EXHIBIT 1002
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1002
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01797
`
`
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1002
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01797
`
`
`
`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. 8,835,459
`
`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.
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`Patent No. 8,835,459 (the “’459 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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`
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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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`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 of 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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`
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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 ’459 patent, the file history of the ’459 patent, the Petition
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`for Inter Partes Review of the ’459 patent, and the prior art including i) Great
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`Britain patent publication GB2399286A by Calvin John Ross et al, entitled “Sub-
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`2
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`
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`lingual fentanyl formulation.” published September 15, 2004 (“Ross_GB,” Exhibit
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`1003), 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,”
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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) “New Concepts For Administration of Drugs In Tablet Form: Formulation and
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`Evaluation Of A Sublingual Tablet For Rapid Absorption and Presentation Of An
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`Individualised Dose Administration System,” by Susanne Bredenberg, Uppsala
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`University, Tryck & Medier, Uppsala 2003 (“Bredenberg_2003,” Exhibit 1006), v)
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`The ACTIQ Label (Exhibit 1008).
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`C. Legal Standards
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`
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`9.
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`In my opinion, given the disclosure of the ’459 patent, I consider a
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`person of ordinary skill in the art at the time of filing of these patents to be
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`someone who holds a B.S. degree in pharmacy, chemistry, engineering, or related
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`fields with several years of experience, or a Ph.D. degree in the same fields, and is
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`a 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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`
`
`3
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`
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`invention of the ’459 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) the
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`"differences between the prior art and the claims at issue," (3) "the level of ordinary
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`skill in the pertinent art," and (4) "secondary considerations" such as "commercial
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`success, long felt but unsolved needs, failure of others, etc. I have also been told
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`that the combination of familiar elements according to known methods is likely
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`to be obvious when it does no more than yield predictable 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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`D. Background and the ’459 Patent
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`
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`11. The ‘459 patent “is directed to sublingual formulations containing
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`fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, suitable
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`for administration to humans, and methods for treatment with the sublingual
`
`formulations.”1 The sublingual formulations “are useful in the treatment of
`
`
`1 Exhibit 1001, ‘459 patent, col. 1, ll. 12-15.
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`
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`4
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`
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`moderate to severe pain.”2
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`12. The ‘459 patent explains that “[w]ithin the oral cavity, there are three
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`generally recognized routes of administration of an active agent, namely local,
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`buccal and sublingual.”3 Local administration, “is mainly limited to applications
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`regarding disruptions occurring within the oral cavity itself, such as a canker
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`sore.”4 The ‘459 patent explains that there are known disadvantages associated
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`with buccal administration:
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`13. The buccal mucosa area encompasses the mucosal membranes of the
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`inner lining of the cheeks. The buccal mucosa is however, less permeable than the
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`sublingual area. One of the major disadvantages associated with buccal mucosa
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`delivery of an active agent has been the relatively low passage of active agents
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`across the mucosal epithelium, thereby resulting in low agent bioavailability,
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`which translates into a substantial loss of usable active agent within each dosage.5
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`14. The ‘459 patent notes that a third method of delivery called sublingual
`
`delivery has an advantage of rapid onset of action:
`
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`2 Id. at col. 10, ll. 29-30.
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`3 Id. at col. 10, ll. 8-10.
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`4 Id. at col. 10, ll. 11-13.
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`5 Id. at col. 10, ll. 14-21.
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`
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`5
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`
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`Sublingual delivery is achieved through the mucosal membranes lining the
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`floor of the mouth. Because of the high permeability and the rich blood supply,
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`transport via the sublingual route results in a rapid onset of action, providing a
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`delivery route appropriate for highly permeable drugs with short delivery period
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`requirements and an infrequent dosing regimen.6
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`
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`E. Claim Construction
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`15.
`
`I understand that the claims in an IPR proceeding are construed in
`
`accordance with the broadest reasonable construction consistent with the
`
`specification.
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`16.
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`I have been told that the claim term “mean Tmax” is properly construed
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`as “average time to achieve the maximum concentration in plasma.” I have been
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`told that the claim term “mean Cmax” is properly construed as the “average
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`maximum concentration in plasma.” I have been told that the claim term “AUClast”
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`is properly construed as the “area under the concentration-time curve from time-
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`zero to the time of the last quantifiable measurement.” I have been told that the
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`claim term “AUCinf” is properly construed as the “area under the plasma
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`concentration time curve from time-zero extrapolated to infinity.” I agree with
`
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`6 Id. at col. 10, ll. 22-28.
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`
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`6
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`
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`these constructions because they are consistent with the broadest reasonable
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`construction as understood by one of ordinary skill in the art.
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`F. Claim 1 is unpatentable as obvious over Ross_GB, in view of
`
`Ross_US2006, and the ’862 patent.
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`17.
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`It is my opinion that claim 1 of the ‘459 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.
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`a. sublingual formulation
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`18. Ross_GB teaches a “pharmaceutical formulation comprising (i)
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`fentanyl.”7 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.”8
`
`Accordingly, the claimed ‘sublingual formulation’ is specifically taught by
`
`Ross_GB.
`
`
`7 Exhibit 1003, Ross_GB, Abstract.
`
`8 Id. at page 3, ll. 29-33 (emphasis added).
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`
`
`7
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`
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`b. from about 0.001% to about 15% by weight fentanyl, a free base, or a
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`pharmaceutically acceptable salt thereof
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`19. 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
`
`citrate buffer.9 Based on this disclosure, the fentanyl concentration is calculated to
`
`be 0.028g fentanyl / (0.028g + 0.0177g + 2.8336g + 0.0531g + 4.1516g) x 100% =
`
`0.395% by weight of fentanyl, which is within the claimed range of 0.001% to
`
`15% by weight of fentanyl.
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`20.
`
` Ross_GB also teaches that the fentanyl formulation may be a
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`pharmaceutically acceptable salt:
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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.10
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`c.
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`the sublingual formulation comprising … from about 20% to about 60% by
`
`weight of ethanol
`
`
`9 Exhibit 1003, Ross_GB, p. 11, ll. 1-9.
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`10 Exhibit 1003, Ross_GB, p. 3, l. 21-27 (emphasis added).
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`
`
`8
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`
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`21. 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
`
`citrate buffer.11 Based on this disclosure, the ethanol concentration is calculated to
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`be 2.8336g ethanol / (0.028g + 0.0177g + 2.8336g + 0.0531g + 4.1516g) x 100% =
`
`40% by weight of ethanol, which is within the claimed range of 20% to 60% by
`
`weight of ethanol.
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`d.
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`the sublingual formulation comprising … from about 4% to about 6% by
`
`weight of propylene glycol
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`22. Ross_GB teaches that its sublingual fentanyl formulation comprises
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`propylene glycol:
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`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.12
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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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`11 Exhibit 1003, Ross_GB, page 11, ll. 1-9.
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`12 Exhibit 1003, Ross_GB, page 5, ll. 1-4 (emphasis added).
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`
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`9
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`
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`organic solvents such as glycols, especially propylene glycol.”13
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`23.
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`In addition, the ‘862 patent teaches a buccal spray comprising
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`propylene glycol in a broad range of 2% to 30% by weight.14 The range of
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`propylene glycol taught by the ‘862 patent encompasses the claimed range of about
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`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.15 This
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`percentage of propylene glycol meets the upper bound of the range recited in claim 1
`
`of the ‘459 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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`weight that is taught by the ‘862 patent in the fentanyl formulation taught by
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`Ross_GB. Ross_GB specifically calls for an amount of polar organic solvent to
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`“enhance the solubility of fentanyl . . .”16 Ross_GB indicates that “the formulations
`
`are well tolerated when administered to sensitive sublingual mucosa and the
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`sublingual spray administration will result in rapid onset of the therapeutic effect of
`
`
`13 Id. at page 7, ll. 11-14 (emphasis added).
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`14 Exhibit 1004, the ’862 patent, col. 4, l. 63.
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`15 Exhibit 1004, ‘862 patent, col. 4, l. 47.
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`16 Exhibit 1003, Ross_GB, page 3, ll. 26-27.
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`
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`10
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`
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`fentanyl”17 and specifically identifies propylene glycol. Thus, one skilled in the art
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`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
`
`should be fast acting.” One skilled in the art would adjust the amount of propylene
`
`glycol to account for the solubility of the drug substance as a matter of routine.
`
`Accordingly it would have been obvious to arrive at the claimed range based on the
`
`teachings Ross_GB and in combination with the ‘862 patent.
`
`
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`e. administered sublingually to humans
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`25. Ross_GB teaches administration of “formulations of fentanyl,
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`especially pump spray formulations suitable for sublingual delivery”18 and “the
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`formulations of the invention are preferably administered sublingually as a spray.”19
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`Ross_GB further teaches “monitor[ing] patients for evidence of self medication.”20
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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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`17 Id. at p. 3, ll. 30-32.
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`18 Exhibit 1003, Ross_GB, page 1, ll. 3-4.
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`19 Id. at page 3, ll. 29-30
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`20 Id. at page 1, l. 15.
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`
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`11
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`
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`f.
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`the formulation providing a mean Tmax of about 1.28+/−0.60 hours
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`26. Using simple arithmetic, the claimed range of about 1.28 +/- 0.60 hours
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`can be expressed as about 76.8 minutes +/- 36 minutes, which can also be expressed
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`as a range from about 40.8 minutes to about 112.8 minutes.
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`27. Ross_US teaches in Table 2 a median Tmax of 0.5 hours (30 minutes)
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`with a range between 0.333 and 0.833 hours (20 minutes and 50 minutes,
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`respectively) following sublingual administration of 200 microgram (mcg or µg) of
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`fentanyl with a non-pressurized pump spray device to 12 patients. Table 2 of
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`Ross_US also teaches a mean Tmax of 0.486 hours (about 29 minutes) following
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`sublingual administration of 200 microgram of fentanyl with a non-pressurized
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`pump spray device to 12 patients. A mean Tmax of 29 minutes is within the claimed
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`range of “about 40.8 minutes to about 112.8 minutes” because the adjective “about”
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`preceding 40.8 minutes indicates that the lower bound is approximate and because a
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`mean time of 29 minutes is close to the approximate lower bound. Moreover, the
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`mean Tmax for a subgroup of patients including patients 11 and 12 is 0.75 hour (45
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`minutes) and the mean Tmax for a subgroup of patients including patients 6, 11, and
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`12 is 0.72 hour (43.2 minutes). Both are within the claimed limitation of about
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`1.28+/-0.60 hour (about 40.8 minutes to about 112.8 minutes).”21
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`21 Exhibit 1005, Ross_US2006, page 8, Table 2.
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`
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`12
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`
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`28.
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`It would have been obvious to have a sublingual fentanyl formulation
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`providing a mean Tmax of fentanyl of from about 40.8 to about 112.8 minutes in light
`
`of the teachings of Ross_US2006 and Ross_GB. As described in Paragraph 14, the
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`‘459 patent describes sublingual delivery having an advantage of rapid onset of
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`action. Thus, the ‘459 patent teaches that the faster onset of action is more desirable.
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`Accordingly, the formulation in Table 2 of Ross_US is a better formulation than that
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`of the ‘459 patent because it has a faster onset. Delaying the mean Tmax as described
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`in the ‘459 patent would not be difficult and would be undesirable. The fentanyl
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`formulations taught by Ross_US2006 and Ross_GB are very similar. The data in
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`Table 2 of Ross_US2006 was obtained from Formulation 2 in which the Fentanyl
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`Base is 0.011g, Ethanol is 2.2319g, Menthol is 0.0417g, Citrate buffer is 3.2675g,
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`and Saccharin is 0.0139g.22 This gives a composition by weight of 0.2% fentanyl,
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`40.1% ethanol, 0.75% menthol, 58.7% citrate buffer, and 0.25% saccharin.
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`29. The formulation of Example 1 of Ross-GB includes 0.028g fentanyl,
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`0.0177g saccharin, 2.8336g ethanol, 0.0531g menthol, and 4.1516g citrate buffer.23
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`This gives a composition by weight of 0.4% fentanyl, 0.25% saccharin, 40%
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`ethanol, 0.75% menthol, and 58.6% citrate buffer.
`
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`22Exhibit 1005, Ross_US2006, Formulation 2, page 7, ¶ [0115].
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`23 Exhibit 1003, Ross_GB, Example 1, page 11, ll. 1-9.
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`
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`13
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`
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`30.
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`In light of the similarities between the fentanyl formulations taught by
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`Ross_US2006 and Ross_GB, one of ordinary skill in the art would have been
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`motivated to combine the teachings of Ross_US2006 and Ross_GB. One
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`important aspect of the administration of a drug is how long it takes to achieve the
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`maximum (or peak) drug concentration in the plasma within the patient’s body
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`(Tmax). Both Ross_GB and ROSS-US2006 teach fentanyl formulations that are
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`similar to each other as well as the claimed formulation of the ‘972 patent.
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`Accordingly, one of ordinary skill in the art would have been motivated to
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`combine the fentanyl teachings of Ross_US2006 and Ross_GB to achieve a Tmax in
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`the range of 40.8 minutes to about 112.8 minutes for the administration of a drug
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`so that the patient would more quickly experience the effects of the drug.
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`G. Claim 2 is unpatentable as obvious over Ross_GB, in view of
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`Ross_US2006, the ‘862 patent, and Bredenberg_2003.
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`31. Claim 2 would have been obvious to one of ordinary skill in the art
`
`in light of the teachings of Ross_GB, Ross_US2006, the ‘862 Patent and the
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`Bredenberg_2003.
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`
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`a. sublingual formulation
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`32. Ross_GB teaches a “pharmaceutical formulation comprising (i)
`
`
`
`14
`
`
`
`fentanyl.”24 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.”25
`
`Accordingly, the claimed ‘sublingual formulation’ is specifically taught by
`
`Ross_GB.
`
`b. from about 0.001% to about 15% by weight fentanyl, a free base, or a
`
`pharmaceutically acceptable salt thereof
`
`33. 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.26 Based on this disclosure, the fentanyl concentration is calculated
`
`to be 0.028g fentanyl / (0.028g + 0.0177g + 2.8336g + 0.0531g + 4.1516g) x 100%
`
`= 0.395% by weight of fentanyl, which is within the claimed range of 0.001% to
`
`15% by weight of fentanyl. Ross_GB also teaches that the fentanyl formulation
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`may be a pharmaceutically acceptable salt:
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`(a) fentanyl or a pharmaceutically acceptable salt thereof;
`
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`24 Exhibit 1003, Ross_GB, Abstract.
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`25 Id. at page 3, ll. 29-33 (emphasis added).
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`26 Exhibit 1003, Ross_GB, p. 11, ll. 1-9.
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`
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`15
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`
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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.27
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`c. the sublingual formulation comprising … from about 50% to about 60% by
`
`weight of ethanol
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`34. 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.28 Based on this disclosure, the ethanol concentration is calculated to
`
`be 2.8336g ethanol / (0.028g + 0.0177g + 2.8336g + 0.0531g + 4.1516g) x 100% =
`
`40% by weight of ethanol. A percentage by weight of ethanol of 40% is within the
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`claimed range of “about 50% to about 60%” because the adjective “about”
`
`preceding 50% indicates that the lower bound is approximate and because a value of
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`40% is close to the approximate lower bound of 50%.
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` Moreover, Ross_GB teaches “the concentration of polar organic solvent is
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`in the range preferably of between 6 and 50%” and “the preferred polar organic
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`solvent is ethanol”.29 A percentage by weight of ethanol of 50% is within the
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`claimed range of “about 50% to about 60%”.
`
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`27 Exhibit 1003, Ross_GB, p. 3, ll. 21-27 (emphasis added).
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`28 Exhibit 1003, Ross_GB, page 11, ll. 1-9.
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`29 Exhibit 1003, Ross_GB, page 5, ll. 21-22 and ll. 6-7
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`
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`16
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`
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`
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`d. the sublingual formulation comprising … from about 4% to about 6% by
`
`weight propylene glycol
`
`35. Ross_GB teaches that its sublingual fentanyl formulation comprises
`
`propylene glycol:
`
`Examples of polar organic solvents that may be used to enhance the
`
`solubility of fentanyl, or the physiologically acceptable salt thereof in
`
`the water, include: lower alcohols (e.g. C2.4 alcohols) such as ethanol;
`
`lower polyols (e.g. C2-4 polyols) such as glycerol and propylene
`
`glycol.30
`
`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.”31
`
`36.
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`In addition, the ‘862 patent teaches a buccal spray comprising
`
`propylene glycol in a broad range of 2% to 30% by weight.32 The range of
`
`
`30 Exhibit 1003, Ross_GB, page 5, ll. 1-4 (emphasis added).
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`31 Id. at page 7, ll. 11-14 (emphasis added).
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`32 Exhibit 1004, the ’862 patent, col. 4, line 63.
`
`
`
`17
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`
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`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.33 This
`
`percentage of propylene glycol meets the upper bound of the range recited in claim 2
`
`of the ‘459 patent as about 6% of propylene glycol.
`
`37.
`
`It would have been obvious to use the range of propylene glycol by
`
`weight that is taught by the ‘862 patent in the fentanyl formulation taught by
`
`Ross_GB. Ross_GB specifically calls for an amount of polar organic solvent to
`
`“enhance the solubility of fentanyl . . .”34 Ross_GB indicates that “the formulations
`
`are well tolerated when administered to sensitive sublingual mucosa and the
`
`sublingual spray administration will result in rapid onset of the therapeutic effect of
`
`fentanyl” and specifically identifies propylene glycol.35 Thus, 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.” One skilled in the art would adjust the amount of propylene
`
`glycol to account for the solubility of the drug substance as a matter of routine.
`
`
`33 Exhibit 1004, the ‘862 patent, col. 4, l. 47.
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`34 Exhibit 1003, Ross_GB, page 3, ll. 26-27.
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`35 Id. at ll. 30-32.
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`
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`18
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`
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`Accordingly it would have been obvious to arrive at the claimed range based on the
`
`teachings of Ross_GB in combination with the ‘862 patent.
`
`
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`e. after administration to humans
`
`38. Ross_GB teaches administration of “formulations of fentanyl,
`
`especially pump spray formulations suitable for sublingual delivery”36 and “the
`
`formulations of the invention are preferably administered sublingually as a spray.”37
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`Ross_GB further teaches “monitor[ing] patients for evidence of self medication.”38
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`Because only people can self-medicate, the sublingual administration taught by
`
`Ross_GB is to a human, as required by this claim limitation.
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`
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`f. provides a plasma concentration after administration to humans selected
`
`from the group consisting of: about 60% of the mean Cmax in about 10
`
`minutes, about 86% of the mean Cmax by about 20 minutes and a
`
`combination thereof
`
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`36 Exhibit 1003, Ross_GB, page 1, ll. 3-4.
`
`37 Id. at page 3, ll. 29-30
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`38 Id. at page 1, l. 15.
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`
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`19
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`
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`39. Ross_US2006 teaches in Table 2 a mean time to maximum plasma
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`concentration (Tmax) of 0.486 hours (about 29 minutes) and a mean Cmax of 516.3+/-
`
`171.79 pg/ml (0.516 +/-0.172 ng/ml) following sublingual administration of 200
`
`mcg of fentanyl with a non-pressurized pump spray device to 12 patients.39
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`Bredenberg_2003 teaches that administering a sublingual 200 mcg fentanyl tablet
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`produces similar Cmax (0.471 +/- 0.160 ng/ml) and a substantially similar Tmax (48.7
`
`+/-26.3 minutes).40 Giventhat formulations in Ross_US2006 and Bredenberg_2003
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`provide similar pharmacokinetic results, a POSA would have been motivated to
`
`consider the pharmacokinetic parameters taught in Brendenberg_2003 and would
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`have had a reasonable expectation that those pharmacokinetic parameters would also
`
`be similar for Ross_US2006. For example, Bredenberg_2003 teaches that
`
`administering a sublingual 100, 200, and 400 mcg fentanyl tablet results in about
`
`60% of the mean Cmax in about 10 minutes, about 86% of the mean Cmax by about 20
`
`minutes. Table 8 of Bredenberg_2003 is shown below.
`
`
`39 Exhibit 1005, Ross_2006, Table 2, ¶ [0123].
`
`40 Exhibit 1006, Bredenberg_2003, p. 61, Table 8.
`
`
`
`20
`
`
`
`
`
`The Cmax of 100 mcg fentanyl tablet is 0.243±0.14 ng/ml, which is in the
`
`range of 0.103~0.383 ng/ml. 60% of 0.103 ng/ml is 0.0618 ng/ml. Cfirst at Tfirst is
`
`0.051±0.027 ng/ml, and thus, Cfirst ranges from 0.024 to 0.078 ng/ml, which includes
`
`0.0618 ng/ml. The 200 and 400 mcg fentanyl tablets in the table also show reaching
`
`60% of the Cmax in about 10 minutes. For 200 mcg fentanyl tablet, 60% of the Cmax
`
`of 0.311 (= 0.471-0.160) ng/ml is 0.187 ng/ml. At 8.0 minutes, 0.160
`
`(=0.084+0.076) ng/ml is reached. Thus, at about 10 minutes, 0.187 ng/ml can be
`
`easily reached. The calculation for 400 mcg fentanyl tablet shows the same result.
`
`This set of data indicates that it is possible for the fentanyl tablet of
`
`Bredenberg_2003 to achieve about 60% of the mean Cmax in about 10 minutes.
`
`40. Moreover, Bredenberg_2003 also teaches that it takes between 1 to 3
`
`minutes for the tablet to dissolve.41 It would have been obvious to one of ordinary
`
`
`41 Exhibit 1006, Bredenberg_2003, page 61, figure 14.
`
`
`
`21
`
`
`
`skill in the art that a comparable spray such as Ross_US2006 can achieve the same
`
`Cfirst about 1 to 3 minutes faster than the fentanyl tablet of Bredenberg_2003 because
`
`the fentanyl by the spray is immediately available for absorption upon
`
`administration. Also, if the Tfirst were the same, the fentanyl spray of Ross_US2006
`
`would achieve a similar or even slightly higher Cfirst than the tablet of
`
`Bredenberg_2003. Hence the recited limitation of ‘about 60% of the mean Cmax in
`
`about 10 minutes’ would have been obvious in light of the teachings of
`
`Ross_US2006 and Bredenberg_2003.
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`In addition, Bredenberg_2003 teaches in Figure 15 plasma concentration-time
`
`profiles of fentanyl following a single sublingual dose of 200 mcg fentanyl base.42 It
`
`can be concluded from the data that plasma concentrations of fentanyl are about 0.20
`
`+/- 0.05 ng/ml and about 0.33+/- 0.07 ng/ml at about10 minutes and about 20
`
`minutes following administration, which correspond to about 23.8% to 80% of Cmax,
`
`and about 41.2% to 128.6% Cmax at 10 minutes and 20 minutes, respectively, using
`
`Cmax of 0.471 +/- 0.160 ng/ml as disclosed in Table 8. Hence the claimed limitation
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`of “about 60% of the mean Cmax in about 10 minutes, about 86% of the mean Cmax
`
`by about 20 minutes and a combination thereof” would have been obvious over
`
`Ross_US2006 and Bredenberg_2003.
`
`
`42 Exhibit 1006, Bredenberg_2003, p. 62, Figure 15.
`
`
`
`22
`
`
`
`
`
`H. Claim 3 is unpatentable as obvious over Ross_GB, in view of
`
`Ross_US2006, the ‘862 patent, and Bredenberg_2003.
`
`41.
`
`It is my opinion that claim 3 of the ‘459 patent would have been
`
`obvious to one of ordinary skill in the art in light of the teachings of Ross_GB,
`
`in view of Ross_US2006, the ‘862 patent, and Bredenberg_2003.
`
`
`
`a. when administered to humans provides a plasma concentration that is
`
`greater than about 80% of the mean Cmax for about 2 hours
`
`42. Bredenberg_2003 teaches that a sublingual 200 mcg fentanyl tablet
`
`delivers a Cmax = 0.471 +/- 0.16 ng/ml (i.e., from 0.311 ng/ml to 0.631 ng/ml).43
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`Accordingly, 80% of the Cmax ranges from 0.249 ng/ml to 0.505 ng/ml. Figure 15 of
`
`Bredenberg_2003 shows that the sublingual 200 mcg fentanyl tablet provides a
`
`concentration of above 0.249 ng/ml (i.e., 80% of the mean Cmax) from about 15
`
`minutes to 150 minutes (i.e., for about 2.25 hours).44 This concentration is provided
`
`greater than the two hour time period required by claim 3. Thus, in light of the
`
`teachings of Bredenberg_2003, it would have been obvious to one of ordinary skill
`
`
`43 Exhibit 1006, Bredenberg_2003, page 61, table 8.
`
`44 Exhibit 1006, Bredenberg_2003, page 62.
`
`
`
`23
`
`
`
`in the art at the time of the invention of the ‘459 patent to provide a sublingual
`
`fentanyl formulation that when administered to humans provides a plasma
`
`concentration that is greater than about 80% of the mean Cmax for about 2 hours, as
`
`required by claim 3.
`
`I. Claim 4 is unpatentable as obvious over Ross_US2006 In View Of
`
`Bredenberg_2003.
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`43. Claim 4 would have been obvious to one of ordinary skill in the art in
`
`light of the teachings of Ross_US2006 in view of Bredenberg_2003. Ross_US2006
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`teaches a “pharmaceutical composition…comprises (a) fentanyl.”45 Ross_US2006
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`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.”46 Accordingly, the claimed “sublingual
`
`spray formulation” is specifically taught by Ross_US2006. Bredenberg_2003 in
`
`Table 8 teaches that the AUC0-∞ (i.e., AUCinf) for 400 mcg is 290.84 +/-92.53
`
`
`45 Exhibit 1005, Ross_US2006, [0018]-[0019].
`
`46 Id. at [0022] (emphasis added).
`
`
`
`24
`
`
`
`ng/ml*min.47 The value of 290.84 +/- 92.53 ng/ml*min is equal to 4.85 +/- 1.54
`
`ng/mL*hr,48 which is within the scope of the claimed value for AUCinf because the
`
`claimed value 5.761+/−1.916 ng/mL*hr ranges from 3.845 to 7.677 ng/mL*hr and
`
`the value of 4.85 +/- 1.54 ng/mL*hr of Bredenberg_2003 clearly falls within that
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`range.49
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`Moreover, one of ordinary skill in the art would have understood that
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`Bredenberg_2003’s disclosure of the AUCinf values was applicable to the fentanyl
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`spray formulation of Ross_US2006 because both Ross_US2006 and
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`Bredenberg_2003 are directed to the sublingual application of a fentanyl formulation
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`and both provide similar pharmacokinetic parameters of Cmax and Tmax as set forth
`
`above. In addition, the tablet formulation described in Brendenberg 2003 is a fast
`
`dissolving tablet having rapid dissolution property resulting in rapid sublingual
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`absorption. Hence, a person of ordinary skill in the art would have understood that
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`both would also have provided similar AUCinf because of the rapid release of
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`fentanyl after sublingual administration. Accordingly, this claim limitation would
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`have been obvious to one of ordinary skill in the art in light of Bredenberg_2003’s
`
`
`47 Exhibit 1006, Bredenberg_2003, page
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