]



2

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.


3

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 Petitioner’s 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:

[email protected] and [email protected].

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



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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


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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.

1 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.


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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 PA R 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.


7

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.


8

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 μm to about 200 μm.

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.


9

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;

3 Exhibit 1001, the ‘972 patent, claim 1.


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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 μ-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.


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

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


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


11

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.


12

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


13

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.


14

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 µm to about 500 µm, and a mean diameter of about 20

µm to about 200 µm;

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 µg

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 pg·hour/mL to about

1061 pg·hour/mL per 100 µg 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.


15

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

31Id. at pp. 4, 6.


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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

Dillaha’s 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


17

“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.


18

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 fast-

acting 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.


19

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).


20

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


21

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 Dillaha’s conclusion, Portenoy and co-

workers 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 Exhibit 1008, Portenoy R K et al, A multicenter, placebo-controlled, double-


treatment of breakthrough cancer pain, 151 Pain 617 (2010) at p. 623.


22

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.


23

Anesth Analg 1999; 89:732–8;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; 89:732–8 at p. 736.

53 Exhibit 1016, US Patent Application No. 20030178031 at paragraph [0360].


24

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

phrase’s broadest reasonable construction must be construed as meaning the

“average time to achieve the maximum concentration of fentanyl in a patient’s

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 Parameter”54

and defined in the specification as

the “Time to reach Cmax”55

. “Cmax” is defined as “Peak plasma concentration.”56

The

54

Exhibit 1001, ‘972 patent, col. 28, ll. 26-28.

55 Id. at col. 25, ll. 62.

56 Id.


25

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 Webster’s Dictionary, p. 821, mean3 definition 4a.


59 Exhibit 1007, Random House Webster’s College Dictionary, Random House,

Inc., April, 2000, p. 1270.


26

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. Park’s Declaration, ¶ 9.


27

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


28

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.


29

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 Exhibit 1002, Dr. Park’s Declaration, ¶ 16.

67 Exhibit 1007, Random House Webster’s College Dictionary, Random House,

Inc., April, 2000, p. 1270.


69 Exhibit 1003, Ross_GB, page 8, ll. 10-11 (emphasis added).


30

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.



31

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. C2·4 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

Exhibit 1003, Ross_GB, page 11, ll. 1-9.


75 Exhibit 1003, Ross_GB, page 5, ll. 1-4 (emphasis added).


32

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.


79 Exhibit 1004, the ‘862 patent, col. 4, l. 47.


81 Id. at ¶ 24.


33

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 fentanyl”83

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

Exhibit 1003, Ross_GB, page 3, ll. 26-27.

83 Id. at ll. 30-32

84 Exhibit 1002, Dr. Park’s Declaration, ¶ 24 quoting Exhibit 1004, the ’862 patent,

col. 1 ll. 19-20.

85 Exhibit 1002, Dr. Park’s Declaration, ¶ 24


34

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 delivery”87

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. Park’s Declaration, ¶ 24

87 Exhibit 1003, Ross_GB, page 1, ll. 3-4.

88 Id. at page 3, ll. 29-30

89 Id. at page 1, l. 15.



35

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 µg) of fentanyl with a non-

pressurized 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. Park’s Declaration, ¶ 26, citing Exhibit 1005, ROSS_US2006,

page 8, Table 2.

92 Id.


36

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


94Exhibit 1005, ROSS_US2006, Formulation 2, page 7, ¶ [0115].


96 Exhibit 1003, Ross_GB, Example 1, page 11, ll. 1-9.



37

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 patient’s 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.


38

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


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. Park’s Declaration, ¶ 30, citing Exhibit 1005, ROSS_US2006,

page 8, Table 2.

103 Id. at ¶ 29.


39

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. Park’s Declaration, ¶ 30 citing Exhibit 1005, ROSS_US2006,

page 8, Table 2.

105 Id.


107 Id. Supra, § V.A.2.j.


40

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 µm to about 200 µm.


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.



41

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 µm to

about 200 µm.

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].



42

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].



119 Id.


43

C. The Patent Owner’s 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 Owner’s analysis and conclusion, however, are misleading and

120

Exhibit 1015, Dillaha Declaration at ¶¶ 7-8.

121 Id. at ¶ 10.


44

wrong for four groups of reasons, as explained by Dr. Park.122

First, Insys’s

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. Patent Owner’s Argument For Secondary Considerations

Is Not Commensurate With The Scope Of the Claims



45

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 Owner’s 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



46

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



47

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 Owner’s 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 Owner’s fentanyl formulation called

Subsys.”126

Lazanda’s 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.


48

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 5-

min 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

Exhibit 1008, Portenoy R K et al, “A multicenter, placebo-controlled, double-


treatment of breakthrough cancer pain.” 151 Pain 617, 620 (2010).

129 Id.

130 Id at 620-21.


49

used in the study of Patent Owner’s 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.


134 Id. at ¶ 41.


50

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.


137 Id. at ¶ 42.

138 Id. at ¶ 43.


51

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.


52

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; 89:732–8 (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 µg 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.


53

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 Owner’s 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 5-

minutes 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).


146 Exhibit 1009, Subsys NDA Package, Clinical Review, page 23, Figure 5.


54

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.


55

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. Park’s Declaration, ¶ 45, citing Exhibit 1013, the ‘176 Patent,

col 11, ll. 15-7.



56

Reg. No. 43,639

2216 Beacon Lane

Falls Church, Virginia 22043

(571) 419-7252

[email protected]

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

[email protected]


57

Table of Exhibits For Petition For Inter Partes Review Of U.S.

Patent No. 8,486,972

Exhibit Description

1001 U.S. Patent No. 8,486,972

1002 Declaration of Dr. Park

1003 GB2399286A (Ross_GB)

1004 U.S. Patent No. 5,370,862 (the ‘862 patent)

1005 U.S. Patent Application Publication 2006/0062812 (Ross_US2006)

1006 U.S. Patent Application Publication 2002/0055496 (the ‘496

publication)

1007 Random House Webster’s College Dictionary, Random House, Inc.,

April, 2000, p. 1270.

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)

(Portenoy)

1009 Subsys Clinical Review New Drug Application

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 (Peng_1999)

1011 Sebastiano Mercadante and Fabio Fulfaro, Alternatives to Oral

Opioids for Cancer Pain, Oncology, February 01, 1999

(Mercandante_1999)

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; 89:732–8 (Lichtor_1999)

1013 US Patent No. 8,889,176 (the ‘176 patent)

1014 Amendment dated October 8, 2012

1015 Declaration Of Dr. Larry Dillaha To 37 CFR 1.132, dated

September 17, 2012.

1016 US Patent Application No. 20030178031

1017 Response to Restriction dated April 12, 2010.

1018 Non-Final Rejection dated June 9, 2010

1019 Response to Non-Final Office Action dated June 21, 2010

1020 U.S. Application No. 20030190290 (Ross_US 2003)

1021 Non-Final Office Action dated September 15, 2010

1022 Response to Non-Final Office Action dated February 15, 2011


58

1023 Non-Final Rejection dated May 2, 2011

1024 Response to Non-final Rejection dated August 2, 2011

1025 Final Rejection dated November 17, 2011

1026 Amendment dated February 17, 2012

1027 Non-Final Rejection dated June 8, 2012

1028 Notice of Allowance dated April 15, 2013

1029 Random House Webster’s Dictionary, p. 821, mean3 definition 4a.

1030 Fallon community Health Plan, Prior Authorization Approval

Criteria, Subsys (fentanyl sublingual spray), 3/14/2012

1031 Subsys Manufacturing/Pricing – Good RX, 2015

1032 Subsys Manufacture/Pricing – Epocrates Online, 2015


59

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

[email protected]

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Kyle Bass IPR Against Insys Therapeutics, part 2

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