U.S. Patent No. US 8,486,972
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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
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`
`
`U.S. Patent 8,486,972
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`
`
`__________________
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`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
`8,486,972 AND
`MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`Mailed August 24, 2015
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`U.S. Patent No. 8,486,972
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`TABLE OF CONTENTS
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`NOTICE OF RELATED MATTERS...........................................................................................3
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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 ....................................................6
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`II. THE CLAIMS UNDER CONSIDERATION .......................................................................8
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`III. THE ‘972 PATENT AND PROSECUTION HISTORY OF THE '972 PATENT ............9
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`IV. CLAIM CONSTRUCTION .................................................................................................23
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`A. “MEAN TIME TO MAXIMUM PLASMA CONCENTRATION (TMAX) OF
`FENTANYL OF FROM ABOUT 5 TO ABOUT 120 MINUTES” ......................................23
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`B. “DISCRETE LIQUID DROPLETS” .....................................................................................25
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`V. LEVEL OF SKILL IN THE ART .......................................................................................26
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`VI. CLAIMS 1-3 ARE OBVIOUS .............................................................................................26
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`A. GROUND 1 -- CLAIMS 1 AND 3 ARE UNPATENTABLE AS OBVIOUS
`OVER ROSS_GB, IN VIEW OF ROSS_US2006, AND THE ’862 PATENT ..................27
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`1.
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`INDEPENDENT CLAIM 1 .................................................................................................27
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`A. UNIT DOSE ...........................................................................................................................28
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`B. NON-PROPELLANT ............................................................................................................28
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`C. SUBLINGUAL FENTANYL FORMULATION COMPRISING DISCRETE
`LIQUID DROPLETS .............................................................................................................28
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`D. AN EFFECTIVE AMOUNT OF FENTANYL .....................................................................29
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`E. A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER .......................................29
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`F. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION COMPRISES:
`FROM ABOUT 0.1% TO ABOUT 0.8% BY WEIGHT OF FENTANYL OR A
`PHARMACEUTICALLY ACCEPTABLE SALT THEREOF .............................................30
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`G. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES … FROM
`ABOUT 20% TO ABOUT 60% BY WEIGHT OF ETHANOL ............................................31
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`U.S. Patent No. 8,486,972
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`H. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES … FROM
`ABOUT 4% TO ABOUT 6% BY WEIGHT OF PROPYLENE GLYCOL ...........................31
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`I. SUBLINGUAL ADMINISTRATION TO A HUMAN ..........................................................34
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`J. SAID SUBLINGUAL FENTANYL FORMULATION PROVIDES A MEAN TIME
`TO MAXIMUM PLASMA CONCENTRATION (TMAX) OF FENTANYL OF
`FROM ABOUT 5 TO ABOUT 120 MINUTES .....................................................................34
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`3. DEPENDENT CLAIM 3 ......................................................................................................37
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`A. AFTER SUBLINGUAL ADMINISTRATION TO A HUMAN, THE
`SUBLINGUAL FENTANYL FORMULATION PROVIDES A MEAN TIME TO
`MAXIMUM PLASMA CONCENTRATION (TMAX) OF FENTANYL OF FROM
`ABOUT 10 TO ABOUT 60 MINUTES. ................................................................................38
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`B. GROUND 2 -- CLAIM 2 IS UNPATENTABLE AS OBVIOUS OVER
`ROSS_GB, IN VIEW OF ROSS_US2006, THE ‘862 PATENT, AND THE ‘496
`PUBLICATION ....................................................................................................................40
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`1. DEPENDENT CLAIM 2......................................................................................................40
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`2. THE PRIOR ART AND ITS COMPARISON TO CLAIM 2 ..........................................40
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`A. SAID DISCRETE LIQUID DROPLETS HAVE A SIZE DISTRIBUTION OF
`FROM ABOUT 10 µM TO ABOUT 200 µM. .......................................................................41
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`C. THE PATENT OWNER’S ARGUMENT FOR SECONDARY
`CONSIDERATIONS SET FORTH IN THE PROSECUTION FILE HISTORY
`ARE MISLEADING AND WRONG ..................................................................................43
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`1. PATENT OWNER’S ARGUMENT FOR SECONDARY CONSIDERATIONS
`IS NOT COMMENSURATE WITH THE SCOPE OF THE CLAIMS ........................44
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`2. A FAST ONSET OF FIVE MINUTES WAS NOT UNEXPECTED BECAUSE
`A COMMERCIAL FENTANYL NASAL SPRAY ACHIEVED A FIVE
`MINUTES ONSET EFFECT ..............................................................................................47
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`3. A FAST ONSET OF FIVE MINUTES WAS NOT UNEXPECTED BECAUSE
`OTHER PRIOR ART REFERENCES REPORTED EFFICACIOUS PAIN
`RELIEF AT FIVE MINUTES OR LESS ...........................................................................50
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`4. A PRIOR ART FENTANYL NASAL SPRAY ACHIEVED A BLOOD
`CONCENTRATION FIVE MINUTES POST ADMINISTRATION THAT
`WAS HIGHER THAN THE CONCENTRATION OF THE CLAIMED
`INVENTION WITH THE SAME DOSAGE .....................................................................53
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`VII. CONCLUSION ......................................................................................................................55
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`U.S. Patent No. 8,486,972
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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) .................................... 26, 27
`In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 U.S. App. LEXIS 1699,
`Slip. Op. at 21 (Fed. Cir. Feb. 4, 2015). ................................................................. 23
` Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012),
`cert denied, 133 S. Ct. 1736 (2013)). ..................................................................... 27
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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) ................................................................................................ 23
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`U.S. Patent No. 8,486,972
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`Coalition For Affordable Drugs XI LLC ("CFAD" or "Petitioner") requests
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`inter partes review of claims 1 - 3 of U.S. Patent No. 8,486,972 ("the '972 Patent")
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`(Exhibit 1001) assigned to Insys Pharma, Inc. (“Insys”).
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`NOTICE OF LEAD AND BACKUP COUNSEL
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`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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`
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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.
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`(“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”).
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`The RPI hereby certify the following information: CFAD is a wholly owned
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`U.S. Patent No. 8,486,972
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`subsidiary of Credes. Credes is a limited partnership. HOF is a segregated portfolio
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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
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`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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`U.S. Patent No. 8,486,972
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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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`(“IPR”) of U.S. Patent No. 8,835,459 (Case No. Unassigned); and a concurrently
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`filed Petition for IPR of U.S. Patent No. 8,835,460 (Case No. Unassigned). To
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`the best of Petitioner’s knowledge, there are no pending litigations or other
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`related matters related to the ’972 patent that would affect, or be affected by, a
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`decision in this 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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`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 1-3 of the ‘972 patent in this Petition:
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`U.S. Patent No. 8,486,972
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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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`‘972 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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`January 25, 2006, the earliest effective filing date for the claims of
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`the ‘972 patent.
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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 ‘972 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 January 25, 2006, the earliest effective
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`filing date for the claims of the ‘972 patent.
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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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`the ‘972 patent under at least 35 U.S.C. § 102(e) (pre-AIA) because it
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`was filed on September 12, 2005, prior to January 25, 2006, the
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`U.S. Patent No. 8,486,972
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`earliest effective filing date for the claims of the ‘972 patent.
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`4. United States Patent Publication 2002/0055496 by Randall McCoy et
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`al. entitled “Formulation and System For Intra-oral Delivery Of
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`Pharmaceutical Agents,” published May 9, 2002 (“the ‘496
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`publication,” Exhibit 1006). The ‘496 publication is prior art to the
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`‘972 patent under at least 35 U.S.C. § 102(b) (pre-AIA) because it
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`was published on May 9, 2002, more than one year prior to January
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`25, 2006, the earliest effective filing date for the claims of the ‘972
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`patent.
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`Petitioner requests that claims 1-3 of the '972 patent be held unpatentable
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`based on the following grounds:
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`Ground 1. Claims 1 and 3 are unpatentable as obvious over Ross_GB, in
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`view of Ross_US2006, and the ’862 patent. See 35 U.S.C. § 103(a).1 The ‘862
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`patent was not before the Examiner during the prosecution of the application that
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`led to the ‘972 patent.
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`1 The pre-AIA version of § 103 applies in this proceeding, because the ‘972 Patent
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`has an effective filing and issue date before March 16, 2013. The ‘972 patent
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`claims a priority date of January 25, 2006.
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`U.S. Patent No. 8,486,972
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`Ground 2. Claim 2 is unpatentable as obvious over Ross_GB, in view of
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`Ross_US2006, the ‘862 patent, and the ‘496 publication. The ‘496 publication was
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`not cited by the Examiner as basis for rejection during the prosecution of the
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`application that led to the ‘972 patent. See 35 U.S.C. § 103(a).
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`THRESHOLD REQUIREMENT FOR INT ER PA R T ES REVIEW
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`A petition for inter partes review must demonstrate "a reasonable
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`likelihood that the petitioner would prevail with respect to at least one of the
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`claims challenged in the petition." 35 U.S.C. § 314(a). This Petition meets that
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`threshold. All of the elements of claims 1-3 of the '972 Patent are taught or
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`suggested in the prior art, as explained below in the proposed grounds of
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`unpatentability. The reasons to combine the cited references, where applicable,
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`are established under 35 U.S.C. § 103(a). This Petition is supported by the
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`Declaration of Dr. Park (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 1-3 of the ’972 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 ‘972 patent is directed to a sublingual liquid fentanyl formulation. As
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`described herein each element of the claims is clearly taught by the prior art.
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`U.S. Patent No. 8,486,972
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`During the prosecution of the ‘972 patent, after several rejections of obviousness,
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`the patentee argued that unexpected advantages rebutted the prima facie case of
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`obviousness made by the Examiner. The Applicants submitted a Declaration
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`allegedly showing unexpected results (rapid onset of effect) over the prior art. The
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`Examiner accepted the conclusion of the Declaration and allowed the claims.
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`However, as described below, there were no unexpected results so the claims
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`are obvious. The Applicants’ Declaration was not consistent with the scope of the
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`claims, it misinterpreted data from prior art references, and failed to consider a
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`number of more relevant references that contradict the notion that “rapid onset of
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`effect” was unexpected or surprising.
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`Accordingly, the claims of the ‘972 patent are obvious over the prior art and
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`there is no objective evidence of non-obviousness.
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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 ‘972 patent) can cost up to $300 per day per patient.2 The
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`2 See e.g., Exhibit 1030, Fallon community Health Plan, Prior Authorization
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`Approval Criteria, Subsys (fentanyl sublingual spray), 3/14/2012; Exhibit 1031,
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`Subsys Manufacturing/Pricing – Good RX, 2015; and Exhibit 1032, Subsys
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`Manufacture/Pricing – Epocrates Online, 2015.
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`U.S. Patent No. 8,486,972
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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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`‘972 patent.
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`II. THE CLAIMS UNDER CONSIDERATION
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`1.
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`A unit dose of a non-propellant sublingual fentanyl formulation
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`comprising discrete liquid droplets of an effective amount of fentanyl and a
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`pharmaceutically acceptable liquid carrier, wherein the sublingual fentanyl
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`formulation comprises:
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`from about 0.1% to about 0.8% by weight of fentanyl or a pharmaceutically
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`acceptable salt thereof;
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`from about 20% to about 60% by weight of ethanol; and from about 4% to
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`about 6% by weight of propylene glycol;
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`wherein after sublingual administration to a human, said sublingual fentanyl
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`formulation provides a mean time to maximum plasma concentration (Tmax)
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`of fentanyl of from about 5 to about 120 minutes.
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`2.
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`The unit dose of claim 1, wherein said discrete liquid droplets have a
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`size distribution of from about 10 μm to about 200 μm.
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`3.
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`The unit dose of claim 1 wherein after sublingual administration to a
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`human, the sublingual fentanyl formulation provides a mean time to
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`maximum plasma concentration (Tmax) of fentanyl of from about 10 to about
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`60 minutes.
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`U.S. Patent No. 8,486,972
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`III. THE ‘972 PATENT AND PROSECUTION HISTORY OF THE '972
`PATENT
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`A. The '972 Patent
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`The ‘972 patent is directed to non-propellant sublingual fentanyl
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`formulations, which include discrete liquid droplets. The claimed formulations
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`recite specific amounts by weight of fentanyl, ethanol and propylene glycol. The
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`claims also recite that when administered sublingually to a human, the formulation
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`provides a mean time to maximum plasma concentration of fentanyl (Tmax) within
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`a certain range.3 Claim 1 is as follows:
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`1. A unit dose of a non-propellant sublingual fentanyl formulation
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`comprising discrete liquid droplets of an effective amount of fentanyl
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`and a pharmaceutically acceptable liquid carrier, wherein the
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`sublingual fentanyl formulation comprises:
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`from about 0.1% to about 0.8% by weight of fentanyl or a
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`pharmaceutically acceptable salt thereof;
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`from about 20% to about 60% by weight of ethanol; and from about
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`4% to about 6% by weight of propylene glycol;
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`3 Exhibit 1001, the ‘972 patent, claim 1.
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`U.S. Patent No. 8,486,972
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`wherein after sublingual administration to a human, said sublingual
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`fentanyl formulation provides a mean time to maximum plasma
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`concentration (Tmax) of fentanyl from about 5 to about 120 minutes.
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`
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`The formulation of claim 1 contains three recited components: fentanyl;
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`ethanol; and propylene glycol. Fentanyl is a μ-opioid receptor agonist with
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`analgesic potency approximately 80-100 times that of morphine.4 Ethanol and
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`propylene glycol are both identified as organic solvents which are used to enhance
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`the solubility of fentanyl.5
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`In the prior art, fentanyl is administered by way of a number of different
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`routes including oral, parenteral, buccal, transdermal6 and intranasal.7 Orally
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`administered fentanyl is subject to first pass effect metabolism, which leaves 50%
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`or more of the fentanyl unabsorbed.8 The other forms of administration avoid or
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`decrease the first pass effect for fentanyl.9
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`4 Exhibit 1001, ‘972 patent, col. 1, ll. 12-13.
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`5 Exhibit 1001, ‘972 patent, col. 11, ll. 19-26.
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`6 Id. at col. 1, ll. 29-33.
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`7 Exhibit 1013, US Patent 8,889,176, col 2, ll. 10-16.
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`8 Exhibit 1001, ‘972 patent, col. 1, ll. 29-30.
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`9 Id. at col. 1, ll. 29-33.
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`10
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`U.S. Patent No. 8,486,972
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`Transdermal administration of fentanyl is reportedly not suitable for severe
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`pain or breakthrough pain.10 According to the Patentee, buccal administration of
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`fentanyl via transmucosal lozenge is reported to have relatively slow absorption
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`times.11 However, sublingual spray administration of fentanyl that is free of
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`propellant is reported to provide rapid onset of therapeutic effect.12 In addition,
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`oral transmucosal administration of fentanyl is reported as providing rapid onset of
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`effect in as low as five minutes after dosing.13
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`B.
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`The Prosecution History Of The '972 Patent
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`The ‘972 patent has a lengthy and involved prosecution history. The ‘972 patent
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`was filed on January 25, 2007 and claims benefit of U.S. provisional application
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`No. 60/763,057 filed on January 25, 2006. The original claims were amended a
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`number of times during the prosecution and ultimately cancelled in favor of a new
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`10 Exhibit 1013 US Patent 8,889,176, col 1, ll. 50-55.
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`11 Id. at col 1, ll. 58-64.
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`12 Exhibit 1003, GB2399286A, Ross_GB, page 3, ll. 29-33.
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`13 See e.g. Exhibit 1010, Peng_1999, page 587, left column, ¶ 3; Exhibit 1011,
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`Mercadante_1999, page 2, ¶ 5; Exhibit 1012, Lichtor_1999, page 736, right
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`column, ¶ 1.
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`U.S. Patent No. 8,486,972
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`set of claims introduced by way of an RCE. For the sake of completeness a
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`summary of the history of the first set of claims is as follows.
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`
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`First, in response to a Restriction dated March 10, 2010, claim 1 was
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`amended to recite the limitation of claim 9 which introduced a plasma
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`concentration range into claim 1 (the only independent claim not withdrawn).14 A
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`Non-Final Office Action issued on June 9, 2010 provisionally rejecting the claims
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`on the ground of nonstatutory obviousness-type double patenting.15 In response,
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`Applicants argued that the rejection should be withdrawn since it was the only
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`rejection pending.16
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`
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`A second Non-Final Office Action issued on September 15, 2010 rejecting
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`the claims as anticipated by US20030190290 to Ross17 (“Ross_US 2003”).18
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`Applicants argued that Ross US 2003 did not necessarily teach “droplets having a
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`14 Exhibit 1017, Response to Restriction dated April 12, 2010.
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`15 Exhibit 1018, Non-Final Rejection dated June 9, 2010
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`16 Exhibit 1019, Response to Non-Final Office Action dated June 21, 2010.
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`17 Exhibit 1020, US Application No. 20030190290 (“Ross_US 2003”)
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`18 Exhibit 1021, Non-Final Office Action dated September 15, 2010
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`mean diameter of at least 10 microns” as recited in the claims.19 Applicants further
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`argued that the functional limitations were actual limitations and not an intended
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`U.S. Patent No. 8,486,972
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`use.20
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`A third Non-Final Office Action issued on May 2, 2011 rejecting the claims
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`as obvious over US2006006281221 (“Ross_US2006”).22 In response, Applicants
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`argued that the claims were not obvious over Ross_US2006 without amending the
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`claims.23 A Final Rejection issued on November 17, 2011 maintaining the
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`obviousness rejection of the claims over Ross_US2006.24
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`Thereafter Applicants filed an RCE on February 17, 2012 cancelling all the
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`claims and introducing new claims 144-147.25 Claim 144, the only independent
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`claim, eventually issued as claim 1 in the ‘972 patent and is reproduced below:
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`19 Exhibit1022, Response to Non-Final Office Action dated February 15, 2011,
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`page 20-21.
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`20 Id. at p. 22.
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`21 Exhibit 1005, US Application No 20060062812 (“Ross_US2006”)
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`22 Exhibit 1023, Non-Final Rejection dated May 2, 2011
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`23 Exhibit 1024, Response to Non-final Rejection dated August 2, 2011.
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`24 Exhibit 1025, Final Rejection dated November 17, 2011.
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`25 Exhibit 1026, Amendment dated February 17, 2012.
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`U.S. Patent No. 8,486,972
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`144. (New) A unit dose of a non-propellant sublingual fentanyl
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`formulation comprising discrete liquid droplets of an effective amount
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`of fentanyl and a pharmaceutically acceptable liquid carrier, wherein
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`the sublingual fentanyl formulation comprises:
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`from about 0.1 % to about 0.8% by weight of fentanyl or a
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`pharmaceutically acceptable salt thereof;
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`from about 20% to about 60% by weight of ethanol; and
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`from about 4% to about 6% by weight of propylene glycol;
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`wherein said discrete liquid droplets have a size distribution of
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`from about 5 µm to about 500 µm, and a mean diameter of about 20
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`µm to about 200 µm;
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`wherein after sublingual administration to a human, said
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`sublingual fentanyl formulation provides:
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`a mean maximum plasma concentration (Cmax) of
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`fentanyl of from about 158 pg/mL to about 177 pg/mL per 100 µg
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`fentanyl;
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`a mean time to maximum plasma concentration (Tmax) of
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`fentanyl of fromabout 10 to about 60 minutes; and
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`a mean area under the plasma concentration time curve to
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`infinity (AUC∞)of fentanyl of from about 715 pg·hour/mL to about
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`1061 pg·hour/mL per 100 µg fentanyl.26
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`A Non-Final Office Action issued on June 8, 2012 again rejecting the claims as
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`obvious over Ross_US2006.27 The rejection indicated that Ross_US2006 did not
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`26 Id.
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`U.S. Patent No. 8,486,972
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`specifically teach the recited droplet size, the specific weight of propylene glycol,
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`or mean Cmax, but concluded that the broad teaching of Ross_US2006 cured the
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`deficiencies.28
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`Applicants responded by amending the claim to delete the droplet size
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`limitation, the Cmax limitation, and AUC∞ limitations from the claim.29 This
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`amendment left the mean time to plasma concentration (Tmax) as the only so-called
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`“functional limitation” in the claim. The claim was, after the amendment, in the
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`form that it would ultimately be allowed. Applicants argued that Ross_US2006
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`failed to recognize propylene glycol as a result-effective variable.30 Applicants
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`further argued unexpected results of the claimed formulation and submitted the
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`“Dillaha Declaration” Exh.1015 in support of the argument.31 Of particular
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`relevance, the Dillaha Declaration offered the following statements:
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`Continued from previous page
`27 Exhibit 1027, Non-Final Rejection dated June 8, 2012.
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`28 Id. at p. 5
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`29 Exhibit 1014, Amendment and Response dated October 8, 2012, pp 2, 3.
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`30 Id. at p. 6
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`31Id. at pp. 4, 6.
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`U.S. Patent No. 8,486,972
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`1) “[E]ffective treatment for pain in 5 minutes compared to 10 or 15
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`minutes or longer is significant.”32
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`2) “No marketed, competitive fentanyl product has been able to show
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`statistically significant pain relief any earlier than 10 minutes.”33
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`3) “These publications, Exhibits 1-7 described above, demonstrate
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`that the presently claimed unit dose provides effective pain relief at
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`significantly faster times than placebo or competitive fentanyl
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`products.”34
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`Dillaha ultimately concludes:
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`4) “Accordingly the presently claimed unit dose provides efficacious
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`pain relief at significantly faster times relative to other transmucosal
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`immediate release fentanyl formulations, which is both unexpected
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`and, more importantly, a distinct clinical benefit.”35
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`The Dillaha Declaration provided no new data but instead relied entirely on
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`Dillaha’s interpretation of seven publications that purportedly correspond to
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`32 Exhibit 1015, Dillaha Declaration at ¶ 4.
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`33 Id at ¶ 8.
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`34 Id. at ¶ 9.
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`35 Id. at ¶ 10
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`U.S. Patent No. 8,486,972
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`“marketed, competitive products.”36 Further, the Dillaha Declaration did not
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`compare the respective Tmax values of the products but instead compared what is
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`referred to as “1st Positive Efficacy Timepoint (minutes)”37 The only reference
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`related to plasma concentration in the Dillaha Declaration is the following:
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`Patients having breakthrough cancer pain [On SUBSYS®] begin to
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`experience statistically significant pain relief as early as 5 minutes
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`after dosing. This is consistent with the notion that the claimed dose
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`needs to have a meaningful blood concentration at about 5 minutes.38
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`No other explanation is provided to connect or correlate the Tmax to the
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`results in the publication in Exhibit B of the Dillaha Declaration. The Examiner
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`seemingly accepted the time to experience pain relief as a proxy for Tmax.
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`A Notice of Allowance issued on April 15, 2013, which provided reasons for
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`Allowance.39 First, the Examiner rejected the argument that propylene glycol was
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`established as a result-effective variable.40 Second, the Examiner stated, “the fact
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`36 Id. at ¶ 9 and Exhibit B.
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`37 Id. at Exhibit B
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`38 Id. at ¶ 7.
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`39 Exhibit 1028, Notice of Allowance dated April 15, 2013.
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`40 Id. at p. 3.
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`U.S. Patent No. 8,486,972
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`that Applicants’ formulation is effective (onset of action) 5 minutes after
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`administration, which is more rapid than any other formulation on the market (10
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`to 15 minutes at best), provides evidence that the formulation was not appreciated
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`by Ross.”41 Further, the Examiner stated, “Due to the nature of the pain being
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`treated, there was a need in the art at the time of the instant invention for a fast-
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`acting pain reliever. Until the Applicants’ invention, it does not appear that any
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`other formulations were able to act as quickly.”42
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`Applicants made Amendments after Notice of Allowance changing the Tmax
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`time range in claim 144 from 10 to about 60 minutes to 5 to about 120 minutes and
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`the opposite amendment to claim 148. The amendments were entered. The ‘972
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`patent issued on July 16, 2013.
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`During the prosecution of the ‘972 patent, Applicants argued unexpected
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`advantages to overcome a prima facie obviousness rejection. In particular,
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`Applicants argued that clinical efficacy of the claimed formulation provided
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`unexpected advantages over “placebo and all commercial transmucosal immediate
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`release fentanyl formulations . . .:”43 Applicants submitted the Declaration of Dr.
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`41 Id.
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`42 Id.
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`43 Exhibit 1014, Amendment dated 2012-10-08, p.4.
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`U.S. Patent No. 8,486,972
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`Larry Dillaha (the “Dillaha Declaration”)44 in support of such argument. While the
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`Dillaha Declaration was accepted by the Examiner to rebut a prima facie case of
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`obviousness, the Dillaha Declaration was deficient for such purpose for several
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`reasons.
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`First, the conclusion provided in the Dillaha Declaration was not
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`commensurate with the scope of the claimed invention and is therefore ineffective
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`at rebutting obviousness. Second, the Dillaha Declaration incorrectly interpreted a
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`key reference, specifically Portenoy R K et al, A multicenter, placebo-controlled,
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`double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in
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`the treatment of break