U.S. Patent No. US 8,835,459
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
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`Coalition For Affordable Drugs XI LLC,
`Petitioner
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`
`
`v.
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`
`
` Insys Pharma, Inc.,
`Patent Owner
`
`
`
`U.S. Patent 8,835,459
`
`
`
`__________________
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT
`NO. 8,835,459 AND
`MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`Mailed August 17, 2015
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`

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`U.S. Patent No. US 8,835,459
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`TABLE OF CONTENTS
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`NOTICE OF RELATED MATTERS...........................................................................................2
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`NOTICE OF SERVICE INFORMATION ..................................................................................3
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`GROUNDS FOR STANDING ......................................................................................................3
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`STATEMENT OF PRECISE RELIEF REQUESTED ...............................................................3
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`STATEMENT OF REASONS FOR RELIEF REQUESTED ....................................................8
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`I.
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`INTRODUCTION AND SUMMARY OF ARGUMENT ...................................................8
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`II. THE CLAIMS UNDER CONSIDERATION .....................................................................10
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`III. THE ‘459 PATENT AND ITS PROSECUTION HISTORY ............................................12
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`IV. CLAIM CONSTRUCTION .................................................................................................20
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`A. “MEAN TMAX” ......................................................................................................................20
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`B. “MEAN CMAX” ......................................................................................................................21
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`C. “AUCLAST” .............................................................................................................................22
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`D. “AUCINF” ...............................................................................................................................22
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`E. “ABOUT” ...............................................................................................................................22
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`V. PERSON OF ORDINARY SKILL IN THE ART ..............................................................23
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`VI. CLAIMS 1-6 ARE OBVIOUS .............................................................................................23
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`A. GROUND 1 -- CLAIM 1 IS UNPATENTABLE AS OBVIOUS OVER
`ROSS_GB, IN VIEW OF ROSS_US2006, AND THE ’862 PATENT ..............................24
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`1.
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`INDEPENDENT CLAIM 1 .................................................................................................24
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`2. THE PRIOR ART AND ITS COMPARISON TO CLAIM 1 ..........................................25
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`A. SUBLINGUAL FORMULATION .........................................................................................25
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`B. FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT FENTANYL, A FREE
`BASE, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF .......................26
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`C. THE SUBLINGUAL FORMULATION COMPRISING … FROM ABOUT 20%
`TO ABOUT 60% BY WEIGHT OF ETHANOL ...................................................................26
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`U.S. Patent No. 8,835,459
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`D. THE SUBLINGUAL FORMULATION COMPRISING … FROM ABOUT 4% TO
`ABOUT 6% BY WEIGHT OF PROPYLENE GLYCOL ......................................................27
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`E. ADMINISTERED SUBLINGUALLY TO HUMANS ..........................................................30
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`F. THE FORMULATION PROVIDING A MEAN TMAX OF ABOUT 1.28+/−0.60
`HOURS ..................................................................................................................................30
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`B. GROUND 2 -- CLAIMS 2 AND 3 ARE UNPATENTABLE AS OBVIOUS
`OVER ROSS_GB, IN VIEW OF ROSS_US2006, THE ‘862 PATENT, AND
`BREDENBERG_2003...........................................................................................................34
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`1.
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`INDEPENDENT CLAIM 2 .................................................................................................34
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`2. THE PRIOR ART AND ITS COMPARISON TO CLAIM 2 ..........................................35
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`A. SUBLINGUAL FORMULATION .........................................................................................35
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`B. FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT FENTANYL, A FREE
`BASE, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF .......................35
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`C. THE SUBLINGUAL FORMULATION COMPRISING … FROM ABOUT 50%
`TO ABOUT 60% BY WEIGHT OF ETHANOL ...................................................................36
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`D. THE SUBLINGUAL FORMULATION COMPRISING … FROM ABOUT 4% TO
`ABOUT 6% BY WEIGHT PROPYLENE GLYCOL .............................................................37
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`E. AFTER ADMINISTRATION TO HUMANS .......................................................................40
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`F. PROVIDES A PLASMA CONCENTRATION AFTER ADMINISTRATION TO
`HUMANS SELECTED FROM THE GROUP CONSISTING OF: ABOUT 60% OF
`THE MEAN CMAX IN ABOUT 10 MINUTES, ABOUT 86% OF THE MEAN CMAX
`BY ABOUT 20 MINUTES AND A COMBINATION THEREOF .......................................40
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`3. DEPENDENT CLAIM 3......................................................................................................44
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`4. THE PRIOR ART AND ITS COMPARISON TO CLAIM 3 ..........................................45
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`A. WHEN ADMINISTERED TO HUMANS PROVIDES A PLASMA
`CONCENTRATION THAT IS GREATER THAN ABOUT 80% OF THE MEAN
`CMAX FOR ABOUT 2 HOURS ...............................................................................................45
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`C. GROUND 3 -- CLAIM 4 IS UNPATENTABLE AS OBVIOUS OVER
`ROSS_US2006 IN VIEW OF BREDENBERG_2003 .........................................................46
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`1.
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`INDEPENDENT CLAIM 4 .................................................................................................46
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`2. THE PRIOR ART AND ITS COMPARISON TO CLAIM 4 ..........................................47
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`ii
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`U.S. Patent No. 8,835,459
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`A. A SUBLINGUAL SPRAY FORMULATION. .......................................................................47
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`B. 400 MCG DOSE OF FENTANYL ........................................................................................48
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`C. PROVIDES ONE OR MORE MEAN PHARMACOKINETIC VALUES
`SELECTED FROM THE GROUP CONSISTING OF: AUCLAST 4.863+/−1.70821
`HR*NG/ML, AUCINF 5.761+/−1.916 HR*NG/ML, AND AUCEXTRAP
`10.26+/−5.66%, WHEN ADMINISTERED TO HUMANS ..................................................48
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`D. GROUND 4 -- CLAIMS 4 AND 5 ARE UNPATENTABLE AS OBVIOUS
`OVER ROSS_GB IN VIEW OF THE ACTIQ LABEL. ...................................................49
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`1.
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`INDEPENDENT CLAIM 4 .................................................................................................49
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`2. THE PRIOR ART AND ITS COMPARISON TO CLAIM 4 ..........................................50
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`A. A SUBLINGUAL SPRAY FORMULATION. .......................................................................50
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`B. 400 MCG DOSE OF FENTANYL ........................................................................................50
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`C. PROVIDES ONE OR MORE MEAN PHARMACOKINETIC VALUES
`SELECTED FROM THE GROUP CONSISTING OF: AUCLAST 4.863+/−1.70821
`HR*NG/ML, AUCINF 5.761+/−1.916 HR*NG/ML, AND AUCEXTRAP
`10.26+/−5.66%, WHEN ADMINISTERED TO HUMANS ..................................................51
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`3.
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`INDEPENDENT CLAIM 5 .................................................................................................52
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`4. THE PRIOR ART AND ITS COMPARISON TO CLAIM 5 ..........................................53
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`A. A SUBLINGUAL SPRAY FORMULATION COMPRISING A DOSE OF
`FENTANYL. ..........................................................................................................................53
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`B. PROVIDES A SUBSTANTIALLY DOSE PROPORTIONAL MEAN AUCLAST
`BASED ON A MEAN AUCLAST OF ABOUT 4.863+/−1.70821 HR*NG/ML FOR A
`400 MCG FENTANYL DOSE WHEN ADMINISTERED TO HUMANS ..........................53
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`E. GROUND 5 -- CLAIM 6 IS UNPATENTABLE AS OBVIOUS OVER ROSS_GB
`IN VIEW OF THE ACTIQ LABEL, AND BREDENBERG_2003 ...................................55
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`1.
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`INDEPENDENT CLAIM 6 .................................................................................................55
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`2. THE PRIOR ART AND ITS COMPARISON TO CLAIM 6 ..........................................56
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`A. A SUBLINGUAL SPRAY FORMULATION COMPRISING A 400 MCG DOSE
`OF FENTANYL. ....................................................................................................................56
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`B. PROVIDES A MEAN F(AUCLAST) OF ABOUT 0.721+/−0.199 NG/ML WHEN
`ADMINISTERED TO HUMANS .........................................................................................56
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`iii
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`VII. CONCLUSION .....................................................................................................................59
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`U.S. Patent No. 8,835,459
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`U.S. Patent No. 8,835,459
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`TABLE OF AUTHORITIES
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`CASES
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`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) ........................................ 24
`In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 U.S. App. LEXIS 1699,
`Slip. Op. at 21 (Fed. Cir. Feb. 4, 2015). ............................................................... 20
` Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012),
`cert denied, 133 S. Ct. 1736 (2013)). ................................................................... 24
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`
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`RULES
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`37 C.F.R § 42.8(b)(1) ................................................................................................. 1
`37 C.F.R. § 42.100(b) .............................................................................................. 20
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`v
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`U.S. Patent No. 8,835,459
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`Coalition For Affordable Drugs XI LLC ("CFAD" or "Petitioner") requests
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`inter partes review of claims 1 - 6 of U.S. Patent No. 8,835,459 ("the '459 Patent")
`
`(Exhibit 1001) assigned to Insys Pharma, Inc. (“Insys”).
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`NOTICE OF LEAD AND BACKUP COUNSEL
`
`Lead Counsel:
`Dr. Gregory J. Gonsalves
`Reg. No. 43,639
`2216 Beacon Lane
`Falls Church, VA 22043
`(571) 419-7252
`gonsalves@gonsalveslawfirm.com
`
`Backup Counsel:
`Christopher Casieri
`McNeely, Hare & War LLP
`12 Roszel Road, Suite C104
`Princeton, NJ 08540
`Phone: 609 731 3668
`chris@miplaw.com
`
`
`
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`NOTICE OF EACH REAL-PARTY-IN-INTEREST
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`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Coalition For
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`Affordable Drugs XI LLC (“CFAD”), Hayman Credes Master Fund, L.P.
`
`(“Credes”), Hayman Orange Fund SPC – Portfolio A (“HOF”), Hayman Capital
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`Master Fund, L.P. (“HCMF”), Hayman Capital Management, L.P. (“HCM”),
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`Hayman Offshore Management, Inc. (“HOM”), Hayman Investments, L.L.C.
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`(“HI”), nXn Partners, LLC (“nXnP”), IP Navigation Group, LLC (“IPNav”), J Kyle
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`Bass, and Erich Spangenberg are the real parties in interest (collectively, “RPI”).
`
`The RPI hereby certify the following information: CFAD is a wholly owned
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`subsidiary of Credes. Credes is a limited partnership. HOF is a segregated portfolio
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`1
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`U.S. Patent No. 8,835,459
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`company. HCMF is a limited partnership. HCM is the general partner and
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`investment manager of Credes and HCMF. HCM is the investment manager of
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`HOF. HOM is the administrative general partner of Credes and HCMF. HI is the
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`general partner of HCM. J Kyle Bass is the sole member of HI and sole shareholder
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`of HOM. CFAD, Credes, HOF and HCMF act, directly or indirectly, through HCM
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`as the general partner and/or investment manager of Credes, HOF and HCMF. nXnP
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`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
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`Manager and majority member of IPNav. Other than HCM and J Kyle Bass in his
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`capacity as the Chief Investment Officer of HCM and nXnP and Erich Spangenberg
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`in his capacity as the Manager/CEO of nXnP, no other person (including any
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`investor, limited partner, or member or any other person in any of CFAD, Credes,
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`HOF, HCMF, HCM, HOM, HI, nXnP or IPNav) has authority to direct or control (i)
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`the timing of, filing of, content of, or any decisions or other activities relating to this
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`Petition or (ii) any timing, future filings, content of, or any decisions or other
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`activities relating to the future proceedings related to this Petition. All of the costs
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`associated with this Petition will be borne by HCM, CFAD, Credes, HOF and/or
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`HCMF.
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`NOTICE OF RELATED MATTERS
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`Petitioner is aware of a concurrently filed Petition for inter partes review
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`2
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`U.S. Patent No. 8,835,459
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`(“IPR”) of U.S. Patent No. 8,486,972, upon which the ‘459 patent claims priority
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`as a divisional patent application (Case No. Unassigned); and a concurrently filed
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`Petition for IPR of U.S. Patent No. 8,835,460 (Case No. Unassigned). To the best
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`of Petitioner’s knowledge, there are no pending litigations or other matters related
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`to the ’459 patent that would affect, or be affected by, a decision in this
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`proceeding.
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`NOTICE OF SERVICE INFORMATION
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`Please address all correspondence to the lead and backup counsel at the
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`address shown above. Petitioner also consents to electronic service by e-mail at:
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`gonsalves@gonsalveslawfirm.com and chris@miplaw.com.
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`
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`GROUNDS FOR STANDING
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`Petitioner certifies that the patent for which review is sought is available for
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`inter partes review, and that Petitioner is not barred or estopped from requesting an
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`inter partes review on the grounds identified in the petition.
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`STATEMENT OF PRECISE RELIEF REQUESTED
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`Petitioner relies on the following patents and printed publications to support
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`its grounds of challenge to claims 1-6 of the ‘459 patent in this Petition:
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`1. Great Britain patent publication GB2399286A by Calvin John Ross et
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`al, entitled “Sub-lingual fentanyl formulation.” published September
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`15, 2004 (“Ross_GB,” Exhibit 1003). Ross_GB is prior art to the
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`3
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`U.S. Patent No. 8,835,459
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`‘459 patent under at least 35 U.S.C. § 102(b) (pre-AIA) because it
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`was published on September 15, 2004, more than one year prior to
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`August 2, 2007, the earliest effective filing date for the claims of the
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`‘459 patent. Ross_GB was not considered by the Examiner during
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`the prosecution of the application that led to the ‘459 patent.1
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`2. United States Patent 5,370,862 by Karin Klokkers-Bethke et al.,
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`entitled “Pharmaceutical hydrophilic spray containing nitroglycerin for
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`treating angina,” issued December 6, 1994 (“the ‘862 patent,” Exhibit
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`1004). The ‘862 patent is prior art to the ‘459 patent under at least 35
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`U.S.C. § 102(b) (pre-AIA) because it issued on December 6, 1994,
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`more than one year prior to August 2, 2007, the earliest effective
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`filing date for the claims of the ‘459 patent. The ‘862 patent was not
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`considered by the Examiner during the prosecution of the application
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`that led to the ‘459 patent.2
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`3. United States Patent Application Publication 2006/0062812 by Calvin
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`John Ross et al. entitled “Novel compositions,” published March 23,
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`2006 (“Ross_US2006,” Exhibit 1005). Ross_US2006 is prior art to
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`1 Exhibit 1001, ‘459 patent, References Cited, pp. 1-2.
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`2 Id.
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`4
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`U.S. Patent No. 8,835,459
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`the ‘459 patent under at least 35 U.S.C. § 102(b) (pre-AIA) because it
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`was published more than one year prior to August 2, 2007, the earliest
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`effective filing date for the claims of the ‘459 patent.
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`4. “New Concepts For Administration of Drugs In Tablet Form:
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`Formulation and Evaluation Of A Sublingual Tablet For Rapid
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`Absorption and Presentation Of An Individualised Dose
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`Administration System,” by Susanne Bredenberg, Uppsala University,
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`Tryck & Medier, Uppsala 2003 (“Bredenberg_2003,” Exhibit 1006).
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`Bredenberg_2003 is prior art to the ‘459 patent under at least 35
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`U.S.C. § 102(b) (pre-AIA) because it was published in 2003, more
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`than one year prior to August 2, 2007, the earliest effective filing date
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`for the claims of the ‘459 patent. Clearly, Bredenberg_2003 was made
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`available to the extent that persons interested and ordinarily skilled in
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`the subject matter or art, exercising reasonable diligence, could have
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`located it as evidenced at least by the facts that it was assigned both an
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`ISBN (International Standard Book Number) and an ISSN
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`(International Standard Serial Number) when it was published in
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`5
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`U.S. Patent No. 8,835,459
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`2003.3 Bredenberg_2003 was not considered by the Examiner during
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`the prosecution of the application that led to the ‘459 patent.4
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`5. The ACTIQ Label (Exhibit 1008). The ACTIQ Label is prior art to
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`the ‘459 patent under at least 35 U.S.C. § 102(b) (pre-AIA) because
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`the copyright date printed on the ACTIQ Label is 2000, 2001.5
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`Moreover, a label revision approval letter for the ACTIQ Label was
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`issued by the Department of Health and Human Services on September
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`24, 2004,6 leaving no doubt that the ACTIQ Label was made available
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`to the extent that persons interested and ordinarily skilled in the subject
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`matter or art, exercising reasonable diligence, could have located it
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`more than one year before the earliest effective filing date of the ‘459
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`patent. The ACTIQ Label was not considered by the Examiner
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`during the prosecution of the application that led to the ‘459 patent.7
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`3 Exhibit 1006, Bredenberg_2003, p. 2.
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`4 Exhibit 1001, ‘459 patent, References Cited, pp. 1-2.
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`5 Exhibit 1008, ACTIQ Label, p. 32.
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`6 Exhibit 1009, ACTIQ Label revision approval letter.
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`7 Exhibit 1001, ‘459 patent, References Cited, pp. 1-2.
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`6
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`U.S. Patent No. 8,835,459
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`Petitioner requests that claims 1-6 of the '459 Patent be held unpatentable
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`based on the following grounds:
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`Ground 1. Claim 1 is unpatentable as obvious over Ross_GB, in view of
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`Ross_US2006, and the ’862 patent. See 35 U.S.C. § 103(a).8
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`Ground 2. Claims 2 and 3 are unpatentable as obvious over Ross_GB, in
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`view of Ross_US2006, the ‘862 patent, and Bredenberg_2003. See 35 U.S.C. §
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`103(a).
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`Ground 3. Claim 4 is unpatentable as obvious over Ross_US2006 in view of
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`Bredenberg_2003.
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`Ground 4. Claims 4 and 5 are unpatentable as obvious over Ross_GB in
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`view of the ACTIQ Label.
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` Ground 5. Claim 6 is unpatentable as obvious over Ross_GB, the ACTIQ
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`Label, and Bredenberg_2003.
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`Neither any of the proposed grounds of rejections nor any of the
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`combinations of references asserted within those grounds were considered by the
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`Examiner during the prosecution of the application that issued as the ‘459 patent.
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`THRESHOLD REQUIREMENT FOR INT ER PA R T ES REVIEW
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`8 The pre-AIA version of § 103 applies in this proceeding, because the ‘459 Patent
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`has an effective filing and issue date before March 16, 2013. The ‘459 patent
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`claims a priority date of August 2, 2007.
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`7
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`U.S. Patent No. 8,835,459
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`A petition for inter partes review must demonstrate "a reasonable likelihood
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`that the petitioner would prevail with respect to at least one of the claims
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`challenged in the petition." 35 U.S.C. § 314(a). This Petition meets that threshold.
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`All of the elements of claims 1-6 of the '459 Patent are taught or suggested in the
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`prior art, as explained below in the proposed grounds of unpatentability. The
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`reasons to combine the cited references, where applicable, are established under
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`35 U.S.C. § 103(a). This Petition is supported by the Declaration of Dr. Park
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`(Exhibit 1002).
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`Therefore, in accordance with 37 C.F.R. § 42.22, Petitioner respectfully
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`requests cancellation of claims 1-6 of the ’459 patent.
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`I.
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`STATEMENT OF REASONS FOR RELIEF REQUESTED
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`INTRODUCTION AND SUMMARY OF ARGUMENT
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`The ‘459 patent is directed to sublingual liquid fentanyl formulations. After
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`the Examiner rejected claims 1-6 as obvious over the prior art including
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`Ross_US2006, the Applicant amended claims 1-2 to recite particular percentages
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`by weight of fentanyl, ethanol and propylene glycol for a fentanyl formulation and
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`argued that the prior art did not teach the recited weight percentages or the recited
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`U.S. Patent No. 8,835,459
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`values for Tmax, Cmax or AUC (area under the curve).9 In response to the
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`Applicant’s claim amendments and argument, the Examiner allowed claims 1-6.10
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` Contrary to the Applicant’s argument, however, the prior art did, in fact,
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`teach the claimed weight percentages of fentanyl, ethanol and propylene glycol as
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`well as the claimed values for Tmax, Cmax and AUC.11 Indeed, Ross_GB, a prior art
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`patent publication in Great Britain that is closely related to — and has the same
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`inventor as — Ross_US2006, when combined with the ‘862 patent, teaches the
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`weight percentages of fentanyl, ethanol and propylene glycol that are claimed in
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`the fentanyl formulation of the ‘459 patent.12 Moreover, additional prior art
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`publications including Bredenberg_2003 and the ACTIQ Label, teach the claimed
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`values for Tmax, Cmax and AUC.13
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`Neither any of the grounds of rejection proposed in this Petition, nor any of
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`the combinations of prior art references asserted in those grounds were considered
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`by the Examiner during the prosecution of the application that issued as the ‘459
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`9 Exhibit 1017, Amendment mailed April 15, 2014, pp. 2-5.
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`10 Exhibit 1019, Notice of Allowance mailed May 1, 2014.
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`11 Infra, § VI.
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`12 Id.
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`13 Id.
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`9
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`U.S. Patent No. 8,835,459
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`patent. The Examiner would not have allowed any of the claims of the ‘459 patent
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`if he had known of Ross_GB, the ‘862 patent, Bredenberg_2003, and the ACTIQ
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`Label. For these reasons as expressed more fully below, there is a reasonable
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`likelihood that the Petitioner will prevail on one or more claims of the ‘459 patent
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`and therefore, this IPR should be instituted.
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`The public has a significant interest in ensuring monopoly privileges are not
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`granted by an invalid patent particularly where, as here, Subsys® (the drug
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`corresponding to the ‘459 patent) can cost up to $300 per day per patient.14 The
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`patent owner can attempt to secure such high prices through FDA regulatory
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`exclusivity but should not be allowed to extend these privileges with an obvious
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`‘459 patent.
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`II. THE CLAIMS UNDER CONSIDERATION
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`
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`1. A sublingual formulation comprising from about 0.001% to about 15% by
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`weight fentanyl, a free base, or a pharmaceutically acceptable salt thereof,
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`from about 20% to about 60% by weight ethanol, and from about 4% to
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`14 See e.g., Exhibit 1010, Fallon community Health Plan, Prior Authorization
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`Approval Criteria, Subsys (fentanyl sublingual spray), 3/14/2012; Exhibit 1011,
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`Subsys Manufacturing/Pricing – Good RX, 2015; and Exhibit 1012, Subsys
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`Manufacture/Pricing – Epocrates Online, 2015.
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`10
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`U.S. Patent No. 8,835,459
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`about 6% by weight propylene glycol, the formulation providing a mean
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`Tmax of about 1.28+/−0.60 hours when a dose is administered sublingually to
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`humans.
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`2. A sublingual formulation comprising from about 0.001% to about 15% by
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`weight fentanyl, a free base, or a pharmaceutically acceptable salt thereof,
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`from about 50% to about 60% by weight ethanol, and from about 4% to
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`about 6% by weight propylene glycol, which provides a plasma
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`concentration after administration to humans selected from the group
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`consisting of: about 60% of the mean Cmax in about 10 minutes, about 86%
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`of the mean Cmax by about 20 minutes and a combination thereof.
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`3.
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`The sublingual formulation of claim 1, that when administered to humans
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`provides a plasma concentration that is greater than about 80% of the mean
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`Cmax for about 2 hours.
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`4. A sublingual spray formulation comprising 400 mcg dose of fentanyl, a free
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`base, or a pharmaceutically acceptable salt thereof, which provides one or
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`more mean pharmacokinetic values selected from the group consisting of:
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`AUClast 4.863+/−1.70821 hr*ng/mL, AUCinf 5.761+/−1.916 hr*ng/mL, and
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`AUCextrap10.26+/−5.66%, when administered to humans.
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`5. A sublingual spray formulation comprising a dose of fentanyl, a free base, or
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`a pharmaceutically acceptable salt thereof, which provides a substantially
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`11
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`U.S. Patent No. 8,835,459
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`dose proportional mean AUClast based on a mean AUClast of about
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`4.863+/−1.70821 hr*ng/mL for a 400 mcg fentanyl dose when administered
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`to humans.
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`6. A sublingual spray formulation comprising a 400 mcg dose of fentanyl, a
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`free base, or a pharmaceutically acceptable salt thereof, which provides a
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`mean F(AUClast) of about 0.721+/−0.199 ng/mL when administered to
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`humans.
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`III. THE ‘459 PATENT AND ITS PROSECUTION HISTORY
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`
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`A. The '459 Patent
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`The ‘459 patent “is directed to sublingual formulations containing fentanyl,
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`a pharmaceutically acceptable salt thereof, or derivative thereof, suitable for
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`administration to humans, and methods for treatment with the sublingual
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`formulations.”15 The sublingual formulations “are useful in the treatment of
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`moderate to severe pain.”16
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`The ‘459 patent explains that “[w]ithin the oral cavity, there are three
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`generally recognized routes of administration of an active agent, namely local,
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`15 Exhibit 1001, ‘459 patent, col. 1, ll. 12-15.
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`16 Id. at col. 10, ll. 29-30.
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`U.S. Patent No. 8,835,459
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`buccal and sublingual.”17 Local administration, “is mainly limited to applications
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`regarding disruptions occurring within the oral cavity itself, such as a canker
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`sore.”18 The ‘459 patent explains that there are known disadvantages associated
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`with buccal administration.19 The ‘459 patent further notes that sublingual delivery
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`has an advantage of rapid onset of action:
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`Sublingual delivery is achieved through the mucosal membranes
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`lining the floor of the mouth. Because of the high permeability and the
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`rich blood supply, transport via the sublingual route results in a rapid
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`onset of action, providing a delivery route appropriate for highly
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`permeable drugs with short delivery period requirements and an
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`infrequent dosing regimen.20
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`Claims 1 and 2 of the ‘459 patent recites specific ranges of fentanyl, ethanol
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`and propylene by weight in a sublingual formulation.21 All of the claims include
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`17 Id. at col. 10, ll. 8-10.
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`18 Id. at col. 10, ll. 11-13.
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`19 Id. at col. 10, ll. 14-21.
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`20 Id. at col. 10, ll. 22-28.
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`21 Supra. § II.
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`U.S. Patent No. 8,835,459
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`statements of pharmacokinetic parameters for the fentanyl formulation when
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`administered to humans.22
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`B.
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`The Prosecution History Of The '459 Patent
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`
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`The application that issued as the ‘459 patent (application no. 13/895,111)
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`was filed on May 15, 2013 with claims 1 – 3. On November 21, 2013, the
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`Examiner rejected claims 1-3 “under 35 U.S.C. 112, first paragraph, because the
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`specification … does not reasonably provide enablement for all formulations
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`having said claimed properties. The specification does not enable any person
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`skilled in the art to which it pertains, or with which it is most nearly connected, to
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`make the invention commensurate in scope with these claims.”23 The Examiner
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`reasoned that “[t]he breadth of the claims is excessive with regard to claiming all
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`sublingual formulations having a Tmax of 1.28 +/- 0.60 hrs as well as the claimed
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`Cmax.”24
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`The Examiner also rejected claims 1-3 “under 35 U.S.C. 112, first
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`paragraph, as containing subject matter which was not described in the
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`
`22 Id.
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`23 Exhibit 1014, Office action, mailed November 21, 2013, p. 3.
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`24 Id. at p. 4.
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`U.S. Patent No. 8,835,459
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`specification in such a way as to reasonably convey to one skilled in the relevant
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`art that the inventor(s), at the time the application was filed, had possession of the
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`claim invention.”25 The Examiner reasoned that “the specification and claims do
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`not indicate what distinguishing attributes are shared by the members of the genus.
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`Thus the scope of [the] claims includes numerous variants, and the genus is highly
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`variant because a significant number of formulations genus members is
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`permitted.”26
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`
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`The Examiner also rejected claims 1-3 as anticipated by or obvious over
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`McCarty (US 2007/0071806) or Ross_US2003 (US 2003/01900290).27 With
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`respect to the obviousness rejections, the Examiner reasoned that it would have
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`“been obvious at the time of the instant invention to have optimized the conditions
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`to provide a formulation with a rapid/desired onset of action to reduce pain as
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`quickly as possible.”28
`
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`25 Id.
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`26 Id. at pg. 5.
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`27 Id. at pp. 5-7.
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`28 Id. at p. 7.
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`U.S. Patent No. 8,835,459
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`Finally, the Examiner rejected claims 1-3 on the ground of nonstatutory
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`double patenting as being unpatentable over the claims of U.S. Patent No.
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`8,486,972 (“the ‘972 patent”) and 8,486,973 (“the ‘973 patent”).29 The Examiner
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`reasoned that the claims of the application and each of the ‘972 patent and the ‘973
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`patent were “not patentably distinct from each other because both sets of claims are
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`drawn to sublingual fentanyl formulations.”30
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`In an Amendment dated March 6, 2014, the Applicants added claims 4-6 and
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`argued that claims 1-3 met the enablement requirement because a person of
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`ordinary skill in the art would be a highly trained formulation chemist and that
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`such a person would have been able to derive the claimed formulation with routine
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`experiments:
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`[The Specification] provided Cmax and Tmax values for other
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`formulations that were administered to rabbits (see examples 1-6). A
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`PHOSITA [person having ordinary skill in the art] would be able to
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`extrapolate this data to aid in the formulation of doses to administer to
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`humans that would provide the claimed Tmax and Cmax.
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`Additionally a PHOSITA is a highly trained formulation chemist,
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`well-versed in developing formulations. Assuming, for the sake of the
`
`
`29 Id. at 7.
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`30 Id.
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`U.S. Patent No. 8,835,459
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`analysis, that the number of experiments based on the claim breadth
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`was high, the experiments themselves would be routine given the
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`guidance and working examples of the instant specification.”31
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`Similarly, the Applicants argued that the written description was also met because
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`“the PHOSITA is a formulation chemist well versed in developing formulations for
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`administration to humans and measuring the resulting Tmax and Cmax. This
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`highly level of skill of the PHOSITA and knowledge in the art sets a low bar for
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`‘the specificity of the disclosure necessary to satisfy the written description
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`requirement.”32 The Applicants also argued that neither McCarty nor
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`RossUS_2003 “teaches or makes obvious a sublingual fentanyl formulation having
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`the claimed Tmax, Cmax, and AUC values.”33
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`On March 24, 2014, the Examiner mailed an Office Action maintaining the
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`obviousness rejections of claims 1-3 and withdrawing the enablement and written
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`description based on the Applicant’s admission that one of ord