Paper No. ______
`Filed: December 11, 2015
`
`Filed on behalf of: Insys Pharma, Inc
`
`By: Gerald J. Flattmann (CFAD-Insys@paulhastings.com)
`
`Naveen Modi (CFAD-Insys@paulhastings.com)
`
`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 IPR2015-01800
`Patent 8,486,972
`
`______________________
`
`Patent Owner’s Preliminary Response
`to Petition for Inter Partes Review
`of U.S. Patent No. 8,486,972
`
`
`
`
`
`
`
`

`
`TABLE OF CONTENTS
`
`Page
`Introduction ...................................................................................................... 1
`
`Background ...................................................................................................... 2
`
`I.
`
`II.
`
`III. The Board Should Exercise Its Discretion Under 35 U.S.C. § 325(d) ............ 4
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Ross_US2006 (Ex. 1005) Was Considered by the Office .................... 4
`
`Substantially the Same Information as That Contained in Ross_GB
`(Ex. 1003) Was Considered by the Office ............................................ 5
`
`The ’496 Publication (Ex. 1006) Was Considered by the Office ......... 9
`
`CFAD’s Newly Presented Reference Is Deficient ................................ 9
`
`Conclusion ........................................................................................... 10
`
`IV. CFAD Advances Flawed Obviousness Analyses .......................................... 10
`
`A. Ground 1: Claims 1 and 3 Are Not Obvious Over Ross_GB
`(Ex. 1003), Ross_US2006 (Ex. 1005), and the ’862 Patent (Ex. 1004)
` ............................................................................................................. 11
`
`1.
`
`2.
`
`3.
`
`1.
`
`2.
`
`B.
`
`CFAD Fails to Explain How the References Disclose or Suggest
`the Features of Claims 1 and 3 ....................................................... 12
`
`CFAD Fails to Explain Why One of Ordinary Skill Would Have
`Combined the Asserted References ............................................... 16
`
`CFAD Resorts to Non-Analogous Art and Conclusory Allegations
`of Obviousness ............................................................................... 20
`
`Ground 2: Claim 2 Is Not Obvious Over Ross_GB (Ex. 1003),
`Ross_US2006 (Ex. 1005), the ’862 Patent (Ex. 1004), and the ’496
`Publication (Ex. 1006) ......................................................................... 25
`
`CFAD Fails to Explain How the References Disclose or Suggest
`the Features of Claim 2 .................................................................. 26
`
`CFAD Fails to Explain Why One of Ordinary Skill Would Have
`Combined the Asserted References ............................................... 28
`
`i
`
`

`
`TABLE OF CONTENTS
`(continued)
`
`Page
`CFAD’s Grounds Rely on Improper Hindsight .................................. 30
`
`CFAD Fails to Adequately Address Secondary Considerations Set
`Forth During Prosecution .................................................................... 32
`
`
`
`C.
`
`D.
`
`1.
`
`2.
`
`3.
`
`4.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`E.
`
`CFAD’s Argument That Secondary Considerations Are Not
`Commensurate With the Scope of the Claims Is Deficient ........... 32
`
`CFAD’s Argument That Fast Onset of Five Minutes Was Not
`Unexpected Due to a Fentanyl Nasal Spray Is Deficient ............... 34
`
`CFAD’s Argument That Fast Onset of Five Minutes Was Not
`Unexpected Due to Allegedly Newly Identified References Is
`Deficient ......................................................................................... 36
`
`CFAD’s Attempt to Compare Blood Concentration Between
`Subsys® and a Nasal Spray Is Deficient ......................................... 40
`
`CFAD Fails to Adequately Address Additional Evidence of
`Secondary Considerations ................................................................... 42
`
`Commercial Success ...................................................................... 42
`
`Failure of Others ............................................................................ 44
`
`Long-Felt Need .............................................................................. 44
`
`Skepticism ...................................................................................... 46
`
`Unexpected Results ........................................................................ 46
`
`V.
`
`CFAD’s Claim Construction Analysis Is Deficient ...................................... 47
`
`VI. Conclusion ..................................................................................................... 50
`
`ii
`
`

`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Apple Inc. v. ITC,
`725 F.3d 1356 (Fed. Cir. 2013) .......................................................................... 42
`
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1342 (Fed. Cir. 2013) .................................................................... 27, 30
`
`Circuit Check Inc. v. QXQ Inc.,
`795 F.3d 1331 (Fed. Cir. 2015) .......................................................................... 21
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ........................................................ 11, 20, 33, 34
`
`Dynamic Drinkware v. Nat’l Graphics,
`No. 15-1214 (Fed. Cir. Sept. 4, 2015) ................................................................ 34
`
`Excelsior Med. Corp. v. Lake,
`IPR2013-00494, Paper 10 (Feb. 6, 2014) ............................................................. 4
`
`In re Fay,
`347 F.2d 597 (C.C.P.A. 1965) ............................................................................ 24
`
`Graham v. John Deere Co. of Kan. City,
`383 U.S. 1 (1966) ................................................................................................ 10
`
`Hulu LLC v. Intertainer, Inc.,
`IPR2014-01456, Paper 8 (Mar. 6, 2015) .............................................................. 4
`
`Intri-Plex Techs., Inc. v. Saint-Gobain Performance Plastics Rencol
`Ltd.,
`IPR2014-00309, Paper 83 (Mar. 23, 2015) .................................................. 11, 42
`
`Jiawei Tech. (HK) Ltd. et al. v. Richmond,
`IPR2014-00938, Paper 20 (Dec. 16, 2014)................................................... 47, 48
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 11
`
`iii
`
`

`
`TABLE OF AUTHORITIES
`(continued)
`
`In re Kao,
`
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 33
`
`Page(s)
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................ 10, 11, 19
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 23
`
`Monarch Knitting Mach. Corp. v. Sulzer Moral GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 46
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .................................................................... 23, 46
`
`Panduit Corp. v. Dennison Mfg. Co.,
`774 F.2d 1082 (Fed. Cir. 1985) .......................................................................... 44
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 23, 24
`
`Prism Pharma Co. v. Choogwae Pharma Corp.,
`IPR2014-00315, Paper 14 (July 8, 2014) ............................................................. 4
`
`Rambus Inc. v. Rea,
`731 F.3d 1248 (Fed. Cir. 2013) .......................................................................... 33
`
`Schott Gemtron Corp. v. SSW Holding Co., Inc.,
`IPR2014-00367, Paper 62 (May 26, 2015) ......................................................... 21
`
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ............................................................................ 23
`
`Star Sci., Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .......................................................................... 42
`
`Syntex (USA) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) .......................................................................... 44
`
`iv
`
`

`
`TABLE OF AUTHORITIES
`(continued)
`
`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling
`
`USA, Inc.,
`699 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 33
`
`Page(s)
`
`STATUTES
`
`35 U.S.C.
`§ 103(a) ......................................................................................................... 10, 11
`§ 313 ...................................................................................................................... 1
`§ 325(d) ........................................................................................................... 4, 10
`
`OTHER AUTHORITIES
`
`37 C.F.R.
`§ 42.65 ........................................................................................................... 16, 34
`§ 42.100(b) .......................................................................................................... 49
`§ 42.104(b)(3) ..................................................................................................... 47
`§ 42.107 ................................................................................................................. 1
`
`Office Patent Trial Practice Guide,
`77 Fed. Reg. 48756 (Aug. 14, 2012) ............................................................ 16, 34
`
`
`
`v
`
`

`
`Case IPR2015-01800
`
`LIST OF EXHIBITS
`
`2001. Allen et al., Disperse Systems, in ANSEL’S PHARMACEUTICAL DOSAGE
`FORMS AND DRUG DELIVERY SYSTEMS (L. Allen & H. Ansel, eds., 2014).
`
`2002. U.S. Food & Drug Admin. Oral Solutions and Suspensions, in FDA GUIDE
`TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994).
`
`2003. U.S. Food & Drug Admin. Metered Dose Inhaler (MDI) and Dry Powder
`Inhaler (DPI) Drug Products (Draft Guidance Document) Center for Drug
`Evaluation and Research (October 1998).
`
`2004. U.S. Food & Drug Admin. Bioavailability and Bioequivalence Studies for
`Nasal Aerosols and Nasal Sprays for Local Action (Draft Guidance
`Document) Center for Drug Evaluation and Research (June 1999).
`
`2005. U.S. Food & Drug Admin. Summary Review for Regulatory Action
`(NDA # 202788, Insys Therapeutics, Inc.) Center for Drug Evaluation and
`Research (January 4, 2012).
`
`2006. Feierman & Lasker, 1996. “Metabolism of fentanyl, a synthetic opioid
`analgesic, by human liver microsomes. Role of CYP3A4.” Drug Metab
`Dispos 24(9):932–39.
`
`2007. Graff & Pollack, 2005. “Nasal drug administration: potential for targeted
`central nervous system delivery.” J Pharm Sci. 94(6):1187–95.
`
`2008.
`[Reserved]
`2009. Subsys® Highlights of Prescribing Information. Revised: 01/2012.
`2010. Murthy & Kar, Disperse Systems, in PHARMACEUTICAL TECHNOLOGY
`VOLUME I (NEW AGE INTERNATIONAL (P) LTD., PUBLISHERS, 2013).
`
`2011. Ross et al., 2004. “Novel Compositions.” (WO 2004/080382).
`
`2012.
`
`[Reserved]
`
`2013. Sakane et al., 1991. “The transport of a drug to the cerebrospinal fluid
`directly from the nasal cavity: the relation to the lipophilicity of the drug.”
`Chem Pharm Bull (Tokyo) 39(9):2456–68.
`
`vi
`
`

`
`Case IPR2015-01800
`
`LIST OF EXHIBITS
`(continued)
`2014. Sarkar, 1992. “Drug metabolism in the nasal mucosa.” Pharm Res 9(1):1–
`9.
`
`2015. Watts et al., 2015. “Intranasal Spray Device Containing Pharmaceutical
`Composition.” U.S. Patent Application Publication 2015/0283123 A1.
`
`2016. Bredenberg. Copy of Ex. 1006 from Coal. For Affordable Drugs XI LLC v.
`Insys Pharma, Inc., IPR2015-01797.
`
`2017.
`
`[Reserved]
`
`2018. U.S. Patent No. 8,835,459 to Kottayil et al., issued on Sept. 16, 2014.
`
`2019. McCoy et al., 2001. “Formulation and system for intra-oral delivery of
`pharmaceutical agents.” (WO 00/47203 A1).
`
`2020.
`
`[Reserved]
`
`2021.
`
`[Reserved]
`
`2022.
`
`[Reserved]
`
`2023.
`
`[Reserved]
`
`2024.
`
`2025.
`
`Information Disclosure Sheet, filed Aug. 15, 2011, in U.S. Patent
`Application No. 11/698,739. (Initialed by Examiner).
`
`Information Disclosure Sheet, filed June 21, 2010, in U.S. Patent
`Application No. 11/698,739. (Initialed by Examiner).
`
`2026. Vasisht et al., 2010. “Single-dose pharmacokinetics of fentanyl buccal
`soluble film.” Pain Med 11(7): 1017–23.
`
`2027. Chen et al., 2002. “Identification of the enzymatic mechanism of
`nitroglycerin bioactivation.” PNAS 99(12): 8306–8311.
`
`2028.
`
`[Reserved]
`
`2029.
`
`[Reserved]
`
`vii
`
`

`
`Case IPR2015-01800
`
`LIST OF EXHIBITS
`(continued)
`2030. Coal. For Affordable Drugs XI LLC v. Insys Pharma, Inc., IPR2015-
`01797, Paper 1 (Aug. 24, 2015).
`
`
`
`viii
`
`

`
`
`I.
`
`Introduction
`
`Case IPR2015-01800
`
`U.S. Patent No. 8,486,972 (“the ’972 patent”) is one of four U.S. patents
`
`directed to Subsys®, the first and only fentanyl sublingual spray, developed by
`
`Patent Owner Insys Pharma, Inc. (“Patent Owner” or “Insys”). Subsys is the most-
`
`prescribed brand-name drug of its class for treating breakthrough cancer pain.
`
`Petitioner Coalition For Affordable Drugs XI, LLC (“Petitioner” or “CFAD”), a
`
`subsidiary of an investment fund managed by Kyle Bass, filed the petition for inter
`
`partes review (“the Petition”). CFAD also has filed petitions against two related
`
`patents directed to Subsys®: U.S. Patent Nos. 8,835,459 (at issue in IPR2015-
`
`01797) and 8,835,460 (at issue in IPR2015-01799).
`
`This Preliminary Response, submitted in accordance with 35 U.S.C. § 313
`
`and 37 C.F.R. § 42.107, explains the many reasons why the Patent Trial and
`
`Appeal Board (“the Board”) should not institute a trial. As demonstrated below,
`
`CFAD has asserted grounds based on information the Examiner already considered
`
`and in fact applied during prosecution. In addition, CFAD’s obviousness
`
`arguments do not address each and every claim feature, and they fail to explain
`
`why one of ordinary skill would have arrived at the claimed invention. CFAD
`
`makes hindsight-driven attempts to plug the holes in each ground, relying on bald
`
`assertions that some claim elements could have been discovered through routine
`
`optimization and that others would have been known from non-analogous art. To
`
`1
`
`

`
`
`make matters worse, CFAD sidesteps its obligation to construe critical claim terms.
`
`Case IPR2015-01800
`
`In sum, CFAD simply has not shown a reasonable likelihood that it would prevail
`
`on any ground. Therefore, Patent Owner respectfully submits that the Board
`
`should decline to institute a trial.
`
`II. Background
`Many cancer patients suffer periodic flares of pain, varying in intensity and
`
`duration, that come quickly and without warning. Every second is agony, and
`
`patients need convenient, strong, and fast-acting medication. To fill that need,
`
`Insys developed Subsys®, the first and only FDA-approved sublingual spray for
`
`treating breakthrough cancer pain.
`
`Unlike the breakthrough pain medications marketed before it (e.g., Actiq®
`
`lozenges and Abstral® tablets), Subsys® conveniently provides significant pain
`
`relief as soon as five minutes after dosing. See, e.g., Ex. 1015. Doctors and
`
`patients have overwhelmingly accepted this benefit such that within three years of
`
`entering the market, Subsys® has achieved nearly 50% market share, surpassing all
`
`five pre-existing competitors (including Actiq® and its generic counterpart) to
`
`become the most prescribed branded drug of its kind. See infra at 43–44 (sales
`
`data).
`
`Developing Subsys® was no easy task. Its solid-form competitors (e.g.,
`
`lozenges and buccal tablets) require release and dispersal before absorption from
`
`2
`
`

`
`
`dissolved form—a relatively slow process that increases the likelihood of
`
`Case IPR2015-01800
`
`swallowing the drug, which decreases bioavailability and relief of breakthrough
`
`pain. See, e.g., Ex. 1001, col. 1, l. 59–col. 2, 1. 2. Insys set out to create a faster,
`
`more reliable alternative: liquid sublingual formulations. This new path was
`
`fraught with technical challenges. Among other things, the ’972 patent’s inventors
`
`were concerned with optimizing the in vivo permeability profile for faster onset of
`
`action; stability in solution; sufficient solubility; palatability; preventing microbial
`
`growth without creating unwanted chemical reactions; and creating a liquid
`
`capable of being dispersed in a fine mist comprising droplets with high surface
`
`area, but without being prone to inhalation and deposition in the airways. See, e.g.,
`
`Ex. 2010, pp. 4, 13; Ex. 2002, p. 1.
`
`After years of research and development—which CFAD now dismisses as a
`
`“matter of routine”—Insys created and developed Subsys® through clinical trials.
`
`Claims 1–3 of the ’972 patent recite specific combinations of three particular
`
`ingredients (fentanyl, ethanol, and propylene glycol), as well as specific
`
`pharmacokinetic parameters. Extensive clinical trials have shown that the claimed
`
`inventions provide, among other things, significant pain relief in as few as five
`
`minutes. See, e.g., Ex. 1015.
`
`3
`
`

`
`
`III. The Board Should Exercise Its Discretion Under 35 U.S.C. § 325(d)
`Under 35 U.S.C. § 325(d), “the Director may take into account whether, and
`
`Case IPR2015-01800
`
`reject the petition or request because, the same or substantially the same prior art or
`
`arguments previously were presented to the Office.” The Board has exercised that
`
`authority to deny institution of IPRs based on art or arguments presented during
`
`prosecution. See e.g., Hulu LLC v. Intertainer, Inc., IPR2014-01456, Paper 8, at
`
`7–8 (Mar. 6, 2015); Prism Pharma Co. v. Choogwae Pharma Corp., IPR2014-
`
`00315, Paper 14, at 12–13 (July 8, 2014); Excelsior Med. Corp. v. Lake, IPR2013-
`
`00494, Paper 10, at 20 (Feb. 6, 2014).
`
`References asserted in all grounds of the Petition, or references disclosing
`
`the same or substantially the same information, were considered by and discussed
`
`with the Office during prosecution of the ’972 patent. To the extent the allegedly
`
`new secondary reference was not expressly considered, it is deficient for other
`
`reasons (e.g., it is not analogous art). As explained in detail below, and pursuant to
`
`35 U.S.C. § 325(d), the Board should deny the Petition in its entirety.
`
`A. Ross_US2006 (Ex. 1005) Was Considered by the Office
`Grounds 1 and 2 of the Petition rely on U.S. Patent Application Publication
`
`2006/0062812 by Calvin Ross, et al. (“Ross_US2006”; Ex. 1005). (Pet. at 5–6.)
`
`Ross_US2006 is a published U.S. patent application by Calvin Ross et al. (Pet.
`
`at 4–5.) CFAD alleges that it discloses aspects of sublingual fentanyl spray
`
`4
`
`

`
`
`formulations having certain pharmacokinetic parameters as recited in claims 1–3 of
`
`Case IPR2015-01800
`
`the ’972 patent. (Pet. at 35–41.) However, the Examiner already considered
`
`Ross_US2006—in fact, it served as the basis of multiple rejections during
`
`prosecution of the ’972 patent. (Pet. at 12–15.)
`
`B.
`Substantially the Same Information as That Contained in Ross_GB
`(Ex. 1003) Was Considered by the Office
`
`Grounds 1 and 2 of the Petition rely on Great Britain Patent Publication
`
`GB2399286A by Calvin Ross, et al. (“Ross_GB”; Ex. 1003). (Pet. at 4–6.) CFAD
`
`alleges that it discloses aspects of sublingual fentanyl formulations as recited in
`
`claims 1–3 of the ’972 patent. (Pet. at 27–42.) The Examiner considered the
`
`content of Ross_GB at least twice. First, the Examiner considered International
`
`Patent Application Publication WO 2004/080382 by Calvin Ross, et al. (“the ’382
`
`publication”; Ex. 2011), the disclosure of which is identical to Ross_GB.
`
`Ex. 2025, p. 2. Second, the Examiner repeatedly applied Ross_US2006 (as
`
`discussed above), whose disclosure subsumes that of Ross_GB. Indeed, CFAD’s
`
`arguments hinge on disclosures in Ross_GB that also appear in Ross_US2006:
`
` Ross_GB states that “single or multiple use devices comprising a
`
`single or multiple dose of the formulation of the invention [are]
`
`envisaged.” Ex. 1003, p. 8, ll. 25–26. Ross_US2006 recites the same.
`
`Ex. 1005, ¶ [0066].
`
`5
`
`

`
`
`
`Case IPR2015-01800
`
` Ross_GB states that “[t]he formulations of the present invention are
`
`also preferably free of any propellant.” Ex. 1003, p. 4, l. 1.
`
`Ross_US2006 states that “[t]he formulations . . . are free of
`
`propellants.” Ex. 1005, ¶ [0029].
`
` Ross_GB recites a “pharmaceutical formulation comprising
`
`(i) fentanyl.” Ex. 1003 (Abstract). Ross_US2006 discloses a
`
`“pharmaceutical formulation compris[ing]: (a) fentanyl.” Ex. 1005,
`
`¶¶ [0018]–[0019].
`
` Ross_GB recites a product “preferably administered sublingually as a
`
`spray.” It further states, “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.” Ex. 1003, p. 3, ll. 29–32. Ross_US2006 recites the
`
`same. Ex. 1005, ¶ [0022].
`
` Ross_GB states that “a therapeutically effective amount of a
`
`formulation for the treatment of pain according to the invention is
`
`used.” Ex. 1003, p. 8, ll. 10–11. Ross_US2006 recites the same.
`
`Ex. 1005, ¶ [0063].
`
` Ross_GB recites “(a) fentanyl or a pharmaceutically acceptable salt
`
`thereof; (b) water as carrier; and (c) a polar organic solvent in
`
`6
`
`

`
`
`
`Case IPR2015-01800
`
`sufficient amount to enhance the solubility of the fentanyl or
`
`pharmaceutically acceptable salt thereof in the water.” Ex. 1003, p. 3,
`
`ll. 24–27. Ross_US2006 recites the same. Ex. 1005, ¶ [0019]–
`
`[0021].
`
` Ross_GB contains Example 1, as a formulation comprising fentanyl
`
`base (0.0280g), saccharin (0.0177g), absolute ethanol (2.8336g),
`
`menthol (0.0531g), and citrate buffer (4.1516g). Ex. 1003, p. 11,
`
`ll. 1–9. Ross_US2006 discloses an Example 1 formulation
`
`comprising the same. Ex. 1005, ¶ [0096].
`
` Ross_GB states, “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.” Ex. 1003, p. 5, ll. 1–4.
`
`Ross_US2006 recites the same. Ex. 1005, ¶ [0037].
`
` Ross_GB states, “Suitable moisturizing agents include, for example,
`
`the polar organic solvents such as glycols, especially propylene
`
`glycol.” Ex. 1003, p. 7, ll. 11–14. Ross_US2006 recites the same.
`
`Ex. 1005, ¶ [0057].
`
`7
`
`

`
`
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`Case IPR2015-01800
`
` Ross_GB recites “formulations of fentanyl, especially pump spray
`
`formulations suitable for sublingual delivery.” Ex. 1003, p. 1, ll. 3–4.
`
`Ross_US2006 discloses “formulations of opioid analgesics and in
`
`particular fentanyl, especially pump spray formulations suitable for
`
`sublingual delivery.” Ex. 1005, ¶ [0002].
`
` Ross_GB states, “[T]he formulations of the invention are preferably
`
`administered sublingually as a spray.” Ex. 1003, p. 3, ll. 29–30.
`
`Ross_US2006 discloses “[t]he formulations of the invention may be
`
`used in analgesia and for the treatment of pain. They are preferably
`
`administered sublingually as a spray.” Ex. 1005, ¶ [0022].
`
` Ross_GB recites “monitor[ing] patients for evidence of
`
`self[-]medication.” Ex. 1003, p. 1, l. 15. Ross_US2006 recites the
`
`same. Ex. 1005, ¶ [0007].
`
`Rather than admitting that information cited in Ross_GB also exists in the
`
`already-considered-and-applied Ross_US2006, CFAD presents Ross_GB as if it
`
`contains distinct and complementary disclosures that “one of ordinary skill in the
`
`art would have been motivated to combine [with] the teachings of Ross_US2006.”
`
`(Pet. at 36–37.) As shown above, CFAD’s position is incorrect. CFAD’s
`
`arguments hinge on disclosures in Ross_GB that also appear in Ross_US2006.
`
`8
`
`

`
`
`C. The ’496 Publication (Ex. 1006) Was Considered by the Office
`Ground 2 of the Petition relies on U.S. Patent Application Publication
`
`Case IPR2015-01800
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`2002/0055496 A1 by Randall McCoy, et al. (“the ’496 publication”; Ex. 1006).
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`(Pet. at 5–6.) CFAD alleges that it discloses discrete liquid droplets having a size
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`distribution of from about 10 µm to about 200µm, as recited in claim 2 of the ’972
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`patent. (Pet. at 40–42.) However, the Examiner already considered the ’496
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`publication. Ex. 2024.
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`In addition to considering the ’496 publication itself, the Examiner
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`considered a related application by McCoy et al. (International Publication Number
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`WO 00/47203 (“the ’203 publication”; Ex. 2019)), which contains language
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`identical to that CFAD cites in the ’496 publication. Ex. 2025, p. 2. More
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`specifically, CFAD cites to three particular paragraphs in the ’496 publication:
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`[0041], [0019], and [0031]. (Pet. at 41 nn.112–13, 42 n.116.) Each of these
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`paragraphs appears, verbatim, in the ’203 publication. Ex. 2019, p. 16, ll. 11–22;
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`id., p. 6, l. 20–p. 7, l. 6; id., p. 11, ll. 5–23 (corresponding to Ex. 1006, ¶¶ [0041],
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`[0019], and [0031], respectively).
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`D. CFAD’s Newly Presented Reference Is Deficient
`Though CFAD’s secondary reference (U.S. Patent 5,370,862 (“the ’862
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`patent”; Ex. 1004) may not have been considered by the Examiner during
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`prosecution of the ’972 patent, it is deficient for other reasons. For example, the
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`’862 patent does not concern non-propellant formulations of fentanyl, as claimed
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`in the ’972 patent. Rather, it concerns an aerosol (i.e., propellant-containing)
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`nitroglycerin spray for treating angina (see infra Section IV.A.3).
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`E. Conclusion
`In sum, three of the four references asserted in the Petition, or references
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`disclosing the same or substantially the same information, were considered by the
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`Examiner during prosecution of the ’972 patent. While one secondary reference
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`was not expressly considered, it is deficient, at least because it pertains to non-
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`analogous art. Therefore, the Board should exercise its discretion under 35 U.S.C.
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`§ 325(d) and deny the Petition in its entirety.
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`IV. CFAD Advances Flawed Obviousness Analyses
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences between
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`the subject matter sought to be patented and the prior art are such that the subject
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`matter as a whole would have been obvious at the time the invention was made to a
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`person having ordinary skill in the art to which said subject matter pertains. KSR
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`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). Obviousness is a question of
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`law based on underlying factual findings, including: (1) the scope and content of
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`the prior art; (2) the differences between the claims and the prior art; (3) the level
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`of ordinary skill in the art; and (4) objective indicia of nonobviousness. Graham v.
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`John Deere Co. of Kan. City, 383 U.S. 1, 17–18 (1966). All four Graham factors
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`must be considered in considering an assertion of obviousness. In re
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`Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d
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`1063, 1075, 1077, 1080 (Fed. Cir. 2012); Intri-Plex Techs., Inc. v. Saint-Gobain
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`Performance Plastics Rencol Ltd., IPR2014-00309, Paper 83, at 45–46 (Mar. 23,
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`2015).
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`A determination of unpatentability on the ground of obviousness must
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`include “articulated reasoning with some rational underpinning to support the legal
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`conclusion of obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The
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`obviousness analysis “should be made explicit” and it “can be important to identify
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`a reason that would have prompted a person of ordinary skill in the relevant field to
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`combine the elements in the way the claimed new invention does.” KSR, 550 U.S.
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`at 418.
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`CFAD proposes two grounds of rejection against the ’972 patent, each
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`asserting that certain claims are obvious under 35 U.S.C. § 103(a). In each
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`instance, however, CFAD’s obviousness analysis is defective and should be
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`rejected.
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`A. Ground 1: Claims 1 and 3 Are Not Obvious Over Ross_GB (Ex. 1003),
`Ross_US2006 (Ex. 1005), and the ’862 Patent (Ex. 1004)
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`Claim 1 is directed to a unit dose of a non-propellant sublingual formulation
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`comprising discrete liquid droplets of an effective amount of fentanyl and a
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`pharmaceutically acceptable liquid carrier, wherein the sublingual fentanyl
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`formulation comprises from about 0.1% to about 0.8% by weight fentanyl or a
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`pharmaceutically acceptable salt thereof, from about 20% to about 60% by weight
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`ethanol, and from about 4% to about 6% by weight propylene glycol, the
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`formulation providing a mean Tmax of about 5 to about 120 minutes when a dose is
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`administered sublingually to humans. Claim 3 depends from claim 1 and further
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`recites that administration to humans provides a mean Tmax of about 10 to about
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`60 minutes.
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`CFAD asserts that claims 1 and 3 are obvious over the combination of
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`Ross_GB, Ross_US2006, and the ’862 patent. CFAD’s analysis is deficient for a
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`number of reasons. In particular, CFAD fails to show how the references disclose
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`each and every feature recited in claim 1 (see infra Section IV.A.1), fails to explain
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`why one of ordinary skill would have been motivated to combine the asserted
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`references in the manner proposed (see infra Section IV.A.2), and resorts to non-
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`analogous art and conclusory allegations of obviousness (see infra Section IV.A.3).
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`1.
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`CFAD Fails to Explain How the References Disclose or
`Suggest the Features of Claims 1 and 3
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`CFAD cites Example 1 of Ross_GB, which purportedly discloses a fentanyl
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`formulation comprising 0.395% by weight of fentanyl and 40% by weight of
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`ethanol. (Pet. at 30.) CFAD also points to two generic disclosures of propylene
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`glycol in Ross_GB (Pet. at 31–32.), the first mentioning propylene glycol among a
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`list of many possible polar organic solvents (Ex. 1003, p. 5, ll. 1–5) and the second
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`mentioning propylene glycol among a list of many possible moisturizing agents
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`(Ex. 1003, p. 7, ll. 11–14). In addition, CFAD cites the ’862 patent, which is
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`directed to an aerosol nitroglycerin product, allegedly comprising propylene glycol
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`in a general range of 2% to 30% by weight, with a specific formulation comprising
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`propylene glycol at 7.28% by weight. (Pet. at 32.) Finally, CFAD argues that the
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`claimed Tmax element is obvious in view of Ross_US2006’s Table 2. (Pet. at 34–
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`37.)
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`The asserted references, however, fail to disclose elements of claim 1 of the
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`’972 patent. For example, none of the asserted references disclose the specific
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`range of “about 4% to about 6% by weight propylene glycol.” While Ross_GB
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`generically mentions propylene glycol among many possible polar organic solvents
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`and moisturizing agents, it does not teach or suggest the specific claimed range of
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`“about 4% to about 6% by weight propylene glycol.” In an attempt to cure that
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`deficiency, CFAD relies on the ’862 patent. (Pet. at 32–33.)
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`Though the ’862 patent discloses broad ranges of propylene glycol, such as
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`2–60% (see, e.g., Ex. 1004, Abstract) and 2–30% (see, e.g., id., col. 4, l. 63), it
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`does not teach or suggest the much narrower claimed range of “about 4% to about
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`6% by weight propylene glycol.” And to the extent that CFAD alleges the ’862
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`patent discloses a formulation comprising 7.28% by weight propylene glycol,
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`which it argues “meets the upper bound of . . . about 6% of propylene glycol” (Pet.
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`at 32), CFAD proposes no construction for the claim term “about.” In any event,
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`accepting CFAD’s argument on this point would mean the claims encompass
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`concentrations more than 20% above the recited amounts.
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`Furthermore, CFAD has not addressed how the percentage by weight of
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`propylene glycol in a closed and charged aerosol canister would change upon
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`dispensation, prior to sublingual delivery. Indeed, when an aerosol is dispensed,
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`its once-liquid CFC components rapidly evaporate and disperse into the air,
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`leaving non-evaporated components to take on an increased percentage by weight
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`of the formulation actually delivered to target tissue. Ex. 2003, p. 3; Ex. 2001,
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`p. 492. With respect to the ’862 patent, CFAD cites to formulations within aerosol
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`canisters. (Pet. at 32 (citing Ex. 1004 at col. 4, l. 63, which are clos