Trials@uspto.gov
`Tel.: 571-272-7822
`
`
`
`
`Paper No. 9
`Entered: March 10, 2016
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`COALITION FOR AFFORDABLE DRUGS XI LLC,
`Petitioner,
`
`v.
`
`INSYS PHARMA, INC.,
`Patent Owner.
`______________
`
`Case IPR2015-01797
`Patent 8,835,459 B2
`_______________
`
`
`
`Before DEBORAH KATZ, GRACE KARAFFA OBERMANN,
`and SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
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`IPR2015-01797
`Patent 8,835,459 B2
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`
`I. INTRODUCTION
`Petitioner requests an inter partes review of claims 1–6 of U.S.
`Patent 8,835,459 B2 (“the ’459 patent”). Paper 1 (“Pet.”). Patent Owner filed a
`Preliminary Response. Paper 8 (“Prelim. Resp.”). We have statutory authority
`under 35 U.S.C. § 314(a), which provides that an inter partes review may not be
`instituted unless the Petition demonstrates “a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in the
`petition.” Taking account of the information presented in the Preliminary
`Response, we conclude that the Petition fails to make that showing. On this
`record, we deny the Petition and decline to institute review.
`A.
`Related Proceedings
`Petitioner identifies no related district court proceedings. Pet. 2–3. With
`this decision, we issue decisions denying inter partes review in IPR2016-01799
`and IPR2016-01800, which involve the same parties and related patents.
`B.
`The ’459 Patent
`The ’459 patent relates to a sublingual formulation of fentanyl, an opioid
`receptor agonist with analgesic potency up to 100 times that of morphine.
`Ex. 1001, 1:19–20. Sublingual delivery is achieved through the mucosal
`membranes lining the floor of the mouth. Id. at 10:22–23. The ’459 patent
`describes a sublingual formulation of fentanyl useful for relieving “breakthrough
`pain” in cancer patients almost immediately after administration. Id. at 8:14–27.
`The ’459 patent distinguishes sublingual (floor of the mouth) administration
`from other routes of delivery, for example, buccal (lining of the cheeks)
`administration. Id. at 9:45–10:28. The specification recognizes solid (such as
`lozenge) and liquid (such as spray pump) forms of sublingual fentanyl. Id. at 2:1–
`3; 11:8–11. The ’459 patent discloses a fentanyl formulation delivered “to the
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`sublingual mucosa via spray,” which “results in a rapid onset of therapeutic effect
`of” the active agent. Id. at 11:41–43. The specification identifies embodiments
`that “provide a mean time to maximum plasma concentration (Tmax) of fentanyl”
`within certain ranges after sublingual administration to humans. Id. at 11:45–50.
`
`C.
`
`Illustrative Claim
`
`Claims 1 is illustrative and reads as follows:
`1. A sublingual formulation comprising from about 0.001% to about
`15% by weight fentanyl, a free base, or a pharmaceutically acceptable
`salt thereof, from about 20% to about 60% by weight ethanol, and from
`about 4% to about 6% by weight propylene glycol, the formulation
`providing a mean Tmax of about 1.28+/-0.60 hours when a dose is
`administered sublingually to humans.
`Claims 1, 2, and 3 require “from about 4% to about 6% by weight of
`propylene glycol.” Claims 1 and 3 specify a mean Tmax range for the sublingual
`formulation. Claims 4, 5, and 6 do not require propylene glycol, or specify a mean
`Tmax range; however, those claims specify pharmacokinetic properties of the
`formulation, as represented by an area-under-the-curve (“AUC”) limitation.
`
`The Asserted Prior Art
`D.
`The Petition asserts the following references in the grounds of
`unpatentability:
`1. UK Patent App. No. GB 2399286 A, pub. Sept. 15, 2004. (Ex. 1003)
`(“Ross GB”).
`2. US Patent Pub. No. 2006/0062812 A1, pub. Mar. 23, 2006 (Ex. 1005)
`(“Ross US”).
`3. US Patent No. 5,370,862, issued Dec. 6, 1994 (Ex. 1004) (“Klokkers-
`Bethke”).
`4. Susanne Bredenberg, New Concepts in Administration of Drugs in Tablet
`Form: Formulation and Evaluation of a Sublingual Tablet for Rapid Absorption
`of an Individualised Dose Administration System, Comprehensive Summaries of
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`Uppsala Dissertations from the Faculty of Pharmacy 287, 1–83 (2003) (Ex. 1006)
`(“Bredenberg”).
`5. Cephalon, Inc., ACTIQ® (oral tansmucosal fentanyl citrate) Label
`NDA20-747/S-017, 2–32 (2001) (Ex. 1008) (“the ACTIQ label”).
`
`E.
`
`Asserted Grounds of Unpatentability
`
`The Petition asserts the following grounds of unpatentability:
`
`References
`
`Ross GB, Ross US, and
`Klokkers-Bethke
`Ross GB, Ross US, Klokkers-
`Bethke, and Bredenberg
`Ross US
`and Bredenberg
`Ross GB and
`the ACTIQ label
`Ross GB, the ACTIQ label,
`and Bredenberg
`
`Basis
`
`§ 103
`
`§ 103
`
`§ 103
`
`§ 103
`
`§ 103
`
`Claim(s)
`Challenged
`1
`
`2, 3
`
`4
`
`4, 5
`
`6
`
`In addition to the asserted prior art references, the Petition advances
`declaration testimony of Dr. Kinam Park. Ex. 1002 (“Park Declaration”).
`
`II. ANALYSIS
`
`A. Claim Construction
`In an inter partes review, we construe claim terms of an unexpired patent
`according to their broadest reasonable interpretation in light of the patent
`specification. 37 C.F.R. § 42.100(b). Under that standard, we assign terms their
`ordinary and customary meaning as understood by one of ordinary skill in the art
`in the context of the entire patent disclosure. In re Translogic Tech., Inc., 504 F.3d
`1249, 1257 (Fed. Cir. 2007). Any special definition for a claim term must be set
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`forth in the specification with reasonable clarity, deliberateness, and precision. In
`re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). We construe only those terms
`necessary to resolve the controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795, 803 (Fed. Cir. 1999).
`No claim term requires express construction for the purposes of this
`decision. The prior art, itself, demonstrates the appropriate level of ordinary skill
`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d 1350,
`1355 (Fed. Cir. 2001) (the prior art, itself, can reflect the level of skill in the art).
`
`B. A Problem Common to All Grounds Asserted in the Petition
`A problem common to all grounds asserted in the Petition is a failure to
`identify a persuasive reason why a person of ordinary skill in the art would have
`been prompted to combine the various elements of the prior art in the precise
`fashion required by the challenged claims. “[A] patent composed of several
`elements is not proved obvious merely by demonstrating that each of its elements
`was, independently, known in the prior art.” KSR Int’l Co. v. Teleflex Inc., 550
`U.S. 398, 418 (2007). “If identification of each claimed element in the prior art
`were sufficient to negate patentability, very few patents would ever issue.” In re
`Rouffet, 149 F.3d 1350, 1357 (Fed. Cir. 1998).
`Obviousness can be established when the prior art, itself, would have
`suggested the claimed subject matter. In re Rinehart, 531 F.2d 1048, 1051
`(CCPA 1976). But the Petition identifies no persuasive reason why the prior art
`would have recommended the combination of elements upon which the challenges
`depend. In that regard, the Petition strives to identify each element of the claims,
`from among disparate disclosures in the art, but neglects to explain adequately why
`one would have selected and combined those particular features to arrive at the
`sublingual fentanyl formulation required by the challenged claims. The Petition is
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`replete with examples of that deficiency. We focus our analysis on three examples,
`which together are dispositive and require denial of review.
`
`C. The Propylene Glycol Limitation of Claims 1, 2, and 3
`Claims 1, 2, and 3 are directed to a sublingual fentanyl formulation
`comprising fentanyl (or fentanyl active forms), ethanol, and propylene glycol in
`specified weight-percent amounts. The Petition relies on the combined disclosures
`of Ross GB and Klokkers-Bethke to establish the obviousness of the limitation that
`requires “from about 4% to about 6% by weight” of propylene glycol.
`The Petition relies on a modification to Example 1 in Ross GB, which
`discloses a formulation that includes fentanyl base, saccharin, ethanol, menthol,
`and citrate buffer—but no propylene glycol. Pet. 27–30 (citing Ex. 1003, 11:1–9
`(Ross GB’s Example 1)). For the teaching of the propylene glycol limitation,
`Petitioner directs us to two disclosures in Ross GB that mention that ingredient;
`first, as a suitable solubility enhancer for fentanyl (Ex. 1003, 5:1–4), and second,
`as a suitable moisturizing agent (id. at 7:11–14). Pet. 27–28. The Petition does not
`identify in Ross GB any disclosure or suggestion of a weight-percent range of
`propylene glycol that would be useful in Ross GB’s Example 1 formulation. Id.
`Instead, the Petition directs us to Klokkers-Bethke’s disclosure of propylene
`glycol in a nitroglycerin formulation for treating angina. Pet. 28; Ex. 1004, Title,
`1:16–18. The Petition identifies no disclosure in Klokkers-Bethke that mentions
`fentanyl or pain management. Pet. 27–30. The Petition ignores that Ross GB’s
`fentanyl formulation is “preferably free of any propellant,” whereas Klokkers-
`Bethke’s nitroglycerin formulation is delivered via a closed and charged aerosol
`canister and, thus, includes propellant. Ex. 1003, 4:1; see Ex. 1004, Abstract,
`3:20–23, 4:2, 6:10; Prelim Resp. 14 (discussing that distinction between the
`applied references) (citations omitted).
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`The Petition identifies Klokkers-Bethke’s disclosure of a “broad range
`of 2% to 30% by weight” for propylene glycol in the aerosol nitroglycerin
`formulation, and then argues, without adequate analysis, that an ordinary artisan,
`by routine experimentation, would have modified that range in the nitroglycerin
`formulation to reach an optimal range “of about 4% to about 6%” by weight.
`Pet. 28–30. The Petition does not direct us to a disclosed purpose for propylene
`glycol in Klokkers-Bethke’s nitroglycerin formulation—for example, a purpose
`comparable to one described for the fentanyl formulation of Example 1 in
`Ross GB. Id. at 27–29. The closest the Petition comes to identifying some reason
`that would have prompted one to import the optimized weight-percent of propylene
`glycol from the propellant-containing nitroglycerin formulation of Klokkers-
`Bethke, into the propellant-free fentanyl formulation of Ross GB, is in the
`argument that both formulations are “used in emergencies when the medication
`should be fast acting.” Id. at 29 (quoting Ex. 1002 ¶ 24).
`Critically lacking is any objective evidence—for example, a suggestion in
`the prior art—that a person of ordinary skill in the art would have understood that
`the amount of propylene glycol, optimized for use in an aerosol nitroglycerin
`formulation, would match the optimal amount of propylene glycol, useful in a
`propellant-free fentanyl formulation. Id. at 28–30. The Petition fails to address
`adequately how the compositional differences between the disparate formulations
`of Ross GB and Klokkers-Bethke would have informed that understanding.
`Compare Ex. 1003, 11:1–9 (Example 1 of Ross GB includes fentanyl, saccharin,
`ethanol, menthol, and citrate buffer), with Ex. 1004, 3:65–4:8 (Klokkers-Bethke’s
`formulation includes nitroglycerin, ethanol, propylene glycol, and propellant).
`Even if we set aside those shortcomings, the Petition is still deficient. As
`Patent Owner points out, the Petition is silent on “how the percentage by weight of
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`propylene glycol in a closed and charged aerosol canister would change upon
`dispensation, prior to sublingual delivery.” Prelim. Resp. 14. The Petition also
`fails to take into account how the addition of propylene glycol would upset the
`weight-percent amounts of fentanyl or ethanol in Ross GB’s Example 1
`formulation, upon which the Petition relies for disclosure of the other weight-
`percent limitations of the challenged claims. Pet. 26–30.
`Ross GB discloses that propylene glycol is useful in fentanyl formulations
`that are “free of [] alcohol.” Prelim. Resp. 16 (quoting Ex. 1003, 5:14–15).
`Ross GB’s Example 1 formulation comprises “40% by weight of ethanol.” Pet. 27;
`Ex. 1003, 11:1–9 (Example 1). Petitioner does not explain adequately why one
`would have imported Klokkers-Bethke’s optimized amount of propylene glycol
`into the ethanol-containing formulation of Ross GB’s Example 1.
`In sum, the information presented does not show sufficiently that an
`ordinary artisan would have modified the formulation of Ross GB’s Example 1 to
`include propylene glycol in a weight-percent amount that satisfies claim 1, 2, or 3.
`Each asserted challenge to those claims depends upon that modification. Pet. 28,
`38. On this record, the Petition fails to establish a reasonable likelihood of
`prevailing with respect to claim 1, 2, or 3.
`
`D. The mean Tmax Limitation of Claims 1 and 3
`The challenge to claims 1 and 3 is deficient for a second reason. Those
`claims require a fentanyl formulation that provides a mean Tmax value that, by
`Petitioner’s own calculation, falls within the range of 40.8 to 112.8 minutes.
`Pet. 31. The Petition directs us to Tmax values reported in Table 2 of Ross US,
`relating to a fentanyl preparation designated as Formulation 2. Pet. 31–32.
`Petitioner then argues that one would have modified a different fentanyl
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`formulation—the one disclosed in Example 1 of Ross GB—to attain the same Tmax
`values. Id. at 31–34.
`The crux of Petitioner’s argument is that Ross US’s Formulation 2 exhibits
`“a mean Tmax of 29 minutes for 12 patients,” and that 29 minutes “is within the
`claimed range of ‘about 40.8 minutes to about 112.8 minutes.’” Pet. 31–32
`(quoting Ex. 1002 ¶ 27). Petitioner relies on the Park Declaration for evidence
`that 29 minutes is “about 40.8” minutes as claimed. Id. Dr. Park testifies that 29
`minutes is within the claimed range “because the adjective ‘about’ preceding 40.8
`minutes indicates that the lower bound is approximate and because a mean time
`of 29 minutes is close to the approximate lower bound.” Ex. 1002 ¶ 27. Dr. Park’s
`opinion is conclusory and unpersuasive because it is not keyed to objective proof,
`regarding the understanding of a person of ordinary skill in the art. See 37 C.F.R.
`§ 42.65(a) (opinion testimony that does not disclose underlying facts “is entitled to
`little or no weight”); Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776
`F.2d 281, 294 (Fed. Cir. 1985) (lack of objective support for opinion testimony
`“may render the testimony of little probative value in a validity determination”).
`We find insufficient Petitioner’s further argument, and Dr. Park’s testimony,
`that “a subgroup” of two patients—plucked from among the larger group of twelve
`patients for which data is reported in Table 2 of Ross US—makes obvious a mean
`Tmax of 45 minutes in a fentanyl formulation. Pet. 32 (focusing on patients 11
`and 12); see Ex. 1005, Table 2 (reporting data for patients 1 through 12); see also
`Ex. 1002, ¶ 27. Petitioner arrives at a mean Tmax of 45 minutes by averaging data
`reported for patients 11 and 12, to the exclusion of other data reported for
`patients 1 through 10. Id. We discern no reason for Petitioner’s focus on those
`two particular patients, except that the exercise produces a result that falls within
`the mean Tmax range of claim 1. That exercise is fraught with hindsight bias.
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`Petitioner also argues generally that one would have combined the
`disclosures of Ross GB and Ross US “to achieve a Tmax in the range of 40.8
`minutes to about 112.8 minutes . . . so that the patient would more quickly
`experience the effects of the drug.” Pet. 33–34 (quoting Ex. 1002 ¶ 30). That
`argument depends on an opinion that runs counter to objective evidence advanced
`elsewhere in the Petition. Id. By Petitioner’s own calculation, the prior art
`suggests a mean Tmax value of 29 minutes, when all twelve patients in Table 2 of
`Ross US are considered in the mean calculation. Id. at 31; see Ex. 1005, Table 2.
`It is unclear on this record, and Petitioner does not explain adequately, why one
`would have adjusted upward (from 29 to 40.8 minutes) the mean Tmax value
`suggested in the art, if the goal was to allow the patient to “more quickly
`experience the effects of the drug.” Pet. 33–34 (quoting Ex. 1002 ¶ 30).
`The Petition fails to provide a logical explanation of why or how one would
`have modified the prior art formulations to attain a mean Tmax range of 40.8
`to 112.8 hours as required by claims 1 and 3. On this record, Petitioner does not
`show a reasonable likelihood of prevailing at trial with respect to claims 1 or 3.
`
`E. The AUC Limitations of Claims 4, 5, and 6
`Petitioner challenges claims 4, 5, and 6 on the basis of references that
`include Bredenberg and the ACTIQ label. Pet. 46, 49, 55. Bredenberg relates to
`the administration of drugs in tablet form, and mentions “a lollipop containing
`fentanyl citrate (Actiq™),” which is “designed to allow rapid absorption of the
`drug from the oral cavity.” Ex. 1006, 56. Similarly, the ACTIQ label is directed to
`“a solid formulation of fentanyl citrate” that is “intended for oral transmucosal
`administration.” Ex. 1008, 2. The ACTIQ label describes a “solid drug matrix on
`a handle” that “is designed to be dissolved slowly in the mouth in a manner to
`facilitate transmucosal absorption.” Id. “[T]he handle allows the Actiq unit to be
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`removed from the mouth if signs of excessive opioid effects appear during
`administration.” Id.
`Patent Owner challenges the prior art status of both Bredenberg and the
`ACTIQ label. Prelim. Resp. 44–49. Patent Owner, however, acknowledges that
`the pharmacokinetic properties of Actiq® were before the Examiner during
`prosecution of the ’459 patent; in fact, the specification places them side-by-side
`for contrast with those of the claimed liquid formulations. Prelim. Resp. 34 (citing
`Ex. 1001, Tables 51–54). For the following reasons, even if we accept Petitioner’s
`view that Bredenberg and the ACTIQ label qualify as prior art, we are not
`persuaded that the asserted combination of references supports a decision to
`institute inter partes review of claim 4, 5, or 6.
`Claims 4, 5, and 6 include an AUC limitation that relates to pharmacokinetic
`properties of the specified sublingual spray formulation of fentanyl. The nub of
`Petitioner’s argument is that one would have combined the liquid spray
`formulations of Ross GB or Ross US with the AUC data reported for the tablet or
`lollipop forms of fentanyl citrate, as disclosed in Bredenberg or the ACTIQ label.
`Pet. 46–59. Petitioner does not address why or how one would have replicated the
`AUC data reported in Bredenberg or the ACTIQ label in the compositionally
`dissimilar formulations of Ross GB or Ross US. Id.
`The Petition is essentially silent regarding the compositional differences
`between the solid transmucosal and liquid sublingual formulations disclosed in the
`various asserted references. Id. Bredenberg discloses solid-form tablets that
`include granulated quality mannitol, cross-linked polyvinylpyrrolidone, silicified
`microcrystalline cellulose, and magnesium stearate. Prelim. Resp. 27 (and
`citations therein to Ex. 1006). The ACTIQ label discloses lollipops or lozenges
`that include hydrated dextrates, citric acid, dibasic sodium phosphate, artificial
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`berry flavor, magnesium stearate, modified food starch, and confectioner’s sugar.
`Id. at 33 (and citations therein to Ex. 1008). The Petition identifies no comparable
`compositional elements in the liquid sublingual formulations of Ross GB or
`Ross US. Pet. 46–59.
`Nor does the Petition address how the different delivery routes of the solid
`transmucosal and liquid sublingual formulations would have informed the
`understanding of an ordinary artisan. Id.; see Ex. 1001, 1:41–211 (the ’459 patent
`specification, discussing the Actiq® lollipop, and distinguishing its “oral
`transmucosal administration” from the liquid sublingual administration of the
`invention); Pet. 12–13 (recognizing the distinctions between local, buccal, and
`sublingual administrations of active agents). The specification of the ’459 patent
`explains that those delivery routes are quite different, because the active agent in
`Actiq® “must first be released and dispersed prior to being available for resorption
`in dissolved form.” Ex. 1001, 2:3–6. On this record, the Petition fails to identify a
`persuasive reason why the asserted references would have led one, at the time of
`the invention, to modify a liquid sublingual formulation of fentanyl to exhibit the
`pharmacokinetic properties of a solid tablet or lozenge. Id. In sum, the Petition
`does not explain adequately how or why an ordinary artisan would have been led
`to the invention of claims 4, 5, and 6. Prelim. Resp. 32.
`
`III. CONCLUSION
`Taking account of the information in the Petition and Preliminary Response,
`we decline to institute review because the information presented does not
`demonstrate a reasonable likelihood that Petitioner would prevail with respect to at
`least one of the claims challenged in the Petition. 35 U.S.C. § 314(a).
`
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`IV. ORDER
`
`For the reasons given, it is
`ORDERED that the Petition is denied.
`
`FOR PETITIONER:
`Gregory J. Gonsalves
`gonsalves@gonsalveslawfirm.com
`
`Christopher Casieri
`MCNEELY, HARE & WAR LLP
`chris@miplaw.com
`
`FOR PATENT OWNER:
`Gerald J. Flattmann
`Naveen Modi
`PAUL HASTINGS LLP
`CFAD-Insys@paulhastings.com
`
`
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