Exhibit 1002
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1002
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01799
`
`
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1002
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01799
`
`
`
`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. 8,835,460
`
`DECLARATION OF Dr. Kinam Park
`
`I, Kinam Park, do hereby declare:
`
`1.
`
`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.
`
`Patent No. 8,835,460 (the “’460 patent’”), as set forth in the above caption.
`
`2.
`
`I am being compensated for my work in this matter at the rate of
`
`$600.00 per hour. My compensation in no way depends on the outcome of this
`
`proceeding.
`
`A. Education and Professional Background
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`I am currently the Showalter Distinguished Professor of Biomedical
`
`3.
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`Engineering and Professor of Pharmaceutics at Purdue University.
`
`4.
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`I have a Ph.D. in Pharmaceutics from the University of Wisconsin at
`
`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
`
`A to this Declaration.
`
`B. Materials Considered
`
`
`8. The list of materials I considered in forming the opinions set forth in this
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`declaration includes1 the ’460 Patent (Exhibit 1001), the file history of ’460 Patent,
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`the Petition for Inter Partes Review of the ’460 Patent, and the prior art including i)
`
`Great Britain patent publication GB2399286A by Calvin John Ross et al, entitled
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`“Sub-lingual fentanyl formulation.” published September 15, 2004 (“Ross_GB,”
`
`Exhibit 1003), ii) United States Patent 5,370,862 by Karin Klokkers-Bethke et al.,
`
`
`
`1
`
` Exhibit numbers refer to the Exhibit numbers listed in the Petition.
`
`
`
`2
`
`
`
`entitled “Pharmaceutical hydrophilic spray containing nitroglycerin for treating
`
`angina,” issued December 6, 1994 (“the ‘862 patent,” Exhibit 1004), iii) United
`
`States Patent Publication 2002/0055496 by Randall McCoy et al. entitled
`
`“Formulation and System For Intra-oral Delivery Of Pharmaceutical Agents,”
`
`published May 9, 2002 (“the ‘496 publication,” Exhibit 1005), iv) United States
`
`Patent 6,946,150 by Brian Whittle entitled “Pharmaceutical formulation” issued
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`September 20, 2005 (“the ‘150 patent,” Exhibit 1007), v) P. W. H. Peng et al., A
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`Review of the Use of Fentanyl Analgesia in the Management of Acute Pain in
`
`Adults, Anesthesiology. 1999 Feb; 90(2):576-99 at p. 587, (Exhibit 1009), vi)
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`Sebastiano Mercadante and Fabio Fulfaro, Alternatives to Oral Opioids for Cancer
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`Pain, Oncology, February 01, 1999 (Exhibit 1010), vii) J. Lance Lichtor et al., The
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`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 (Exhibit 1011), viii) US Patent Application
`
`No. 20030178031 at paragraph [0360] (Exhibit 1016), and ix) U.S. Patent No.
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`8,889,176 (“the ‘176 Patent”) (Exhibit 1006).
`
`
`
`C. Legal Standards
`
`9.
`
`In my opinion, given the disclosure of the ’460 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
`
`
`
`3
`
`
`
`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
`
`invention of the ’460 Patent and continue to meet and/or exceed those
`
`requirements.
`
`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
`
`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
`
`results.
`
`I have also been told that the motivation to combine may be found in many
`
`different places and forms. Thus, for example, a challenger is not limited to the
`
`same motivation that the patentee had.
`
`I have been told a claim is anticipated only if each and every element as set
`
`forth in the claim is found, either expressly or inherently described, in a single
`
`prior art reference. Further, I have been told if the prior art discloses its own range,
`
`
`
`4
`
`
`
`rather than a specific point, then the prior art is only anticipatory if it describes the
`
`claimed range with sufficient specificity such that a reasonable fact finder could
`
`conclude that there is no reasonable difference in how the invention operates over
`
`the ranges.
`
`
`
`D. Background and the ’460 Patent
`
`11. The ‘460 patent is directed to sublingual fentanyl formulations, a
`
`multi-dose device for administering a sublingual fentanyl formulation, and a
`
`method of treating pain using the sublingual fentanyl formulation. The common
`
`feature of the four independent claims is that each recites a fentanyl formulation
`
`comprising discrete liquid droplets (claims 1, 2 and 3) or a multi-dose device
`
`capable of delivering a fentanyl formulation in the form of liquid droplets (claim
`
`4). The discrete liquid droplets have a mean diameter of from about 30 to about 70
`
`microns in independent claims 1 and 4 and at least about 10 microns in
`
`independent claims 2 and 3. In addition, independent claims 2 and 3 recite specific
`
`amounts by weight of fentanyl, ethanol and propylene glycol.
`
`The sublingual formulation of the independent claims (except for claim 1)
`
`contains three recited components: fentanyl2; ethanol; and propylene glycol.
`
`
`
`2
`
` The claims of the ‘460 patent recite various forms of fentanyl and fentanyl
`
`derivatives. For convenience the group of fentanyl and fentanyl derivatives is
`
`
`
`
`
`5
`
`
`
`Fentanyl is a µ-opioid receptor agonist with analgesic potency approximately 80-
`
`100 times that of morphine.3 Ethanol and propylene glycol are both identified as
`
`organic solvents which are used to enhance the solubility of fentanyl.4
`
`12.
`
`In the prior art, fentanyl is administered by way of a number of
`
`different routes including oral, parenteral, buccal, transdermal5 and intranasal.6
`
`Orally administered fentanyl is subject to first-pass effect metabolism, which
`
`leaves 50% or more of the fentanyl unabsorbed.7 The other forms of
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`administration avoid or decrease the first pass effect for fentanyl.8
`
`Transdermal administration of fentanyl is reportedly not suitable for severe
`
`pain or breakthrough pain.9 Buccal administration of fentanyl via transmucosal
`
`
`
`referred to as “fentanyl” unless otherwise noted.
`
`3 Exhibit 1001, ‘460 patent, col. 1, ll. 13-14.
`
`4 Id. at col. 11, ll. 22-29.
`
`5 Id. at col. 1, ll. 30-34.
`
`6 Exhibit 1006, US Patent 8,889,176, col 2, ll. 10-16.
`
`7 Exhibit 1001, ‘460 patent, col. 1, ll. 30-31.
`
`8 Id. at col. 1, ll. 32-34.
`
`9 Exhibit 1006, US Patent 8,889,176, col 1, ll. 50-55.
`
`
`
`6
`
`
`
`lozenge is reported to have relatively slow absorption times.10 However,
`
`sublingual spray administration of fentanyl that is free of propellant is reported to
`
`provide rapid onset of therapeutic effect.11 In addition, intranasal administration of
`
`fentanyl is reported as providing rapid onset of effect in as low as 5 minutes after
`
`dosing.12
`
`
`
`E. Claim Construction
`
`I understand that the claims in an IPR proceeding are construed in
`
`13.
`
`accordance with the broadest reasonable construction consistent with the
`
`specification.
`
`14.
`
` I have been told that the phrase “discrete liquid droplets” or “liquid
`
`droplets” is properly construed to mean “water or other liquid broken up into
`
`minute droplets and blown, ejected into, or falling through the air.” I agree with
`
`this construction because it is consistent with the broadest reasonable construction
`
`as understood by one of ordinary skill in the art.
`
`
`
`10 Id. at col 1, ll. 58-64.
`
`11 Exhibit 1003, Ross_GB, GB2399286A, page 3, lines 29-33.
`
`12 See e.g. Exhibit 1010, Peng_1999, page 587, left column, ¶ 3; Exhibit 1011,
`
`Mercadante_1999, page 2, ¶ 5; Exhibit 1012, Lichtor_1999, page 736, right
`
`column, ¶ 1.
`
`
`
`7
`
`
`
`I have been told the phrase “pharmaceutically acceptable liquid carrier” is
`
`properly construed to mean “water (including aqueous buffers and saline), one or
`
`more organic solvents, or a mixture of both water and one or more organic
`
`solvents.” I agree with this construction because it is consistent with the broadest
`
`reasonable construction as understood by one of ordinary skill in the art.
`
`I have been told that claim 3 phrase “wherein the sublingual fentanyl
`
`formulation consists essentially of:” is properly construed to mean “excluding any
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`component in the fentanyl formulation, not including the pharmaceutically
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`acceptable liquid carrier, that would interfere or prevent the fentanyl formulation
`
`from the formation of droplets in the cited diameter range.” 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 the
`’496 Publication.
`
`15.
`
`It is my opinion that claim 1 of the ‘460 patent would have been
`
`obvious to one of ordinary skill in the art in light of the teachings of Ross_GB,
`
`and the ‘496 publication for the reasons explained in detail below.
`
`a. sublingual formulation comprising discrete liquid droplets
`
`16. Ross_GB teaches a “pharmaceutical formulation comprising (i)
`
`
`
`8
`
`
`
`fentanyl.”13 Ross_GB further teaches that its fentanyl formulation is “preferably
`
`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
`
`administration will result in rapid onset of the therapeutic effect of the fentanyl.”14
`
`Moreover, one of ordinary skill in the art as of the alleged effective filing date of the
`
`’460 patent (i.e., January 25, 2006) would have understood that the spray disclosed
`
`in Ross_GB comprises discrete liquid droplets. For example, a spray was defined
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`prior to the alleged effective filing date of the ‘460 patent as having discrete liquid
`
`droplets: “water or other liquid broken up into minute droplets and blown, ejected
`
`into, or falling through the air.”15
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`Accordingly, it is my opinion that the claimed “sublingual formulation
`
`comprising discrete liquid droplets” would have been obvious over the teachings of
`
`Ross_GB.
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`b. an effective amount of fentanyl or a fentanyl derivative selected from the
`group consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free
`base or a pharmaceutically acceptable salt thereof,
`
`
`
`13 Exhibit 1003, Ross_GB, Abstract.
`
`14 Id. at p. 3, ll. 29-33 (emphasis added).
`
`15 Exhibit 1024, Random House Webster’s College Dictionary, Random House,
`
`Inc., April, 2000, p. 1270.
`
`
`
`9
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`
`
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`17. Ross_GB teaches that “a therapeutically effective amount of a
`
`[fentanyl] formulation for the treatment of pain according to the invention is
`
`used.”16
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`c. a pharmaceutically acceptable liquid carrier
`20. Ross_GB teaches that the dose of the fentanyl formulation includes
`
`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 fentanyl or pharmaceutically acceptable salt thereof in
`the water.”17
`
`d. said droplets having a mean diameter of from about 30 to about 70 microns
`
`21. Like Ross_GB, the ‘496 publication teaches a fentanyl formulation:
`
`“[t]wo formulations containing fentanyl citrate were prepared...”18 The ‘496
`
`publication also teaches that its fentanyl formulation is administered in liquid
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`droplets “sized within the range of about 1 to 200 microns, more preferably within
`
`
`
`16 Id. at page 8, ll. 10-11 (emphasis added).
`
`17 Id. at page 3, ll. 21-27 (emphasis added).
`
`18 Exhibit 1005, ’496 Publication, ¶ [0041].
`
`
`
`10
`
`
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`the range of 10-100 microns.”19 The preferred range of 10 to 100 microns
`
`encompasses the entire claimed range of about 30 microns to about 70 microns
`
`recited in claim 1 of the ‘460 patent. While the preferred range of the ‘496
`
`publication is slightly broader than the claimed range of about 30 to about 70
`
`microns, the ‘460 patent does not identify or suggest there is anything advantageous
`
`about the claimed range as compared to the preferred range of the ‘496 publication.
`
`Accordingly, it is my opinion that the claimed “said droplets having a mean
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`diameter of from about 30 to about 70 microns” would have been obvious over the
`
`teachings of the ‘496 publication.
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`22.
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`It would have been obvious to have a fentanyl formulation with a
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`discrete liquid droplet with a mean diameter of from about 30 to about 70 microns in
`
`light of the teachings of Ross_GB and the ‘496 publication. The ‘496 publication,
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`like Ross_GB, teaches a fentanyl formulation. The ‘496 publication also teaches “a
`
`decreased droplet size translates to a higher surface area to be absorbed by the
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`mucosa of the intra-oral cavity.”20 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_GB.
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`
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`19 Id. at ¶ [0019].
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`20 Exhibit 1005, ’496 Publication, ¶ [0031].
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`
`
`11
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`
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`23. Moreover, one aspect of the administration of a drug is to achieve a
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`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_GB with the small droplet
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`size of the ‘496 publication to eliminate or decrease any discomfort to the patient
`
`from administration of the drug.
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`G. Claim 4 is unpatentable as obvious over Ross_GB, in view of the
`’496 publication.
`
`24.
`
`It is my opinion that claim 4 of the ‘972 patent would have been
`
`obvious to one of ordinary skill in the art in light of the teachings of Ross_GB,
`
`and the ‘496 publication for the reasons explained in detail below.
`
`a. a multi-dose device for sublingual administration of a drug
`
`
`25. Ross_GB teaches a “single or multiple use devices comprising a single
`
`or multiple dose of the formulation of the invention is envisaged.”21 Further
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`Ross_GB teaches, “The invention relates to formulations of fentanyl, especially
`
`pump spray formulations suitable for sublingual delivery.”22
`
`
`b. a reservoir containing the liquid formulation
`
`
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`21 Exhibit 1003, Ross_GB, p. 8, ll 25-26.
`
`22 Id. at p. 1, ll. 3-4
`
`
`
`12
`
`
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`26. Ross_GB teaches, “Formulations according to the invention are
`
`preferably packaged as a bulk solution containing multiple doses in a pump
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`spray system comprising a sealed container fitted with a metering pump.
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`Thus as an aspect of the invention we provide a sealed container containing
`
`a plurality of doses of a formulation according to the invention.”23
`
`c. comprising fentanyl, or a fentanyl derivative selected from the group
`consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free base or
`a pharmaceutically acceptable salt thereof,
`
`
`27. Ross_GB teaches that “The invention relates to formulations of
`
`fentanyl, especially pump spray formulations suitable for sublingual
`
`delivery.”24
`
`d. in a pharmaceutically acceptable liquid carrier;
`
`28. Ross_GB teaches that the dose of the fentanyl formulation includes
`
`water as a pharmaceutically acceptable liquid carrier:
`
`
`
`
`
`
`
`“(a) fentanyl or a pharmaceutically acceptable salt thereof;
`(b) water as carrier; and
`
`(c) a polar organic solvent in sufficient amount to enhance the
`
`solubility of the fentanyl or pharmaceutically acceptable salt
`
`
`
`23
`
` Id. at p. 8, ll. 13-18
`
`24 Id at p. 1, ll. 3-4
`
`
`
`13
`
`
`
`thereof in the water. “25
`e. the device having an actuator
`
`
`29. Ross_GB teaches that “Another aspect of the invention is a metered
`
`dose dispensing system comprising a sealed container containing a formulation of
`
`the invention fitted with a metering pump, an actuator and a channelling
`
`device.”26
`
`f. which when actuated delivers a therapeutically effective dose of the liquid
`formulation
`
`
`30. Ross_GB teaches, “Preferably the actuator will be designed to deliver
`a sublingually effective dose.”27
`
`g. in the form of liquid droplets
`
`
`31. See analysis of liquid droplets at ¶ 16.
`
`
`h. having a mean diameter of from about 30 to about 70 microns
`
`
`32. See analysis of mean diameter of from about 30 to about 70 microns
`at ¶¶ 21-23.
`
`
`H. Claim 5 is unpatentable as obvious over Ross_GB, in view of the
`‘496 publication.
`
`33.
`
`It is my opinion that claim 5 of the ‘460 patent would have been
`
`
`
`25 Id. at p. 3, ll 21-27 (emphasis added).
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`26 Id. at p. 9, ll. 4-6. (emphasis added)
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`27 Id. at p. 9, l. 26 (emphasis added)
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`
`
`14
`
`
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`obvious to one of ordinary skill in the art in light of the teachings of Ross_GB
`
`and the ‘496 publication for the reasons explained in detail below.
`
`a. A method of treating pain comprising.
`
`
`34. Ross_GB teaches that, “Formulations of the invention are useful in
`
`analgesia and in the treatment of pain.”28
`
`b. sublingually administering an effective amount of the sublingual
`formulation according to claim 1
`
`
`35. See above (Section F) for analysis of the sublingual formulation
`
`according to claim 1.
`
`36 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 used.”29
`
`Ross_GB further teaches that its fentanyl formulation is “preferably administered
`
`sublingually as a spray. The formulations are well tolerated when administered to
`
`the sensitive sublingual mucosa and the sublingual spray administration will result in
`
`rapid onset of the therapeutic effect of the fentanyl.”30
`
`c. to a human patient experiencing pain.
`
`
`37. Ross_GB teaches, “Fentanyl is a narcotic alkaloid, which has been
`
`
`
`28 Id. at p. 8, l. 5.
`
`29 Id. at p. 8, ll. 10-11 (emphasis added).
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`30 Id. at p. 3, ll. 29-33 (emphasis added).
`
`
`
`15
`
`
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`used for many years as an anaesthetic and an analgesic, especially in the treatment
`
`of moderate to severe pain.31 Ross_GB further teaches administration of
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`“formulations of fentanyl, especially pump spray formulations suitable for
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`sublingual delivery”32 and “the formulations of the invention are preferably
`
`administered sublingually as a spray.”33 Ross_GB further teaches “monitor[ing]
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`patients for evidence of self medication.”34 Because only people can self-
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`medicate, the sublingual administration taught by Ross_GB is to a human, as
`
`required by this claim limitation.
`
`I. Claim 2 is unpatentable as obvious over Ross_GB, in view of the
`‘862 patent and the ‘496 publication.
`
`38.
`
`It is my opinion that claim 2 of the ‘460 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 the ‘496 publication for the reasons explained in detail below.
`
`a. A non-propellant sublingual fentanyl formulation
`
`
`
`
`31 Exhibit 1003, Ross_GB, p. 1, ll. 6-7
`
`32 Exhibit 1003, Ross_GB, p. 1, ll. 3-4.
`
`33 Id. at p. 3, ll. 29-30
`
`34 Id. at p. 1, l. 15.
`
`
`
`16
`
`
`
`39. Ross_GB teaches a “pharmaceutical formulation comprising (i)
`
`fentanyl.”35 Ross_GB further teaches that its fentanyl formulation is “preferably
`
`administered sublingually as a spray. The formulations are well tolerated when
`
`administered to the sensitive sublingual mucosa and the sublingual spray
`
`administration will result in rapid onset of the therapeutic effect of the fentanyl.”36
`
`40. Further, Ross_GB further teaches that “[t]he [fentanyl] formulations
`
`of the present invention are also preferably free of any propellant.”37
`
`b. comprising discrete liquid droplets
`
`See analysis of liquid droplets at ¶ 16.
`
`
`
`
`
`c. of an effective amount of fentanyl a free base or a pharmaceutically
`acceptable salt thereof,
`
` 41. Ross_GB teaches that “a therapeutically effective amount of a
`
`[fentanyl] formulation for the treatment of pain according to the invention is
`
`used.”38
`
`
`d. a pharmaceutically acceptable liquid carrier
`
`
`
`35 Exhibit 1003, Ross_GB, Abstract.
`
`36 Id. at p. 3, ll. 29-33 (emphasis added).
`
`37 Exhibit 1003, Ross_GB, page 4, l. 1(emphasis added).
`
`38 Id. at p. 8, ll. 10-11 (emphasis added).
`
`
`
`17
`
`
`
`
`
`
`
`42. Ross_GB teaches that the dose of the fentanyl formulation includes
`
`water as a pharmaceutically acceptable liquid carrier:
`
`(a) fentanyl or a pharmaceutically acceptable salt thereof;
`
`(b) water as carrier; and
`
`(c) a polar organic solvent in sufficient amount to enhance the solubility of the
`
`fentanyl or pharmaceutically acceptable salt thereof in the water. 39
`
`e. wherein the sublingual fentanyl formulation comprises: from about 0.001%
`to about 15% by weight of fentanyl free base
`43. Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g
`
`
`
`fentanyl, 0.0177g saccharin, 2.8336g ethanol, 0.0531g menthol, and 4.1516g citrate
`
`buffer.40 Based on this disclosure, the fentanyl concentration is calculated to be
`
`0.028g fentanyl / (0.028 g + 0.0177 g + 2.8336 g + 0.0531 g + 4.1516 g) x 100% =
`
`0.395% by weight of fentanyl, which is within the claimed range of 0.001 % to 15 %
`
`by weight of fentanyl.
`
`f. the sublingual fentanyl formulation comprises … from about 50% to about
`60% by weight of ethanol
`
`
`44. Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g
`
`
`
`39 Id. at p. 3, ll. 21-27 (emphasis added).
`
`40 Id. at p. 11, ll. 1-9.
`
`
`
`18
`
`
`
`fentanyl, 0.0177g saccharin, 2.8336 g ethanol, 0.0531g menthol, and 4.1516g citrate
`
`buffer.41 Based on this disclosure, the ethanol concentration is calculated to be
`
`2.8336g ethanol / (0.028 g + 0.0177 g + 2.8336 g + 0.0531 g + 4.1516 g) x 100 % =
`
`40% by weight of ethanol. This meets the lower bound of the range recited in the
`
`claim as “about 50% by weight of ethanol”.
`
`45. Ross_GB teaches “[T]he concentration of polar organic solvent is in
`
`the range preferably of between 6 and 50%”.42 Ross_GB, further teaches
`
`“[E]xamples of polar organic solvents that may be used to enhance the solubility of
`
`fentanyl, or the physiologically acceptable salt thereof in the water, include: lower
`
`alcohols (e.g. C2.4 alcohols) such as ethanol.” 43 Finally, Ross_GB teaches “[T]he
`
`preferred polar organic solvent is ethanol.”44 Accordingly, Ross_GB teaches ethanol
`
`in the amount of 50% by weight, which is within the range of “from about 50% to
`
`about 60% by weight of ethanol.”
`
`g. the sublingual fentanyl formulation comprises … from about 4% to about
`6% by weight of propylene glycol
`
`
`46. Ross_GB teaches that its sublingual fentanyl formulation comprises
`
`
`
`41 Exhibit 1003, Ross_GB, p. 11, ll. 1-9.
`
`42 Exhibit 1003, Ross_GB, p. 5, ll. 21-22.
`
`43 Id. at p. 5, ll. 1-3.
`
`44 Id. at p. 5, ll. 6-7.
`
`
`
`19
`
`
`
`propylene glycol:
`
`Examples of polar organic solvents that may be used to enhance the solubility
`
`of fentanyl, or the physiologically acceptable salt thereof in the water,
`
`include: lower alcohols (e.g. C2.4 alcohols) such as ethanol; lower polyols (e.g.
`C2-4 polyols) such as glycerol and propylene glycol.45
`
`Moreover, Ross_GB mentions a second time that its fentanyl formulation
`
`includes propylene glycol: “[s]uitable moisturizing agents include, for example, the
`
`polar organic solvents such as glycols, especially propylene glycol.”46
`
`In addition, the ‘862 patent teaches a buccal spray comprising propylene
`
`glycol in a broad range of 2% to 30% by weight.47 The range of propylene glycol
`
`taught by the ‘862 patent encompasses the claimed range of about 4% to about 6%
`
`by weight of propylene glycol. Moreover, the ‘862 patent also teaches a buccal
`
`spray comprising propylene glycol of 7.28% by weight.48 This percentage of
`
`propylene glycol meets the upper bound of the range recited in claim 2 of the ‘460
`
`patent as about 6% of propylene glycol.
`
`48.
`
`It would have been obvious to use the range of propylene glycol by
`
`
`
`45 Exhibit 1003, Ross_GB, p. 5, ll. 1-4 (emphasis added).
`
`46 Id. at p. 7, ll. 11-14 (emphasis added).
`
`47 Exhibit 1004, the ’862 patent, col. 4, l. 63.
`
`48 Id. at col. 4, l. 47.
`
`
`
`20
`
`
`
`weight that is taught by the ‘862 patent in the fentanyl formulation taught by
`
`Ross_GB.” Ross_GB specifically calls for an amount of polar organic solvent to
`
`“enhance the solubility of fentanyl . . .”49 Ross_GB indicates that “the formulations
`
`are well tolerated when administered to sensitive sublingual mucosa and the
`
`sublingual spray administration will result in rapid onset of the therapeutic effect of
`
`fentanyl”50 and specifically identifies propylene glycol. One skilled in the art would
`
`look to the teaching of the ‘862 patent as it is a buccal spray for the administration of
`
`a medication that is “used in emergencies when the medication should be fast
`
`acting.” 51 One skilled in the art would adjust and optimize the amount of propylene
`
`glycol to account for the solubility of the drug substance as a matter of routine.
`
`49. Accordingly it would be obvious to arrive at the claimed range based
`
`on the teachings of Ross_GB in combination with the ‘862 patent.
`
`h. said droplets having a mean diameter of at least about 10 microns.
`
`50. Like Ross_GB, the ‘496 publication teaches a fentanyl formulation:
`
`
`
`“[t]wo formulations containing fentanyl citrate were prepared...”52
`
`
`
`49 Exhibit 1003, Ross_GB, p. 3, ll. 26-27.
`
`50 Id. at ll. 30-32
`
`51 Exhibit 1004, the ’862 patent, col. 1 ll. 19-20.
`
`52 Exhibit 1005, ’496 Publication, ¶ [0041].
`
`
`
`21
`
`
`
`
`
`The ‘496 publication also teaches that its fentanyl formulation is administered
`
`in liquid droplets “sized within the range of about 1 to 200 microns, more preferably
`
`within the range of 10-100 microns.”53 A droplet within the preferred range of 10 to
`
`100 microns clearly has a mean diameter of at least about 10 microns as recited in
`
`claim 2 of the ‘460 patent.
`
`
`
`51.
`
`It would have been obvious to have a fentanyl formulation with a
`
`discrete liquid droplet having a mean diameter of at least about 10 microns in light
`
`of the teachings of Ross_GB, the ‘862 patent and the ‘496 publication. The ‘496
`
`publication, like Ross_GB, teaches a fentanyl formulation. 54 The ‘496 publication
`
`also teaches “a decreased droplet size translates to a higher surface area to be
`
`absorbed by the mucosa of the intra-oral cavity.”55 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_GB.
`
`
`
`52 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
`
`
`
`53 Id. at ¶ [0019].
`
`54 Exhibit 1005, ’496 Publication, ¶ [0041].
`
`55 Exhibit 1006, ’496 Publication, ¶ [0031].
`
`
`
`22
`
`
`
`motivated to combine the fentanyl teachings of Ross_GB with the small droplet size
`
`of the ‘496 publication to eliminate or decrease any discomfort to the patient from
`
`administration of the drug.
`
`J. Claim 3 is unpatentable as obvious over Ross_GB, in view of the
`the ‘862 patent and the ‘496 Publication.
`
`53.
`
`It is my opinion that claim 3 of the ‘460 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 the ‘496 publication for the reasons explained in detail below.
`
`a. A non-propellant sublingual fentanyl formulation
`54 Ross_GB teaches a “pharmaceutical formulation comprising (i)
`
`fentanyl.”56 Ross_GB further teaches that its fentanyl formulation is “preferably
`
`administered sublingually as a spray. The formulations are well tolerated when
`
`administered to the sensitive sublingual mucosa and the sublingual spray
`
`administration will result in rapid onset of the therapeutic effect of the fentanyl.”57
`
`
`
`56 Exhibit 1003, Ross_GB, Abstract.
`
`57 Id. at p. 3, ll. 29-33 (emphasis added).
`
`
`
`23
`
`
`
`Further, Ross_GB further teaches that “[t]he [fentanyl] formulations of the
`
`present invention are also preferably free of any propellant.”58
`
`b. comprising discrete liquid droplets
`55. See analysis of liquid droplets above at ¶ 16.
`
`
`
`
`c. of an effective amount of fentanyl a free base or a pharmaceutically
`acceptable salt thereof,
`
`
`56. Ross_GB teaches that “a therapeutically effective amount of a
`
`[fentanyl] formulation for the treatment of pain according to the invention is used.”59
`
`d. a pharmaceutically acceptable liquid carrier
`
`57 Ross_GB teaches that the dose of the fentanyl formulation includes
`
`
`
`water as a pharmaceutically acceptable liquid carrier:
`
`(a) fentanyl or a pharmaceutically acceptable salt thereof;
`
`(b) water as carrier; and
`
`(c) a polar organic solvent in sufficient amount to enhance the
`
`solubility of the fentanyl or pharmaceutically acceptable salt thereof in
`the water.60
`
`
`
`58 Exhibit 1003, Ross_GB, p. 4, l. 1(emphasis added).
`
`59 Id. at p. 8, ll. 10-11 (emphasis added).
`
`60 Id. at p. 3, ll. 21-27 (emphasis added).
`
`
`
`24
`
`
`
`e. wherein the sublingual fentanyl formulation consists essentially of: from
`about 0.001% to about 15% by weight of fentanyl free base
`
`58. Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g
`
`
`
`fentanyl, 0.0177g saccharin, 2.8336g ethanol, 0.0531g menthol, and 4.1516g citrate
`
`buffer.61 Based on this disclosure, the fentanyl concentration is calculated to be
`
`0.028g fentanyl / (0.028 g + 0.0177 g + 2.8336 g + 0.0531 g + 4.1516 g) x 100% =
`
`0.395% by weight of fentanyl, w
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