kyle bass ipr against insys therapeutics

7/23/2019 Kyle Bass IPR Against Insys Therapeutics

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U.S. Patent No. US 8,835,460

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 8,835,460

__________________

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.8,835,460 AND

MANDATORY NOTICES UNDER 37 C.F.R. 42.8

Mailed August 24 2015


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U.S. Patent No. 8,835,460

ii

TABLE OF CONTENTS

NOTICE OF EACH REAL-PARTY-IN-INTEREST .................................................................1

NOTICE OF RELATED MATTERS ..............................................................................................2

NOTICE OF SERVICE INFORMATION ..................................................................................3

GROUNDS FOR STANDING ......................................................................................................3

STATEMENT OF PRECISE RELIEF REQUESTED ...............................................................3

STATEMENT OF REASONS FOR RELIEF REQUESTED ....................................................6

I. INTRODUCTION AND SUMMARY OF ARGUMENT ...................................................7

II. THE 460 PATENTAND PROSECUTION HISTORY OF THE '460 PATENT ............8

III.

CLAIM CONSTRUCTION .................................................................................................13

A. DISCRETE LIQUID DROPLETS.................................................................................14

B. PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER................................14

C. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION CONSISTS

ESSENTIALLY OF:..........................................................................................................16

IV. LEVEL OF SKILL IN THE ART ..................................................................................... 17

V.

CLAIMS 1-5 ARE OBVIOUS .............................................................................................18

A. GROUND 1 -- CLAIMS 1, 4AND 5 ARE UNPATENTABLE AS OBVIOUS

OVER ROSS_GB, IN VIEW OF THE 496 PUBLICATION .........................................18

1. INDEPENDENT CLAIM 1 .................................................................................................19

2. THE PRIOR ART AND ITS COMPARISON TO CLAIM 1 ..........................................19

A. SUBLINGUAL FORMULATION COMPRISING DISCRETE LIQUID

DROPLETS ...........................................................................................................................19

B.

OF AN EFFECTIVE AMOUNT OF FENTANYL OR A FENTANYLDERIVATIVE SELECTED FROM THE GROUP CONSISTING OF

SUFENTANIL, CARFENTANIL, LOFENTANIL AND ALFATENIL, A FREE

BASE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF,......................20

C. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER................................20


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D. SAID DROPLETS HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO

ABOUT 70 MICRONS..........................................................................................................21

3. INDEPENDENT CLAIM 4 ..................................................................................................22


A. A MULTI-DOSE DEVICE FOR SUBLINGUAL ADMINISTRATION OF A

DRUG.....................................................................................................................................23

B. A RESERVOIR CONTAINING THE LIQUID FORMULATION....................................23

C. COMPRISING FENTANYL, OR A FENTANYL DERIVATIVE SELECTED

FROM THE GROUP CONSISTING OF SUFENTANIL, CARFENTANIL,

LOFENTANIL AND ALFATENIL, A FREE BASE OR A

PHARMACEUTICALLY ACCEPTABLE SALT THEREOF,...........................................23

D.

IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER;...............................24

E. THE DEVICE HAVING AN ACTUATOR..........................................................................24

F. WHICH WHEN ACTUATED DELIVERS A THERAPEUTICALLY

EFFECTIVE DOSE OF THE LIQUID FORMULATION................................................24

G. IN THE FORM OF LIQUID DROPLETS..........................................................................24

H. HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO ABOUT 70

MICRONS..............................................................................................................................25

5.

DEPENDENT CLAIM 5 ......................................................................................................27


A. A METHOD OF TREATING PAIN COMPRISING..........................................................27

B. SUBLINGUALLY ADMINISTERING AN EFFECTIVE AMOUNT OF THE

SUBLINGUAL FORMULATION ACCORDING TO CLAIM 1........................................27

C. TO A HUMAN PATIENT EXPERIENCING PAIN...........................................................28

B. GROUND 2 -- CLAIMS 2 AND 3 ARE UNPATENTABLE AS OBVIOUS

OVER ROSS_GB, IN VIEW OF THE 862 PATENT, AND THE 496

PUBLICATION. ...................................................................................................................28



A. A NON-PROPELLANT SUBLINGUAL FENTANYL FORMULATION.........................29


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B. COMPRISING DISCRETE LIQUID DROPLETS..............................................................30

C. OF AN EFFECTIVE AMOUNT OF FENTANYL A FREE BASE OR A


D. A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER.....................................31

E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION COMPRISES:

FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF FENTANYL FREE

BASE......................................................................................................................................31

F. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES FROM

ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL...........................................31

G. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES FROM

ABOUT 4% TO ABOUT 6% BY WEIGHT OF PROPYLENE GLYCOL..........................32

H.

SAID DROPLETS HAVING A MEAN DIAMETER OF AT LEAST ABOUT 10MICRONS..............................................................................................................................35

3. INDEPENDENT CLAIM 3. .................................................................................................36







E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION CONSISTS

ESSENTIALLY OF: FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF

FENTANYL FREE BASE....................................................................................................37

F. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY

OF FROM ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL...................37

G. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY

OF FROM ABOUT 1% TO ABOUT 30% BY WEIGHT OF PROPYLENE

GLYCOL................................................................................................................................38

H. SAID DROPLETS HAVING A MEAN DIAMETER OF AT LEAST ABOUT 10

MICRONS..............................................................................................................................40

C. GROUND 3 -- CLAIMS 1, 4 AND 5 ARE UNPATENTABLE AS OBVIOUS

OVER ROSS_GB, IN VIEW OF THE 150 PATENT.....................................................40


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DROPLETS ...........................................................................................................................41

B. OF AN EFFECTIVE AMOUNT OF FENTANYL OR A FENTANYL

DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF


BASE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ......................41



ABOUT 70 MICRONS..........................................................................................................41

3.

INDEPENDENT CLAIM 4 ..................................................................................................43

4. THE PRIOR ART AND ITS COMPARISON TO CLAIM 4..........................................43

A. A MULTI-DOSE DEVICE FOR SUBLINGUAL ADMINISTRATION OF A

DRUG .....................................................................................................................................43

B. A RESERVOIR CONTAINING THE LIQUID FORMULATION ....................................44




PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ...........................................44

D. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER; ...............................44

E. THE DEVICE HAVING AN ACTUATOR ..........................................................................44


EFFECTIVE DOSE OF THE LIQUID FORMULATION ................................................44

G. IN THE FORM OF LIQUID DROPLETS ..........................................................................44


MICRONS ..............................................................................................................................44

5. DEPENDENT CLAIM 5 ......................................................................................................44


A A METHOD OF TREATING PAIN COMPRISING ..........................................................45


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B SUBLINGUALLY ADMINISTERING AN EFFECTIVE AMOUNT OF THE

SUBLINGUAL FORMULATION ACCORDING TO CLAIM 1 ........................................45

C. TO A HUMAN PATIENT EXPERIENCING PAIN. ..........................................................45

D. GROUND 4 -- CLAIMS 2 AND 3 ARE UNPATENTABLE AS OBVIOUS

OVER ROSS_GB, IN VIEW OF THE 862 PATENT, AND THE 150

PATENT. ...............................................................................................................................45





C.

OF AN EFFECTIVE AMOUNT OF FENTANYL A FREE BASE OR APHARMACEUTICALLY ACCEPTABLE SALT THEREOF,...........................................47


E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION COMPRISES:

FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF FENTANYL FREE

BASE......................................................................................................................................47

F. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES FROM

ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL...........................................48

G.

THE SUBLINGUAL FENTANYL FORMULATION COMPRISES FROMABOUT 4% TO ABOUT 6% BY WEIGHT OF PROPYLENE GLYCOL..........................48


MICRONS. .............................................................................................................................48




B.

COMPRISING DISCRETE LIQUID DROPLETS..............................................................50





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E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION CONSISTS

ESSENTIALLY OF: FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF

FENTANYL FREE BASE....................................................................................................50

F. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY

OF FROM ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL...................50

G. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY

OF FROM ABOUT 1% TO ABOUT 30% BY WEIGHT OF PROPYLENE

GLYCOL................................................................................................................................51


MICRONS..............................................................................................................................51

VI. CLAIMS 1, 4 AND 5 ARE ANTICIPATED ......................................................................51

A GROUND 5 -- CLAIMS 1, 4 AND 5 ARE UNPATENTABLE AS

ANTICIPATED BY THE 496 PUBLICATION. .............................................................51




DROPLETS ...........................................................................................................................52

B. OF AN EFFECTIVE AMOUNT OF FENTANYL OR A FENTANYL

DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF


BASE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF,......................53



ABOUT 70 MICRONS..........................................................................................................54

3. INDEPENDENT CLAIM 4 ..................................................................................................54


A.

A MULTI-DOSE DEVICE FOR SUBLINGUAL ADMINISTRATION OF ADRUG.....................................................................................................................................55

B. A RESERVOIR CONTAINING THE LIQUID FORMULATION....................................56






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D. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER;...............................56

E. THE DEVICE HAVING AN ACTUATOR..........................................................................57


EFFECTIVE DOSE OF THE LIQUID FORMULATION................................................57

G. IN THE FORM OF LIQUID DROPLETS..........................................................................57


MICRONS..............................................................................................................................58

5. DEPENDENT CLAIM 5 ......................................................................................................58

6. THE PRIOR ART AND ITS COMPARISON TO CLAIM 5 ........................................ 59

A. A METHOD OF TREATING PAIN COMPRISING ........................................................ 59

B SUBLINGUALLY ADMINISTERING AN EFFECTIVE AMOUNT OF THE

SUBLINGUAL FORMULATION ACCORDING TO CLAIM 1 ...................................... 59

C. TO A HUMAN PATIENT EXPERIENCING PAIN. ........................................................ 60

VII.CONCLUSION .....................................................................................................................60

TABLE OF AUTHORITIES

CASES

KSR Intl Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) .......................................... 18

In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 U.S. App. LEXIS 1699,Slip. Op. at 21 (Fed. Cir. Feb. 4, 2015). ................................................................. 13

Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012), certdenied, 133 S. Ct. 1736 (2013)). ............................................................................ 18

In re Herz,537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) ..................... 16

Verdegaal Bros. V. Union Oil Co. Of California 814 F.2d 628 (Fed. Cir. 1987) ..... 51

Atofina V Great Lakes Chem. Corp., 441 F.3d 991 (Fed. Cir. 2006) ........................ 51

Clearvalue, Inc. V. Pearl River Polymers, Inc., 668 F.3d 1340 (Fed. Cir. 2012) ..... 51


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RULES

37 C.F.R 42.8(b)(1) ................................................................................................... 1

37 C.F.R. 42.100(b) ................................................................................................ 13

OTHER

M.P.E.P 2111.03 .16


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

inter partes review of claims 1 - 5 of U.S. Patent No. 8,835,460 ("the '460 Patent")

(Exhibit 1001) assigned to Insys Pharm, Inc. (Insys).

NOTICE OF LEAD AND BACKUP COUNSEL

Lead Counsel: Backup Counsel:

Dr. Gregory J. GonsalvesReg. No. 43,6392216 Beacon Lane

Falls Church, VA 22043(571) 419-7252

[email protected]

Christopher CasieriMcNeely, Hare & War LLP12 Roszel Road, Suite C104

Princeton, NJ 08540Phone: 609 731 [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), JKyle

Bass, and Erich Spangenberg are the real parties in interest (collectively, RPI).

The RPI hereby certify the following information: CFAD is a wholly owned

subsidiary of Credes. Credes is a limited partnership. HOF is a segregated portfolio
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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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 partesreview


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(IPR) of U.S. Patent No. 8,486,972, upon which the 460 patent claims priority

as a divisional patent application (Case No. Unassigned); and a concurrently

filed Petition for IPR of U.S. Patent No. 8,835,459 (Case No. Unassigned). To

the best of Petitioners knowledge, there are no pending litigations or other

related matters related to the 460patent 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] [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

its grounds of challenge to claims 1-5 of the 460patent 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 460 patent under
mailto:[email protected]:[email protected]:[email protected]


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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 460 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 460 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

460 patent.

3. 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 1005). The

496 publication is prior art to the 460 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 460 patent.

4. United States Patent 6,946,150 by Brian Whittle entitled Pharmaceutical

formulation issued September 20, 2005 (the 150patent,Exhibit 1007).

The 150patent is prior art to the 460 patent under at least 35 U.S.C.


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102(a) (pre-AIA) because it was patented on September 20, 2005 in this

country, before January 25, 2006, the earliest effective filing date for the

claims of the 460 patent.

Petitioner requests that claims 1-5 of the '460 patent be held unpatentable

based on the following grounds:

Ground 1. Claims 1, 4, and 5 are unpatentable as obvious over Ross_GB1,

in view of 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 460 patent. See 35 U.S.C. 103(a).2

Ground 2. Claims 2 and 3 are unpatentable as obvious over Ross_GB, in

view of the 496 publication and the 862patent. The 496 publication was not

cited by the Examiner as basis for rejection during the prosecution of the

application that led to the 460patent and the 862 patent was notbefore the

1Ross_GB is a foreign priority document US2006/0062812, which was the cited

by the examiner during the prosecution of the application that led to the 460

patent.

2The pre-AIA version of 103 applies in this proceeding, because the 460 Patent

has an effective filing and issue date before March 16, 2013. The 460 patent

claims a priority date of January 25, 2006.


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Examiner during the prosecution of the application that led to the 460 patent.See

35 U.S.C. 103(a).

Ground 3.Claims 1, 4 and 5 are unpatentable as obvious over Ross_GB, in

view of the 150 patent. See 35 U.S.C. 103(a).

Ground 4.Claims 2 and 3 are unpatentable as obvious over Ross_GB, in

view of the 862 patent and the 150 patent. See 35 U.S.C. 103(a).

Ground 5.Claims 1, 4, and 5 are unpatentable as anticipated by the 496

publication. See 35 U.S.C. 102(b).

THRESHOLD REQUIREMENT FORINT 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 1-5 of the '460 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 1-5 of the 460 patent.

STATEMENT OF REASONS FOR RELIEF REQUESTED


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I.

INTRODUCTION AND SUMMARY OF ARGUMENT

The 460 patent is directed to a sublingual liquid fentanyl formulation, a

multi-dose device for administering a sublingual liquid fentanyl formulation, and a

method of treating pain using the sublingual liquid fentanyl formulation. The

recited elements were well known in the art at the time of the invention and each

element of the claims is clearly taught by prior art references, alone and in

combination. Further the combination of references would have been obvious to a

person of ordinary skill in the art. No evidence or arguments of unexpected results

or advantages were advanced during the prosecution of the 460 patent.

Accordingly, the claims of the 460 patent are anticipated by or obvious over the

prior art.

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 460 patent) can cost up to $300 per day per patient.3 The

3See e.g., Exhibit 1013, Fallon community Health Plan, Prior Authorization

Approval Criteria, Subsys (fentanyl sublingual spray), 3/14/2012; Exhibit 1014,

Subsys Manufacturing/PricingGood RX, 2015; and Exhibit 1015, Subsys

Manufacture/PricingEpocrates Online, 2015.


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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

460 patent.

II. THE 460 PATENT AND PROSECUTION HISTORY OF THE '460

PATENT

A.

The '460 Patent

The 460 patent is directed to sublingual fentanyl formulations, a multi-dose

device for administering a sublingual fentanyl formulation, and a method of

treating pain using the sublingual fentanyl formulation. The common feature of

the four independent claims is that each recites a fentanyl formulation comprising

discrete liquid droplets (claims 1, 2 and 3) or a multi-dose device capable of

delivering a fentanyl formulation in the form of liquid droplets (claim 4). The

discrete liquid droplets have a mean diameter of from about 30 to about 70 microns

in independent claims 1 and 4 and at least about 10 microns in independent claims

2 and 3. In addition, independent claims 2 and 3 recite specific amounts by weight

of fentanyl, ethanol and propylene glycol.


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The sublingual formulation of the independent claims (except for claim 1)

contains three recited components: fentanyl4; ethanol; and propylene glycol.

Fentanyl is a -opioid receptor agonist with analgesic potency approximately 80-

100 times that of morphine. See460 patent 1:13-14. (Exh. 1001). Ethanol and

propylene glycol are both identified as organic solvents which are used to enhance

the solubility of fentanyl.Id. at 11: 22-29. (Exh. 1001).

In the prior art, fentanyl is administered by way of a number of different

routes including oral, parenteral, buccal, transdermalId. at 1:30-34. (Exh. 1001).

and intranasal. See. U.S. Patent No. 8,889,176 (the 176 patent) 2:10-16. (Exh.

1006). Orally administered fentanyl is subject to first pass effect metabolism,

which leaves 50% or more of the fentanyl unabsorbed. Seethe 460 patent 1:30-

31. (Exh. 1001).The other forms of administration avoid or decrease the first pass

effect for fentanyl.Id. at 1:32-34. (Exh. 1001).

Transdermal administration of fentanyl is reportedly not suitable for severe

pain or breakthrough pain. See. 176 patent 1:58-64. (Exh. 1006). Buccal

administration of fentanyl via transmucosal lozenge is reported to have relatively

slow absorption times. Id.at 1:58-64. (Exh. 1006). However, sublingual spray

4The claims of the 460 patent recite various forms of fentanyl and fentanyl

derivatives, which are referred to as fentanyl unless otherwise noted.


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administration of fentanyl that is free of propellant is reported to provide rapid

onset of therapeutic effect. SeeRoss_GB p. 3, ll. 29-33. (Exh. 1003) In addition,

oral transmucosal administration of fentanyl is reported as providing rapid onset of

effect in as low as 5 minutes after dosing.5

B.

The Prosecution History Of The '460 Patent

The 460 patent was filed on May 15, 2013 as a continuation of Application

No. 11/689,739 (now patent No. 8,486,972), which claims benefit of U.S.

provisional application No. 60/763,057 filed on January 25, 2006. The 460 patent

was filed with 4 original claims.

The claims were subject to a Restriction dated November 21, 2013, to which

the Applicant elected to prosecute claims 1 and 4 drawn to a fentanyl formulation

without traverse. See12/17/2013 Response. (Exh. 1017). Original claim 1 is

reproduced below:

1. (Original) A sublingual fentanyl formulation comprising discrete liquid

droplets of an effective amount of fentanyl, a free base or a pharmaceutically

acceptable salt thereof, or derivative thereof, in a pharmaceutically

5See e.g.Exhibit 1009, Peng_1999, page 587, left column, 3; Exhibit 1010,

Mercadante_1999, page 2, 5; Exhibit 1011, Lichtor_1999, page 736, right

column, 1.


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acceptable liquid carrier; said droplets having a mean diameter of at least

about 10 microns.

A Non-Final Office Action issued on January 10, 2014 (Exh. 1018) rejecting

the claims under 35 U.S.C. 102/103 over three references: 1) McCarty (US

2007/0071806); 2) Ross (US 2003/0190290); and 3) Ross (US 2006/0062812).In

addition several rejections were made for nonstatutory obviousness-type double

patenting including over claims 1-3 of the parent case, US Patent No. 8,486,972.

See01/10/2014 Rejection (Exh. 1018).

Applicants filed an Amendment dated March 6, 2014 making no

amendments to the claims and primarily arguing that none of the cited references

teach the specific droplet size recited in the claims, i.e.discrete droplets having a

mean diameter of at least 10 microns. See03/06/2014 Amendment. (Exh. 1019).

Applicants argued that none of the references teach or suggest that a fentanyl

formulation of any particular droplet size would be useful for treating pain.Id.at

p. 12- 13.

A second Non-Final Office Action issued on March 21, 2014 (Exh. 1020)

maintaining the 35 U.S.C. 102/103 rejection over McCarty and withdrawing the

rejections over Ross_2003 and Ross_2006. The claims were also rejected as as

obvious over Ross_2003 in view of Whittle (U.S. Patent No. 6,946,150).Id.

Applicants submitted an Amendment dated April 15, 2014 (Exh. 1012).

This time Applicants amended independent claim 1 changing the droplet size from


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at least 10 microns to from about 30 to about 70 microns.Id. at p. 2. The

amendment to independent Claim 4 left the droplet size unchanged (at least 10

microns)but amended the range of propylene glycol from 0.1% to about 40%

to 4% to 6%.Id. In addition, new claim 5 was added which was the same as un-

amended claim 4 but used the consisting essentially of transition phrase.Id. No

explanation was supplied for the support in the specification for the new claim.

Applicants again argued that McCarty did not disclose any particular droplet

size. With regard to Ross_2003 in view of Whittle, applicants again argued that

None of the references in view Whittle teach a fentanyl . . . sublingual

formulation with a discrete liquid droplet having a mean diameter of from about 30

to about 70 microns. Id. at p. 6. Applicants did not provide any explanation as to

why or even if the narrowed range of droplet mean diameter provided any benefit

over the broader range originally in the claims. With regard to new claim 5,

Applicants did not argue why, or even if, the transitional phrase consisting

essentially of was advantageous over the prior art.

Applicants filed a terminal disclaimer to obviate the double patenting

rejection over prior patents including the parent patent (the 972 patent) on April

24, 2014. See Terminal Disclaimer. (Exh. 1021).

A Notice of Allowance issued on May 6, 2014 (Exh. 1022) which rejoined

withdrawn claims 2 and 3 but did not provide reasons for allowance. Minor


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Examiners Amendments were made non May 13, 2014 and June 19, 2014. The

460 patent issued on September 16, 2014. A Certificate of Correction was

requested by the Applicants and certified on November 25, 2014 (Exh. 1023) to

add a comma to claim 3 between fentanyl and a free base and to add a carriage

return.

It also appears that in the issued patent, New claim 5 was renumbered as

claim 3, Original claim 2 was renumbered as claim 5, Original claim 3 was

renumbered as 4, and Original claim 4 was renumbered as claim 2.

During the prosecution the Applicants argued that the cited references did

not teach or suggest the specific droplet diameter and/or the specific weight ratios

of the two recited solvents (ethanol and propylene glycol). See04/15/2015

Amendment (Exh. 1012). Applicants did not include arguments of unexpected

results to overcome the obviousness rejection. As described herein however, the

claims would have been obvious to one of ordinary skill in the art in light of the

teachings of the references cited herein.

III. 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).


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A.

discrete liquid droplets

The claim term discrete liquiddroplets(or liquid droplets),which is

recited in claims 1-4, requires construction. The phrase is not explicitly defined in

the 460 specification, but is closely associated with the term spray throughout the

460specification. 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, . . .

See460 patent 3:17-20. (Exh. 1001).

The term spray was defined prior to the alleged effective filing date of the

460 patent as water or other liquid broken up into minute droplets and blown,

ejected into, or falling through the air.6 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

air.

B. pharmaceutically acceptable liquid carrier

6Exhibit 1008, Random House Websters College Dictionary, Random House,

Inc., April, 2000, p. 1270.


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The term pharmaceutically acceptable liquid carrier, which is recited in

claims 1-4, requires construction. The phrase is defined in the 460specification by

way of examples:

Pharmaceutically acceptable carriers include but are not limited to water,

buffer, saline, buffered saline, dextrose solution, propylene glycol,

polyethylene glycols, miglyol, and the like. In a specific embodiment, a

carrier that may be used in the pharmaceutical formulation of the present

invention is phosphate buffered saline, or a buffered saline. In certain

preferred embodiments the carrier is water.See460 patent 12:54-60 (Exh.

1001).

Further, the term carrier is defined by way of examples in thespecification:

Preferably the fentanyl, a pharmaceutically acceptable salt thereof, or

derivative thereof, is dissolved in an organic solvent. Examples of organic

solvents that may be used to enhance the solubility of fentanyl, or the

pharmaceutically acceptable salt thereof in a carrier such as e.g., water,

include for example and without limitation: lower alcohols (e.g. C1-

4 alcohols) such as methanol, ethanol, propyl alcohol, or butyl alcohol; C2-

8 alcohols having two or three hydroxyl groups, preferably glycerol,

propylene glycol or butylene glycol; and polyethylene glycols such as

PEG200 and PEG400 and the like..Id. at 11:20-29.

Accordingly, the term pharmaceutically acceptable liquid carrier includes,

but is not limited to, water. The specification specifically contemplates that organic

solvents can and will be dissolved in the water. Further, the specification


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contemplates that the carrier may be a solvent without any water. The phrase

pharmaceutically acceptable liquid carrier broadest reasonable construction must

be construed as meaning, water (including aqueous buffers and saline), one or

more organic solvents, or a mixture of both water and one or more organic

solvents

C.

wherein the sublingual fentanyl formulation consists essentially of:

Claim 3 recites:

A non-propellant sublingual fentanyl formulation comprising discrete liquid

droplets of an effective amount of fentanyl a free base, or a pharmaceutically

acceptable salt thereof, in a pharmaceutically acceptable liquid carrier,

wherein the sublingual fentanyl formulation consists essentially of:

from about 0.001% to about 15% by weight fentanyl free base;

from about 50% to about 60% by weight of ethanol; and

from about 1% to about 30% by weight of propylene glycol;said droplets having a mean diameter of at least about 10 microns.

The phrase, wherein the sublingual fentanyl formulation consists essentially

of:, which is in claim 3 only, requires construction. The transitional phrase

consisting essentially of limits the scope of a claim to the specified materials or

steps and those that do notmaterially affect the basic and novel characteristic(s)

of the claimed invention. M.P.E.P 2111.03 citingIn re Herz,537 F.2d 549, 551-

52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original). Issued Claim 3 was


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added (as New Claim 5) in the last amendment in the prosecution history. See

04/15/2014 Response. (Exh. 1012). No support for the new claim was provided

and neither the claim nor the transition phrase was addressed by the Applicant or by

the Examiner during the prosecution. With regard to the claims with similar

limitations, during prosecution, Applicants argued that prior art did not teach the

specific ratio of ethanol and propylene glycol and the specific droplet diameter.Id.

at p.7.

Claim 3 is directed to a non-propellant sublingual fentanyl formulation. Of

note is that the transitional phrase appears after the recitation of the claim element

of in a pharmaceutically acceptable liquid carrier.Accordingly, the consists

essentially of transition phrase applies only to the components appearing after the

phrase, i.e., fentanyl free base, ethanol and propylene glycol. The phrasesbroadest

reasonable construction, therefore, must be construed as excluding any component

in the fentanyl formulation, not including the pharmaceutically acceptable liquid

carrier, that would interfere or prevent the fentanyl formulation from the formation

of droplets in the cited diameter range.

IV. 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,


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and is a highly trained formulation chemist, well-versed in developing formulations

from experience with drug formulations in an industrial or academic environment.

Park Decl. 9. (Exh. 1002).

V. CLAIMS 1-5 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

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, 4 and 5 Are Unpatentable As Obvious Over


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Ross_GB, In View Of The 496 Publication

1.

Independent Claim 1

Claim 1 is directed to a sublingual formulation comprising discrete liquid

droplets of an effective amount of fentanyl . . . and a pharmaceutically

acceptable liquid carrier. The droplets have a mean diameter of from about 30

to about 70 microns.

2. The Prior Art And Its Comparison To Claim 1

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 and the 496

publication. Park Decl. 15. (Exh. 1002).

a. Sublingual formulation comprising discrete liquid droplets

Ross_GB teaches a pharmaceutical formulation comprising (i) fentanyl.

Ross_GB, Abstract (Exh. 1003). Ross_GB further teaches that its fentanyl

formulation is preferably administered sublinguallyas a spray. The formulations

are well tolerated when administered to the sensitive sublingual mucosa and the

sublingual spray administration will result in rapid onset of the therapeutic effect of

the fentanyl.Id.at p. 3, ll. 29-33 (emphasis added). Moreover, as explained by Dr.

Park, one of ordinary skill in the art as of the alleged effective filing date of the

460 patent (i.e., January 25, 2006) would have understood that the spray disclosed

in Ross_GB comprises discrete liquid droplets. Park Decl. 16. (Exh. 1002). For


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example, a spray was definedprior to the alleged effecting filing date of the 460

patent as having discrete liquid droplets: water or other liquid broken up into

minute droplets and blown, ejected into, or falling through the air.7

Accordingly, the claimed sublingual formulation comprising discrete liquid

dropletswould have been obvious over the teachings of Ross_GB.Park Decl.

16. (Exh. 1002).

b. of an effective amount of fentanylor a fentanyl derivative selected from the

group consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free

base or a pharmaceutically acceptable salt thereof,

Ross_GB teaches that a therapeutically effective amountof a [fentanyl]

formulation for the treatment of pain according to the invention is used.

Exh. 1003 at p. 8, ll. 10-11 (emphasis added).

c. in a pharmaceutically acceptable liquid carrier

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


Inc., April, 2000, p. 1270.


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solubility of the fentanyl or pharmaceutically acceptable salt thereof in

the water.Id.at p 3, ll. 21-27 (emphasis added).

d. said droplets having a mean diameter of from about 30 to about 70 microns

Like Ross_GB, the 496 publication teaches a fentanyl formulation: [t]wo

formulations containing fentanyl citrate were prepared... See 496 publication,

[0041] (Exh. 1005).

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. Id.at [0019]. As explained

by Dr. Park, [t]he preferred range of 10 to 100 microns encompasses the entire

claimed range of about 30 microns to about 70 microns recited in claim 1 of the

460 patent. Park Decl. 21 (Exh. 1002). As further explained by Dr. Park,

[w]hile the preferred range of the 496 publication is slightly broader than the

claimed range of about 30 to about 70 microns, the 460 patent does not identify or

suggest there is anything advantageous about the claimed range as compared to the

preferred range of the 496 publication..Id. Accordingly the claimed said

droplets having a mean diameter of from about 30 to about 70 micronswould

have been obvious over the teachings of the 496 publication.Id.

As further explained by Dr. Park, [i]twould have been obvious to have a

fentanyl formulation with a discrete liquid droplet with a mean diameter of from

about 30 to about 70 microns in light of the teachings of Ross_GB and the 496


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publication The 496 publication, like Ross_GB, teaches a fentanyl formulation.

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. Id. at 22.

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_GB.Id.

Moreover, as explained by Dr. Park, [o]neaspect 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.Id. at 23. Accordingly, [o]ne of ordinary

skill in the art would have been motivated to combine the fentanyl teachings of

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.Id.

3.

Independent Claim 4

Claim 4 is directed to a multi-dose device for sublingual administration of a

drug. The device comprises a reservoir containing a liquid formulation comprising

fentanyl . . .or a pharmaceutically acceptable salt thereof, and a pharmaceutically

acceptable liquid carrier. The device has an actuator which when actuated delivers

a therapeutically effective dose of the liquid formulation in the form of liquid

droplets having a mean diameter of from about 30 to about 70 microns.

4.

The Prior Art And Its Comparison To Claim 4


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ordinary skill in the art in light of the teachings of Ross_GB, and the 496

publication. Park Decl. 24 (Exh. 1002).

a. a multi-dose device for sublingual administration of a drug

Ross_GB teaches a single or multiple use devices comprising a single or

multiple dose of the formulation of the invention is envisaged. Ross_GB, p. 8, ll.

25-26. (Exh. 1003). Further Ross_GB teaches, The invention relates to

formulations of fentanyl, especially pump spray formulations suitable for

sublingual delivery.Id. at p. 1, ll. 3-4.

b. a reservoir containing the liquid formulation

Ross_GB teaches, Formulations according to the invention are preferably

packaged as a bulk solution containing multiple doses in a pump spray system

comprising a sealed container fitted with a metering pump. Thus as an aspect of the

invention we provide a sealed container containing a plurality of doses of a

formulation according to the invention.Id. at p. 8, ll. 13-18.

c. comprising fentanyl, or a fentanyl derivative selected from the group

consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free base or

a pharmaceutically acceptable salt thereof,

Ross_GB teaches that The invention relates to formulations of fentanyl,

especially pump spray formulations suitable for sublingual delivery.Id.at p. 1, ll.

3-4.


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d. in a pharmaceutically acceptable liquid carrier;






solubility of the fentanyl or pharmaceutically acceptable salt thereof

in the water. Id.at page 3, ll. 21-27 (emphasis added).

e. the device having an actuator

Ross_GB teaches that Another aspect of the invention is a metered dose

dispensing system comprising a sealed container containing a formulation of the

invention fitted with a metering pump, an actuatorand a channelling device.Id.

at p. 9, ll. 4-6. (emphasis added).

f.

which when actuated delivers a therapeutically effective dose of the liquidformulation

Ross_GB teaches, Preferably the actuator will be designed to deliver a

sublingually effective dose. Id. at p. 9, l. 26. (emphasis added).

g. in the form of liquid droplets

Ross_GB further teaches that its fentanyl formulation is preferably

administered sublinguallyas a spray. The formulations are well tolerated when

administered to the sensitive sublingual mucosa and the sublingual spray

administration will result in rapid onset of the therapeutic effect of the fentanyl.Id.


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at p. 3, ll. 29-33 (emphasis added). Moreover, as explained by Dr. Park, one of

ordinary skill in the art as of the alleged effective filing date of the 460 patent (i.e.,

January 25, 2006) would have understood that the spray disclosed in Ross_GB

comprises discrete liquid droplets. Park Decl. 16. (Exh. 1002). For example, a

spray was defined prior to the alleged effecting filing date of the 460 patent as

having discrete liquid droplets: water or other liquid broken up into minute

droplets and blown, ejected into, or falling through the air. Id.

Accordingly, the claimed sublingualformulation comprising discrete liquid

droplets would have been obvious over the teachings of Ross_GB.Id.

h. having a mean diameter of from about 30 to about 70 microns


formulations containing fentanyl citrate were prepared... See 496 publication,

[0041] (Exh. 1005).

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. Id.at [0019]. As explained

by Dr. Park, [t]he preferred range of 10 to 100 microns encompasses the entire

claimed range of about 30 microns to about 70 microns recited in claim 1 of the

460 patent. Park Decl. 21 (Exh. 1002). As further explained by Dr. Park,

while the preferred range of the 496 publication is slightly broader than the


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claimed range of about 30 to about 70 microns, the 460 patent does not identify or

suggest there is anything advantageous about the claimed range as compared to the

preferred range of the 496 publication..Id. Accordingly the claimed said

droplets having a mean diameter of from about 30 to about 70 micronswould

have been obvious over the teachings of the 496 publication.Id.




publication. The 496 publication, like Ross_GB, teaches a fentanyl formulation.

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. Id. at 22.

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_GB.Id.

Moreover, as explained by Dr. Park, [o]ne aspect of the administration of a


felt by a patient in receiving the drug.Id. at 23. Accordingly, [o]ne of ordinary





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5. Dependent Claim 5

Claim 5 depends from independent claim 1 and is directed to a method of

treating pain comprising sublingually administering an effective amount of the

sublingual formulation according to claim 1 to a human patient experiencing pain.

That is, claim 5 requires the same fentanyl sublingual formulation of claim 1 except

that it recites the method steps of administering an effective amount of the

formulation to a human patient experiencing pain.



ordinary skill in the art in light of the teachings of Ross_GB, and the 496

publication. Park Decl. 33. (Exh. 1002).

a. A method of treating pain comprising

Ross_GB teaches that, Formulations of the invention are useful in analgesia

and in the treatment of pain.Ross_GB, p. 8, l. 5. (Exh. 1003).

b. sublingually administering an effective amount of the sublingual

formulation according to claim 1

The analysis of the sublingual formulation according to Claim 1 is provided

above at IV.A.2.


formulation for the treatment of pain according to the invention is used.Id.at p. 8,


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ll. 10-11 (emphasis added). Ross_GB further teaches that its fentanyl formulation

is preferably administeredsublinguallyas a spray. The formulations are well

tolerated when administered to the sensitive sublingual mucosa and the sublingual

spray administration will result in rapid onset of the therapeutic effect of the

fentanyl.Id.at p. 3, ll. 29-33 (emphasis added).

c. to a human patient experiencing pain.

Ross_GB teaches, [f]entanyl is a narcotic alkaloid, which has been used for

many years as an anaesthetic and an analgesic, especially in the treatment of

moderate to severe pain.Id.at p. 1, ll. 6-7. Ross_GB further teaches

administration of formulations of fentanyl, especially pump spray formulations

suitable for sublingual delivery (Ross_GB, page 1, ll. 3-4) and the formulations

of the invention are preferably administered sublingually as a spray.Id. at p. 3, ll.

29-30. Ross_GB further teaches monitor[ing] patients for evidence of self

medication. Id.at p. 1, ll. 15. 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.Park Decl. 37. (Exh. 1002).

B.

Ground 2 -- Claims 2 And 3 Are Unpatentable As Obvious OverRoss_GB, In View Of The 862Patent, And The 496 Publication.

1. Independent Claim 2

Claim 2 is directed to a non-propellant sublingual fentanyl formulation


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comprising discrete liquid droplets of an effective amount of fentanyl . . . in a

pharmaceutically acceptable liquid carrier. The sublingual fentanyl formulation

comprises: from about 0.001% to about 15% by weight fentanyl free base; from

about 50% to about 60% by weight of ethanol; and from about 4% to about 6%

by weight of propylene glycol. The droplets have a mean diameter of at least

about 10 microns.



ordinary skill in the art in light of the teachings of Ross_GB, the 862 patentand the

496publication. Park Decl., 38. (Exh. 1002).

a. A non-propellant sublingual fentanyl formulation

Ross_GB teaches a pharmaceutical formulation comprising (i) fentanyl.

SeeRoss GB, Abstract (Exh. 1003). Ross_GB further teaches that its fentanyl

formulation is preferably administered sublinguallyas a spray. The formulations

are well tolerated when administered to the sensitive sublingual mucosa and the

sublingual spray administration will result in rapid onset of the therapeutic effect of

the fentanyl.Id.at p. 3, ll. 29-33 (emphasis added).

Further, Ross_GB further teaches that [t]he [fentanyl]formulations of the

present invention are also preferablyfree of any propellant.Id.at p 4, l. 1

(emphasis added).


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b. comprising discrete liquid droplets

Ross_GB further teaches that its fentanyl formulation is preferably

administered sublingually as a spray. Id.at p 3, ll. 29-30. As explained by Dr. Park,

one of ordinary skill in the art as of the alleged effective filing date of the 460

patent (i.e., January 25, 2006) would have understood that the spray disclosed in

Ross_GB comprises discrete liquid droplets. Park Decl. 16. (Exh. 1002). For

example, a spray was defined prior to the alleged effecting filing date of the 460

patent as having discrete liquid droplets: water or other liquid broken up into

minute droplets and blown, ejected into, or falling through the air.8

Accordingly, the claimed sublingual formulation comprising discrete liquid

droplets would have been obvious over the teachings of Ross_GB. Park Decl.

16. (Exh. 1002).

c. of an effective amount of fentanyl a free base or a pharmaceutically

acceptable salt thereof,


formulation for the treatment of pain according to the invention is used.Ross_GB,

p 8, ll. 10-11 (emphasis added). (Exh. 1003).


Inc., April, 2000, p. 1270.


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d. a pharmaceutically acceptable liquid carrier






solubility of the fentanyl or pharmaceutically acceptable salt thereof in

the water.Id.at page 3, lines 21-27 (emphasis added).

e.

wherein the sublingual fentanyl formulation comprises: from about 0.001%to about 15% by weight of fentanyl free base

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.

Id.at p. 11, ll. 1-9. As explained by Dr. Park, [b]ased on this disclosure, the

fentanyl concentration is calculated to be 0.028g fentanyl / (0.028 g + 0.0177 g +

2.8336 g + 0.0531 g + 4.1516 g) x 100% = 0.395% by weight of fentanyl, which is

within the claimed range of 0.001 % to 15 % by weight of fentanyl. Park Decl.

43. (Exh. 1002).

f. the sublingual fentanyl formulation comprises from about 50% to about

60% by weight of ethanol



Id.at page 11, ll. 1-9. As explained by Dr. Park, [b]ased on this disclosure, the


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ethanol concentration is calculated to be 2.8336g ethanol/(0.028 g + 0.0177 g +

2.8336 g + 0.0531g + 4.1516g) x 100 % = 40% by weight of ethanol. This meets

the lower bound of the range recited in the claim as about 50% by weight of

ethanol. Park Decl. 44. (Exh. 1002).

Ross_GB teaches [t]he concentration of polar organic solvent is in the range

preferably of between 6 and 50%. Ross_GB, p. 5, ll. 21-22 (Exh. 1003).

Ross_GB, further teaches [e]xamples 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. C2-4alcohols) such as ethanol.Id. at p. 5, ll.

1-3. Finally, Ross_GB teaches [t]he preferred polar organic solvent is ethanol.Id.

at p. 5, ll. 6-7. Accordingly, Ross_GB teaches ethanol in the amount of 50% by

weight, which is within the range of from about 50% to about 60% by weight of

ethanol.Park Decl. 45. (Exh. 1002).

g. 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. C2-4polyols) such as glycerol andpropylene glycol.


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Ross_GB, p. 5, ll. 1-4 (emphasis added). (Exh. 1003).

Moreover, Ross_GB mentions a second time that its fentanyl formulation includes

propylene glycol: [s]uitable moisturizing agents include, for example, the polar

organic solvents such as glycols, especiallypropylene glycol. Id.at p. 7, ll. 11-14

(emphasis added).

In addition, the 862 patent teaches a buccal spray comprising propylene

glycol in a broad range of 2% to 30% by weight. 862 patent 4:63. (Exh. 1004) 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. Park Decl. 47 (Exh. 1002). Moreover, the 862 patent also teaches a

buccal spray comprising propylene glycol of 7.28% by weight. 862 patent4:47

(Exh. 1004). As also explained by Dr. Park, [t]his percentage of propylene glycol

meets the upper bound of the range recited in claim 2 of the 460 patent as about 6%

of propylene glycol. Park Decl. 47 (Exh. 1002).

As further explained by Dr. Park, [i]t would havebeen 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. Id. at 48. Ross_GB specifically calls for an

amount of polar organic solvent to enhance the solubility of fentanyl . . .

Ross_GB, p. 3, ll. 26-27. (Exh. 1003). Ross_GB indicates that the formulations are

well tolerated when administered to sensitive sublingual mucosa and the sublingual


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spray administration will result in rapid onset of the therapeutic effect of fentanyl

and specifically identifies propylene glycol. Id. at ll. 30-32. 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.9 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. Id. at 48.

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

1348, 1369 (Fed. Cir. 2007) citingIn 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 teaching of Ross_GB in combination with the 862 patent.Park Decl. 49.

(Exh. 1002).

9Exhibit 1002, Park Decl. 48 quotingExhibit 1004, 862 patent, col. 1 ll. 19-20.


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h. said droplets having a mean diameter of at least about 10 microns.


formulations containing fentanyl citrate were prepared... 496 Publication,

[0041]. (Exh. 1005).

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. Id.at [0019]. As explained by Dr. Park, [a]

droplet within the preferred range of 10 to 100 microns clearly has a mean diameter

of at least about 10 microns recited in claim 2 of the 460 patent.Park Decl. 50.

(Exh. 1002).

As further explained by Dr. Park, [i]t would have been obvious to have a

fentanyl formulation with a discrete liquid droplet having a mean diameter of at least

about 10 microns in light of the teachings of Ross_GB, the 862 patent and the 496

publication. The 496 publication, like Ross_GB, teaches a fentanyl formulation.

Id. at 51. The 496 publication also teaches adecreased droplet size translates to

a higher surface area to be absorbed by the mucosa of the intra-oral cavity.496

publication, [0031]. (Exh. 1005). 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_GB.Id.



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felt by a patient in receiving the drug. Id. at 52. Accordingly, one of ordinary





Claim 3 is directed to a non-propellant sublingual fentanyl formulation

comprising discrete liquid droplets of an effective amount of fentanyl . . . in a

pharmaceutically acceptable liquid carrier. The sublingual fentanyl formulation

consists essentially of: from about 0.001% to about 15% by weight fentanyl free

base; from about 50% to about 60% by weight of ethanol; and from about 1% to

about 30% by weight of propylene glycol. The droplets have a mean diameter of

at least about 10 microns.



ordinary skill in the art in light of the teachings of Ross_GB, the 862 patentand the

496 Publication.. Park Decl. 53. (Exh. 1002).

a. A non-propellant sublingual fentanyl formulation

Analysis of this element is provided above at IV.B.2.a.


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b. comprising discrete liquid droplets

Analysis of this element is provided above at IV.B.2.b.

c.

of an effective amount of fentanyl

a free base or a pharmaceuticallyacceptable salt thereof,

Analysis of this element is provided above at IV.B.2.c.

d. a pharmaceutically acceptable liquid carrier

Analysis of this element is provided above at IV.B.2.d.

e. wherein the sublingual fentanyl formulation consists essentially of: from

about 0.001% to about 15% by weight of fentanyl free base



Id.at p. 11, ll. 1-9. As explained by Dr. Park, [b]ased on this disclosure, the

fentanyl concentration is calculated to be 0.028g fentanyl / (0.028 g + 0.0177 g +

2.8336 g + 0.0531 g + 4.1516 g) x 100% = 0.395% by weight of fentanyl, which is

within the claimed range of 0.001% to 15% by weight of fentanyl. Park Decl.

58. (Exh. 1002). Further, as explained by Dr. Park, Ross_GB does not require any

component that would interfere or prevent the fentanyl formulation from the

formation of droplets in the recited diameter range.Id.

f. the sublingual fentanyl formulation consists essentially of from about

50% to about 60% by weight of ethanol

Analysis of this element is provided above at IV.D.2.f.


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In addition, as explained by Dr. Park, Ross_GB does not require any

component that would interfere or prevent the fentanyl formulation from the

formation of droplets in the recited diameter range.Id. at 59.

g. the sublingual fentanyl formulation consists essentially of from about

1% to about 30% 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. C2-4polyols) such as glycerol andpropylene glycol.

Ross_GB, p. 5, ll. 1-4 (emphasis added). (Exh. 1003).

Moreover, Ross_GB mentions a second time that its fentanyl formulation includes

propylene glycol: [s]uitable moisturizing agents include, for example, the polar

organic solvents such as glycols, especiallypropylene glycol. Id.at p. 7, ll. 11-14

(emphasis added).

In addition, the 862 patent teaches a buccal spray comprising propylene

glycol in the range of 2% to 30% by weight. The 862 patent 4:63. (Exh. 1004). As

explained by Dr. Park, [t]he range of propylene glycol taught by the 862 patent is

within, and is substantially the same as, the claimed range of about 1% to about 30%

by weight of propylene glycol. Park Decl. 60. (Exh. 1002).


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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. Id. at 61. Ross_GB specifically calls for an

amount of polar organic solvent to enhance the solubility of fentanyl . . .

Ross_GB, p. 3, ll. 26-27. (Exh. 1003). 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

and specifically identifies propylene glycol. Id. at ll. 30-32. 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.10

As further explained by Dr. Park,

[o]ne skilled in the art would adjustand optimize the amount of propylene glycol to

account for the solubility of the drug substance as a matter of routine.Id.

Furthermore, as explained by Dr. Park, neither Ross_GB nor the 862 patent

requires any component that would interfere or prevent the fentanyl formulation

from the formation of droplets in the recited diameter range.Id. at 61.

Accordingly it would be obvious to arrive at the claimed range based on the

10Exhibit 1002, Dr. Parks Declaration, 61 quotingExhibit 1004, the 862 patent,

col. 1 ll. 19-20.


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teaching of Ross_GB in combination with the 862 patent.Id. at 62.

h. said droplets having a mean diameter of at least about 10 microns.

Analysis of this element is provided above at IV.B.2.h.

C.Ground 3 -- Claims 1, 4 and 5 Are Unpatentable As Obvious Over

Ross_GB, In View Of The 150 Patent

As explained above ( IV.A.), Ross_GB (Exh. 1003) teaches all the

elements of claims 1, 4 and 5 of the 460 patent except for specifically identifying

the mean droplet diameter. As further explained above in IV.A the496

publication (Exh. 1005) teaches the claimed droplet diameter; IV.A also explains

how it would have been obvious to one skilled in the art to combine the teaching of

Ross_GB with the teaching of the 496 publication to arriveat claims 1, 4 and 5 of

the 460 patent.

As explained in detail below, the 150 patent (Exh. 1007) also teaches the

claimed droplet diameter. In addition, it would have been obvious to one skilled in

the art combine the teaching of 150 patent with Ross_GB in the same manner as

that of the 496 publication to arrive at claims 1, 4 and 5 of the 460 patent.

Accordingly, in the analysis below, the detailed explanation of how Ross_GB

teaches the elements of claims 1, 4 and 5 is not repeated but is instead referenced

to the prior section.

1.

Independent Claim 1


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Claim 1 is directed to a sublingual formulation comprising discrete liquid

droplets of an effective amount of fentanyl . . . and a pharmaceutically

acceptable liquid carrier. The droplets have a mean diameter of from about 30

to about 70 microns.



ordinary skill in the art in light of the teachings of Ross_GB and the 150 patent.


a. sublingual formulation comprising discrete liquid droplets

Analysis of this element is provided above at IV.A.2.a.

b. of an effective amount of fentanylor a fentanyl derivative selected from the

group consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free

base or a pharmaceutically acceptable salt thereof,

Analysis of this element is provided above at IV.A.2.b.

c. in a pharmaceutically acceptable liquid carrier

Analysis of this element is provided above at IV.A.2.c.

d. said droplets having a mean diameter of from about 30 to about 70 microns

The 150 patent teaches that by using a pump spray with their formulations

they are able to produce a spray in which the particles have a mean aerodynamic

particle size of between 15 and 45 microns, more particularly between 20 and 40


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microns and an average of about 33 microns.The 150 patent 4:46-52. (Exh.

1007). The 150 patent further teaches that in contrast to the propellant driven

system, a pump spray could deliver an aerosol plume in which the particle size

could be controlled to generate a particle size of between 20 and 40 microns (thus

maximizing the amount of material hitting the sublingual/buccal mucosa and thus

the amount of cannabinoids that can be absorbed).Id. at 13:50-55. As explained

by Dr. Park, [t]he mean particle size between 15 and 45 overlaps the claimed

range of about 30 microns to about 70 microns recited in claim 1 of the 460

patent. Moreover, the average of about 33 microns is within the claimed range.

Park Decl. 66. (Exh. 1002). Accordingly the claimed said droplets having a

mean diameter of from about 30 to about 70 micronsis disclosed by the teachings

of the 150 patent.Id.




patent. The 150 patent, like Ross_GB, teaches a pump spray mechanism for

administering droplets sublingually. The 150 patent also teaches a particle size of

between 20 and 40 microns maximizes the amount of material hitting the

sublingual mucosa and thus maximizes the amount of [drug] that can be absorbed.

Id. at 67. Accordingly, as indicated by Dr. Park, one of ordinary skill in the art


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would have been motivated to combine the teachings of the 150 patent with the

teachings of Ross_GB. Id.



felt by a patient in receiving the drug.Id. at 68. Accordingly, one of ordinary


Ross_GB with the small droplet size of the 150 patent to eliminate or decrease

any discomfort to the patient from administration of the drug.Id.


Claim 4 is directed to a multi-dose device for sublingual administration of a

drug. The device comprises a reservoir containing the liquid formulation

comprising fentanyl . . . and a pharmaceutically acceptable liquid carrier. The

device has an actuator which when actuated delivers therapeutically effective dose

of the liquid formulation in the form of liquid droplets having a mean diameter of

from about 30 to about 70 microns.

4.

The Prior Art And Its Comparison To Claim 4


ordinary skill in the art in light of the teachings of Ross_GB, and the 150 patent.


a. a multi-dose device for sublingual administration of a drug


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kyle bass ipr against insys therapeutics

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