Exhibit 1002
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1002
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1002
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`In the Inter Partes Review (IPR) of
`U.S. Patent No. 8,486,972
`
`DECLARATION OF Dr. Kinam Park
`
`I, Kinam Park, do hereby declare:
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`1.
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`I am making this declaration at the request of Petitioner Coalition For
`
`
`
`
`
`
`
`Affordable Drugs XI LLC, in the matters of the Inter Partes Review (IPR) of U.S.
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`Patent No. 8,486,972 (the “’972 Patent”), as set forth in the above caption.
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`2.
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`I am being compensated for my work in this matter at the rate of
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`$600.00 per hour. My compensation in no way depends on the outcome of this
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`proceeding.
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`A. Education and Professional Background
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`3.
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`I am currently the Showalter Distinguished Professor of Biomedical
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`Engineering and Professor of Pharmaceutics at Purdue University.
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`4.
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`I have a Ph.D. in Pharmaceutics from the University of Wisconsin at
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`Madison, Wisconsin. I also completed post-doctoral training in Chemical
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`Engineering at the University of Wisconsin at Madison, Wisconsin.
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`5.
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`I began my independent research since 1986 when I became an
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`Assistant Professor at Purdue University. My research focus has been developing
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`various delivery systems for controlled drug delivery applications. I have served
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`
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`on many scientific advisory boards and journal editorial boards. I have been the
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`Editor-in-Chief of the Journal of Controlled Release since 2005. Details of these
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`and other positions are listed on my curriculum vitae. I'm an inventor on 18 U.S.
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`Patents and have published over 250 papers in multiple peer-reviewed scientific
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`journals.
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`6.
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`I have experience in drug delivery systems, including polymer
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`micelles (for delivery of poorly soluble drugs) and oral formulations (fast-
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`dissolving tablets & gastric retention devices using smart polymers & hydrogels),
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`drug-device combinations such as drug-eluting stents, and microparticles for long-
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`term drug delivery.
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`7.
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`A copy of my curriculum vitae is submitted herewith as Attachment
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`A to this Declaration.
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`B. Materials Considered
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`8. The list of materials I considered in forming the opinions set forth in this
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`declaration includes the ’972 Patent, the file history of ’972 Patent, the Petition for
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`Inter Partes Reviews of the ’972 Patent, and the prior art including i) Great Britain
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`patent publication GB2399286A by Calvin John Ross et al, entitled “Sub-lingual
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`fentanyl formulation.” published September 15, 2004 (“Ross_GB,” Exhibit 1003),
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`ii) United States Patent 5,370,862 by Karin Klokkers-Bethke et al., entitled
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`“Pharmaceutical hydrophilic spray containing nitroglycerin for treating angina,”
`
`
`
`2
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`
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`issued December 6, 1994 (“the ‘862 patent,” Exhibit 1004), iii) United States
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`Patent Application Publication 2006/0062812 by Calvin John Ross et al. entitled
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`“Novel compositions,” published March 23, 2006 (“Ross_US2006,” Exhibit 1005),
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`iv) United States Patent Publication 2002/0055496 by Randall McCoy et al.
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`entitled “Formulation and System For Intra-oral Delivery Of Pharmaceutical
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`Agents,” published May 9, 2002 (“the ‘496 publication,” Exhibit 1006), v) Exhibit
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`1008, Portenoy R K et al, A multicenter, placebo-controlled, double-blind,
`
`multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment
`
`of breakthrough cancer pain, 151 Pain 617 (2010), vi) Exhibit 1010, P. W. H.
`
`Peng et al., A Review of the Use of Fentanyl Analgesia in the Management of Acute
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`Pain in Adults, Anesthesiology. 1999 Feb; 90(2):576-99 at p. 587, vii) Exhibit
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`1011, Sebastiano Mercadante and Fabio Fulfaro, Alternatives to Oral Opioids for
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`Cancer Pain, Oncology, February 01, 1999, viii) Exhibit 1012, J. Lance Lichtor et
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`al., The Relative Potency of Oral Transmucosal Fentanyl Citrate Compared with
`
`Intravenous Morphine in the Treatment of Moderate to Severe Postoperative Pain,
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`Anesth Analg 1999; 89:732–8 at p. 736, ix) Exhibit 1016, US Patent Application
`
`No. 20030178031 at paragraph [0360], and x) Exhibit 1009, NDA_Subsys,
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`Clinical review, pages 62-3, Table 19, xi) Exhibit 1013, U.S. Patent No. 8,889,176
`
`(“the ‘176 Patent”).
`
`C. Legal Standards
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`
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`
`
`3
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`
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`9.
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`In my opinion, given the disclosure of the ’972 Patent, I consider a
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`person of ordinary skill in the art at the time of filing of the patent to be someone
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`who holds a B.S. degree in pharmacy, chemistry, engineering, or related fields
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`with several years of experience, or a Ph.D. degree in the same fields, and is a
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`highly trained formulation chemist, well-versed in developing formulations from
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`experience with drug formulations in an industrial or academic environment. I met
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`or exceeded the requirements for one of ordinary skill in the art at the time of the
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`invention of the ’972 Patent and continue to meet and/or exceed those
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`requirements.
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`10.
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`I have been told that the obviousness inquiry is a question of law
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`based on four factual predicates: (1) "the scope and content of the prior art," (2)
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`the "differences between the prior art and the claims at issue," (3) "the level of
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`ordinary skill in the pertinent art," and (4) "secondary considerations" such as
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`"commercial success, long felt but unsolved needs, failure of others, etc. I have
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`also been told that the combination of familiar elements according to known
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`methods is likely to be obvious when it does no more than yield predictable
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`results.
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`I have also been told that the motivation to combine may be found in many
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`different places and forms. Thus, for example, a challenger is not limited to the
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`same motivation that the patentee had.
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`
`
`4
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`
`
`D. Background and the ’972 Patent
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`11. The '972 Patent is directed to non-propellant sublingual fentanyl
`
`formulation comprising discrete liquid droplets. The claims recite fentanyl
`
`formulations having specific amounts of fentanyl, ethanol and propylene glycol by
`
`weight. The claims also recite that the formulation provides a mean time to
`
`maximum plasma concentration of fentanyl (Tmax) within a certain range after
`
`sublingual administration to a person.1 Claim 1 recites:
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`1. A unit dose of a non-propellant sublingual fentanyl formulation
`
`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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`wherein after sublingual administration to a human, said sublingual
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`fentanyl formulation provides a mean time to maximum plasma
`
`concentration (Tmax) of fentanyl from about 5 to about 120 minutes.
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`
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`
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`1 Exhibit 1001, the ‘972 patent, claim 1.
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`
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`5
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`
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`The formulation of claim 1 includes three ingredients: fentanyl; ethanol; and
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`propylene glycol. Fentanyl is a µ-opioid receptor agonist with an analgesic
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`potency that is approximately 80-100 times than the potency of morphine.2 Both
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`ethanol and propylene glycol are described as organic solvents, which are used to
`
`enhance the solubility of fentanyl.3
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`12.
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`In the prior art, fentanyl was known to be administered in different
`
`ways including oral, parenteral, buccal, transdermal4 and intranasal.5 Orally
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`administered fentanyl is subject to first pass effect metabolism, which leaves 50%
`
`or more of the fentanyl unabsorbed.6 The other forms of administration avoid or
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`decrease the first pass effect for fentanyl.7
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`Transdermal administration of fentanyl is not suitable for severe pain or
`
`breakthrough pain.8 According to the Patentee, buccal administration of fentanyl
`
`
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`2 Exhibit 1001, ‘972 patent, col. 1, ll. 12-13.
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`3 Exhibit 1001, ‘972 patent, col. 11, ll. 19-26.
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`4 Id. at col. 1, ll. 29-33.
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`5 Exhibit 1013, US Patent 8,889,176, col 1, ll. 32-40.
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`6 Exhibit 1001, ‘972 patent, col. 1, ll. 29-30.
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`7 Id. at col. 1, ll. 29-33.
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`8 Exhibit 1013 US Patent 8,889,176, col 1, ll. 50-55.
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`
`
`6
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`
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`via transmucosal lozenge is reported to have relatively slow absorption times.9
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`However, sublingual spray administration of fentanyl that is free of propellant is
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`reported to provide rapid onset of therapeutic effect.10 In addition, intranasal
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`administration of fentanyl is reported as providing rapid onset of effect in as low as
`
`5 minutes after dosing.11
`
`
`
`
`
`E. Claim Construction
`
`
`13.
`
`I understand that the claims in an IPR proceeding are construed in
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`accordance with the broadest reasonable construction consistent with the
`
`specification.
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`14.
`
` I have been told that claim phrase “mean time to maximum plasma
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`concentration (Tmax) of fentanyl of from about 5 to about 120 minutes” is properly
`
`construed to mean that the “average time to achieve the maximum concentration of
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`fentanyl in a patient’s plasma is from about 5 to about 120 minutes.” I agree with
`
`
`
`9 Id. at col 1, ll. 58-64.
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`10 Exhibit 1003, Ross_GB, GB2399286A, page 3, lines 29-33.
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`11 Exhibit 1008 Portenoy R K et al, A multicenter, placebo-controlled, double-
`
`blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the
`
`treatment of breakthrough cancer pain, 151 Pain 617 (2010) at pp 620-621.
`
`
`
`7
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`
`
`this construction because it is consistent with the broadest reasonable construction
`
`as understood by one of ordinary skill in the art.
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`I have been told that the claim phrase “discrete liquid droplet” broadest
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`reasonable construction must be construed as meaning, “water or other liquid
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`broken up into minute droplets and blown, ejected into, or falling through the air.”
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`I agree with this construction because it is consistent with the broadest reasonable
`
`construction as understood by one of ordinary skill in the art.
`
`F. Claim 1 is unpatentable as obvious over Ross_GB, in view of
`Ross_US2006, and the ’862 patent
`
`15.
`
`It is my opinion that claim 1 of the ‘972 patent would have been
`
`obvious to one of ordinary skill in the art in light of the teachings of Ross_GB,
`
`the ‘862 patent, and Ross_US2006 for the reasons explained in detail below.
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`a. sublingual fentanyl formulation comprising discrete liquid droplets
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`16. Ross_GB teaches a “pharmaceutical formulation comprising (i)
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`fentanyl.”12 Ross_GB further teaches that its fentanyl formulation is “preferably
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`administered sublingually as a spray. The formulations are well tolerated when
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`administered to the sensitive sublingual mucosa and the sublingual spray
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`administration will result in rapid onset of the therapeutic effect of the fentanyl.”13
`
`
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`12 Exhibit 1003, Ross_GB, Abstract.
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`13 Id. at page 3, ll. 29-33 (emphasis added).
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`
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`8
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`
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`Moreover, one of ordinary skill in the art as of the alleged effective filing date of the
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`’972 patent (i.e., January 25, 2006) would have understood that the spray disclosed
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`in Ross_GB comprises discrete liquid droplets. For example, a spray was defined
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`prior to the alleged effective filing date of the ‘972 patent as having discrete liquid
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`droplets: “water or other liquid broken up into minute droplets and blown, ejected
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`into, or falling through the air.”14
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`Accordingly, it is my opinion that the claimed “sublingual fentanyl
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`formulation comprising discrete liquid droplets” would have been obvious over the
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`teachings of Ross_GB.
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`b. unit dose
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`17. Ross_GB teaches a unit dose of the fentanyl formulation: “single or
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`multiple use devices comprising a single or multiple dose of the formulation of the
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`invention is envisaged.”15
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`c. non-propellant
`18. Ross_GB teaches that “[t]he [fentanyl] formulations of the present
`
`
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`14 Exhibit 1007, Random House Webster’s College Dictionary, Random House,
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`Inc., April, 2000, p. 1270.
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`15 Exhibit 1003, Ross_GB, page 8, ll. 25-26.
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`
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`9
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`
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`invention are also preferably free of any propellant.”16
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`d. an effective amount of fentanyl
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`19. Ross_GB teaches that “a therapeutically effective amount of a
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`[fentanyl] formulation for the treatment of pain according to the invention is
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`used.”17
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`e. a pharmaceutically acceptable liquid carrier
`20. Ross_GB teaches that the dose of the fentanyl formulation includes
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`water as a pharmaceutically acceptable liquid carrier:
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`(a) fentanyl or a pharmaceutically acceptable salt thereof;
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`(b) water as carrier; and
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`(c) a polar organic solvent in sufficient amount to enhance the solubility of the
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`fentanyl or pharmaceutically acceptable salt thereof in the water.18
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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
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`21. Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g
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`
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`16 Exhibit 1003, Ross_GB, page 4, l. 1.
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`17 Id. at page 8, ll. 10-11 (emphasis added).
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`18 Id. at page 3, ll. 21-27 (emphasis added).
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`
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`10
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`
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`fentanyl, 0.0177g saccharin, 2.8336 g ethanol, 0.0531g menthol, and 4.1516g
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`citrate buffer.19 Based on this disclosure, the fentanyl concentration is calculated
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`to be 0.028g fentanyl / (0.028g + 0.0177g + 2.8336g + 0.0531g + 4.1516g) x 100%
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`= 0.395% by weight of fentanyl, which is within the claimed range of 0.1% to
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`0.8% by weight of fentanyl.
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`g.
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`the sublingual fentanyl formulation comprises … from about 20% to about
`60% by weight of ethanol
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`22. Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g
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`fentanyl, 0.0177g saccharin, 2.8336g ethanol, 0.0531g menthol, and 4.1516g
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`citrate buffer.20 Based on this disclosure, the ethanol concentration is calculated to
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`be 2.8336g / (0.028g + 0.0177g + 2.8336g + 0.0531g + 4.1516g) x 100% = 40% by
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`weight of ethanol, which is within the claimed range of 20% to 60% by weight of
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`ethanol.
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`
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`h.
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`the sublingual fentanyl formulation comprises … from about 4% to about
`6% by weight of propylene glycol
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`23. Ross_GB teaches that its sublingual fentanyl formulation comprises
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`propylene glycol:
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`
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`19 Id. at page 11, ll. 1-9.
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`20 Id.
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`
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`11
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`
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`Examples of polar organic solvents that may be used to enhance the
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`solubility of fentanyl, or the physiologically acceptable salt thereof in
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`the water, include: lower alcohols (e.g. C2.4 alcohols) such as ethanol;
`lower polyols (e.g. C2-4 polyols) such as glycerol and propylene
`glycol.21
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`Moreover, Ross_GB mentions a second time that its fentanyl formulation includes
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`propylene glycol: “[s]uitable moisturizing agents include, for example, the polar
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`organic solvents such as glycols, especially propylene glycol.”22
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`In addition, the ‘862 patent teaches a buccal spray comprising propylene
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`glycol in a broad range of 2% to 30% by weight.23 The range of propylene glycol
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`taught by the ‘862 patent encompasses the claimed range of about 4% to about 6%
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`by weight of propylene glycol. Moreover, the ‘862 patent also teaches a buccal
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`spray comprising propylene glycol of 7.28% by weight.24 This percentage of
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`propylene glycol meets the upper bound of the range recited in claim 1 of the ‘972
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`patent as about 6% of propylene glycol.
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`24.
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`It would have been obvious to use the range of propylene glycol by
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`
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`21 Exhibit 1003, Ross_GB, page 5, ll. 1-4 (emphasis added).
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`22 Id. at page 7, ll. 11-14 (emphasis added).
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`23 Exhibit 1004, the ’862 patent, col. 4, l. 63.
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`24 Id. at col. 4, line 47.
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`
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`12
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`
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`weight that is taught by the ‘862 patent in the fentanyl formulation taught by
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`Ross_GB because Ross_GB specifically calls for an amount of polar organic
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`solvent to “enhance the solubility of fentanyl . . .”25 Ross_GB indicates that “the
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`formulations are well tolerated when administered to sensitive sublingual mucosa
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`and the sublingual spray administration will result in rapid onset of the therapeutic
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`effect of fentanyl”26 and specifically identifies propylene glycol. One skilled in the
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`art would look to the teaching of the ‘862 patent as it is a buccal spray for the
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`administration of a medication that is “used in emergencies when the medication
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`should be fast acting.”27 One skilled in the art would adjust and optimize the amount
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`of propylene glycol to account for the solubility of the drug substance as a matter of
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`routine. Accordingly it would be obvious to arrive at the claimed range based on the
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`teachings of Ross_GB in combination with the ‘862 patent.
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`
`
`i.
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`sublingual administration to a human
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`25. Ross_GB teaches administration of “formulations of fentanyl,
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`
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`25 Exhibit 1003, Ross_GB, page 3, ll. 26-27.
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`26 Id. at ll. 30-32
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`27 Exhibit 1004, the ’862 patent, col. 1 ll. 19-20.
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`
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`13
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`
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`especially pump spray formulations suitable for sublingual delivery”28 and “the
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`formulations of the invention are preferably administered sublingually as a spray.”29
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`Ross_GB further teaches “monitor[ing] patients for evidence of self medication.”30
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`Because only people can self-medicate, the sublingual administration taught by
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`Ross_GB is to a human, as required by this claim limitation.
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`
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`j.
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`said sublingual fentanyl formulation provides a mean time to maximum
`plasma concentration (Tmax) of fentanyl of from about 5 to about 120
`minutes
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`26. Ross_US teaches in Table 2 a median time to maximum plasma
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`concentration (Tmax) of 0.5 hours (30 minutes) with a range between 0.333 and 0.833
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`hours (20 minutes and 50 minutes, respectively) following sublingual administration
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`of 200 microgram (mcg or µg) of fentanyl with a non-pressurized pump spray
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`device to 12 patients.31 Table 2 of Ross_US also teaches a mean time to maximum
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`plasma concentration (Tmax) of 0.486 hours (about 29 minutes) following sublingual
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`administration of 200 microgram of fentanyl with a non-pressurized pump spray
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`
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`28 Exhibit 1003, Ross_GB, page 1, ll. 3-4.
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`29 Id. at page 3, ll. 29-30
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`30 Id. at page 1, line 15.
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`31 Exhibit 1005, Ross_US2006, page 8, Table 2.
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`
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`14
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`
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`device to 12 patients.32 A mean Tmax of 29 minutes is within the claimed range of
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`“about 5 minutes to about 120 minutes.”
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`27.
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`It would have been obvious to have a sublingual fentanyl formulation
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`providing a mean time to maximum plasma concentration (Tmax) of fentanyl of from
`
`about 5 to about 120 minutes in light of the teachings of Ross_US2006 and
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`Ross_GB. The fentanyl formulations taught by Ross_US2006 and Ross_GB are
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`very similar. The data in Table 2 of Ross_US2006 was obtained from Formulation
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`2 in which the Fentanyl Base is 0.011g, Ethanol is 2.2319g, Menthol is 0.0417g,
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`Citrate buffer is 3.2675g, and Saccharin is 0.0139g.33 This gives a composition by
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`weight of 0.2% fentanyl, 40.1% ethanol, 0.75% menthol, 58.7% citrate buffer, and
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`0.25% saccharin.
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`The formulation of Example 1 of Ross-GB includes 0.028g fentanyl,
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`0.0177g saccharin, 2.8336 g ethanol, 0.0531g menthol, and 4.1516g citrate
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`buffer.34 This gives a composition by weight of 0.4% fentanyl, 0.25% saccharin,
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`40% ethanol, 0.75% menthol, and 58.6% citrate buffer.
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`28.
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`In light of the similarities between the fentanyl formulations taught by
`
`
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`32 Id.
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`33 Id., Formulation 2, page 7, ¶ [0115].
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`34 Exhibit 1003, Ross_GB, Example 1, page 11, ll. 1-9.
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`
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`15
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`
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`Ross_US2006 and Ross_GB, one of ordinary skill in the art would have been
`
`motivated to combine the teachings of Ross_US2006 and Ross_GB. Moreover,
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`one important aspect of the administration of a drug is how long it takes to achieve
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`the maximum (or peak) drug concentration in the plasma within the patient’s body
`
`(Tmax). Both Ross_GB and ROSS-US2006 teach fentanyl formulations that are
`
`similar to each other as well as the claimed formulation of the ‘972 patent.
`
`Accordingly, one of ordinary skill in the art would have been motivated to
`
`combine the fentanyl teachings of Ross_US2006 and Ross_GB to achieve a shorter
`
`Tmax for the administration of a drug so that the patient would more quickly
`
`experience the effects of the drug.
`
`G. Claim 3 is unpatentable as obvious over Ross_GB, in view of
`Ross_US2006, and the ’862 patent.
`
`29.
`
`It is my opinion that claim 3 of the ‘972 patent would have been
`
`obvious to one of ordinary skill in the art in light of the teachings of Ross_GB,
`
`the ‘862 patent, and Ross_US2006 for the reasons explained in detail below.
`
`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.
`
`
`30. Ross_US2006 teaches in Table 2 a median time to maximum plasma
`
`concentration (Tmax) of 0.5 hours (30 minutes) with a range between 0.333 and 0.833
`
`hours (20 minutes and 50 minutes, respectively) following sublingual administration
`
`of 200 microgram of fentanyl with a non-pressurized pump spray device to 12
`
`
`
`16
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`
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`patients.35 Table 2 of Ross_US2006 also teaches a mean time to maximum plasma
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`concentration (Tmax) of 0.486 hours (about 29 minutes) following sublingual
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`administration of 200 microgram of fentanyl with a non-pressurized pump spray
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`device to 12 patients.36 A mean time to Tmax of 29 minutes is within the range
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`recited in claim 3 of “about 10 minutes to about 60 minutes.”
`
`31.
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`It would have been obvious to have a sublingual fentanyl formulation
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`providing a mean time to maximum plasma concentration (Tmax) of fentanyl of from
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`about 10 to about 60 minutes in light of the teachings of Ross_US2006 and
`
`Ross_GB. The fentanyl formulations taught by Ross_US2006 and Ross_GB are
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`very similar. In light of the similarities between the fentanyl formulations taught
`
`by Ross_US2006 and Ross_GB, one of ordinary skill in the art would have been
`
`motivated to combine the teachings of Ross_US2006 and Ross_GB.
`
`Moreover, one of ordinary skill in the art would have been motivated to
`
`combine the fentanyl teachings of Ross_US2006 and Ross_GB to achieve a shorter
`
`Tmax for the administration of a drug so that the patient would more quickly
`
`experience the effects of the drug.
`
`
`
`
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`35 Exhibit 1005, Ross_US2006, page 8, Table 2.
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`36 Id.
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`
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`17
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`
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`H. Claim 2 is unpatentable as obvious over Ross_GB, in view of
`Ross_US2006, the ‘862 Patent, and the ‘496 Publication.
`
`32.
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`It is my opinion that claim 2 of the ‘972 patent would have been
`
`obvious to one of ordinary skill in the art in light of the teachings of Ross_GB,
`
`the ‘862 patent, and Ross_US2006 and the ‘496 publication for the reasons
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`explained in detail below.
`
`a. said discrete liquid droplets have a size distribution of from about 10 µm to
`about 200 µm.
`
`
`33. Like Ross_GB and Ross_US2006, the ‘496 publication teaches a
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`fentanyl formulation: “[t]wo formulations containing fentanyl citrate were
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`prepared...”37 The ‘496 publication also teaches that its fentanyl formulation is
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`administered in liquid droplets “sized within the range of about 1 to 200 microns,
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`more preferably within the range of 10-100 microns.”38 A droplet within the
`
`preferred range of 10 to 100 microns is clearly within the range of about 10 microns
`
`to about 200 microns recited in claim 2 of the ‘972 patent.
`
`34.
`
`It would have been obvious to have a fentanyl formulation with a
`
`discrete liquid droplet size of about 10 microns to about 200 microns in light of the
`
`teachings of Ross_US2006, Ross_GB, the ‘862 patent and the ‘496 publication. The
`
`
`
`37 Exhibit 1006, ’496 publication, ¶ [0041].
`
`38 Id. at ¶ [0019].
`
`
`
`18
`
`
`
`‘496 publication, like Ross_US2006 and Ross_GB, teaches a fentanyl formulation.
`
`The ‘496 publication teaches “a decreased droplet size translates to a higher surface
`
`area to be absorbed by the mucosa of the intra-oral cavity.”39 Accordingly, one of
`
`ordinary skill in the art would have been motivated to combine the teachings of the
`
`‘496 publication with the teachings of Ross_US2006 and Ross_GB.
`
`35. Moreover, one aspect of the administration of a drug is to achieve a
`
`small droplet size so as to eliminate or decrease the discomfort felt by a patient in
`
`receiving the drug. Accordingly, one of ordinary skill in the art would have been
`
`motivated to combine the fentanyl teachings of Ross_US2006 and Ross_GB with
`
`the small droplet size of the ‘496 publication to eliminate or decrease any
`
`discomfort to the patient from administration of the drug.
`
`
`
`I. Secondary Considerations Do Not Indicate That The Claims Of
`The ‘972 Patent Are Non-Obvious.
`
`36. My review of the file history of the ‘972 patent indicates that the
`
`Applicant argued that a fast onset of the fentanyl formulation was unexpected and
`
`that this unexpected result as a secondary consideration indicates that the claims
`
`are non-obvious. It is my opinion, however, that the secondary considerations do
`
`not indicate that the claims are non-obvious because i) the patent owner’s
`
`
`
`39 Exhibit 1006, ’496 publication, ¶ [0031].
`
`
`
`19
`
`
`
`argument for secondary considerations is not commensurate with the scope of the
`
`claims of the ‘972 patent ii) a fast onset of five minutes was not unexpected
`
`because a commercial fentanyl nasal spray achieved a five minutes onset effect, iii)
`
`a fast onset of five minutes was not unexpected because other prior art references
`
`reported efficacious pain relief at five minutes, and iv) 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.
`
`a. Patent owner’s argument for secondary considerations is not
`commensurate with the scope of the claims of the ‘972 patent
`
`
`37. Patent Owner’s argument of an unexpected result of time of onset of
`
`therapeutic effect of five minutes as a secondary consideration of nonobviousness is
`
`not commensurate with the scope of the claims. First, none of the claims recite a
`
`time for onset of therapeutic effect of five minutes. The Dillaha Declaration, which
`
`was submitted by the Patent Owner in support of its argument for non-obviousness,
`
`does not establish a relationship between the alleged onset of therapeutic effect of
`
`five minutes and the claimed “mean time to maximum plasma concentration (Tmax).
`
`Further, the Patent Owner failed to establish that the alleged onset of therepeutic
`
`effect of five minutes occurs across the entire range of the recited concentrations of
`
`fentanyl, ethanol, and propylene glycol in the claims.
`
`38. Further, the Dillaha Declaration considered only the low end of the
`
`recited Tmax time range (5-10 minutes); it did not consider the entire claimed time
`
`
`
`20
`
`
`
`range, i.e. “about 5 to about 120 minutes”. For example, there is nothing in the
`
`Dillaha Declaration to establish that the alleged five minute onset of therapeutic
`
`effect would occur if the Tmax was 120 minutes or even close to it. Also, contrary to
`
`the argument set forth in the Dillaha declaration, the data contained in the
`
`declaration shows a significant overlap between the time range of the references
`
`examined therein and the claimed Tmax range.
`
`b. A fast onset of five minutes was not unexpected because a commercial
`fentanyl nasal spray achieved a five minutes onset effect
`
`39. Contrary to Patent Owner’s argument, one competing fentanyl pectin
`
`nasal spray (FPNS), Lazanda, achieved a first onset of effect at 5 minutes post
`
`administration. This rapid effect was achieved even with an average dosage much
`
`lower than Patent Owner’s fentanyl formulation called Subsys. Lazanda’s result
`
`was reported in a publication by Portenoy R K et al, entitled “A multicenter,
`
`placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal
`
`Spray (FPNS) in the treatment of breakthrough cancer pain,” 151 Pain 617 (2010)
`
`(“Portenoy,” Exhibit 1008). In particular, Portenoy reported that “[t]he mean PI
`
`(pain intensity) score for patient-averaged FPNS-treated episodes was significantly
`
`different from that for placebo-treated episodes at the 5-min time point (P = 0.03).”40
`
`
`
`40 Exhibit 1008, Portenoy R K et al, “A multicenter, placebo-controlled, double-
`
`blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the
`
`
`
`
`
`21
`
`
`
`“The analysis of patient-averaged PID (pain intensity difference) scores showed a
`
`trend in favor of Lazanda at 5 min (P = 0.07) and statistical significance from 10 min
`
`(P< 0.01) onward.”41 Based on this data, Portenoy concluded that "[a] rapid onset of
`
`effect was observed, with FPNS achieving statistically significant differences in PI 5
`
`min after dosing."42
`
`40. Dr. Dillaha cited Portenoy in his Declaration but failed to mention that
`
`Portenoy taught an onset of therapeutic effect of five minutes with Lazanda, or
`
`explain how he arrived at his conclusion concerning Portenoy. Dr. Dillaha also
`
`failed to mention or otherwise address the fact that Lazanda achieves the five
`
`minutes onset of effect using a significantly lower dose than the dose used in the
`
`study of Patent Owner’s Subsys.
`
`According to Portenoy and co-workers, a total of 73 patients completed the
`
`study with four different dose levels between 100 mcg and 800 mcg: i) 8 patients
`
`received a dose level of 100 mcg, ii) 7 patients received a dose level of 200 mcg, iii)
`
`24 patients received a dose level of 400 mcg, and iv) 34 patients received a dose
`
`
`
`treatment of breakthrough cancer pain,” 151 Pain 617, 620 (2010).
`
`41 Id.
`
`42 Id at 620-21.
`
`
`
`22
`
`
`
`level of 800 mcg).43 In Portenoy therefore, the average dose given to all 73 patients
`
`is 534 mcg (8 patients x 100 mcg + 7 patients x 200 mcg + 24 patients x 400 mcg +
`
`34 patients x 800 mcg).
`
`41.
`
`In sharp contrast, the average dose in the Subsys trial was much higher.
`
`According to the New Drug Application (NDA) package available from the FDA
`
`website, a total of 92 patients completed the Subsys clinical study with seven
`
`different dose levels between 100 mcg and 1600 mcg: i) 4 patients received a dose
`
`level of 100 mcg, ii) 6 patients received a dose level of 200 mcg, iii) 14 patients
`
`received a dose level of 400 mcg, iv) 14 patients received a dose level of 600 mcg,
`
`v) 22 patients received a dose level of 800 mcg, vi) 20 patients received a dose level
`
`of 1200 mcg, and vii) 12 patients received a does level of 1600 mcg.44 Therefore,
`
`the data in the Subsys NDA indicates that the average dose given to all 92 patients is
`
`830 mcg, which is 55.4% higher than the average dose given to the patients in the
`
`Lazanda study.
`
`42. Therefore, it was not unexpected for Subsys to achieve an onset of
`
`therapeutic effect at 5 minutes because another nasal spray fentanyl, Lazanda, had
`
`achieved statistically significant differences in PI 5 min after dosing, even though
`
`
`
`43 Id. at p. 619, Figure 1.
`
`44 Exhibit 1009, NDA_Subsys, Clinical review, pages 62-3, Table 19.
`
`
`
`23
`
`
`
`the average dosage used in the Subsys study was 55% higher than the one used in
`
`the Lazanda study.
`
`
`
`c. A fast onset of five minutes was not unexpected because other prior art
`references reported efficacious pain relief at five minutes or less
`
`43. The Dillaha Declaration considered only commercial formulations and
`
`not the closest prior art. Several prior art references show that an onset of therapeutic
`
`effect of 5 minutes for fentanyl transmucosal formulations was n
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