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 IPR2015-01797
`Patent 8,835,459
`
`______________________
`
`Patent Owner’s Preliminary Response
`to Petition for Inter Partes Review
`of U.S. Patent No. 8,835,459
`
`
`
`

`

`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.
`
`Ross_US2006 (Ex. 1005) Was Considered by the Office .................... 5
`
`Substantially the Same Information as That Contained in Ross_GB
`(Ex. 1003) Was Considered by the Office ............................................ 5
`
`CFAD’s Newly Presented References Are Deficient ........................... 9
`
`Conclusion ........................................................................................... 10
`
`IV. CFAD Advances Flawed Obviousness Analyses .......................................... 10
`
`A. Ground 1: Claim 1 Is Not Obvious Over Ross_GB (Ex. 1003),
`Ross_US2006 (Ex. 1005), and the ’862 Patent (Ex. 1004)................. 12
`
`B.
`
`1.
`
`2.
`
`3.
`
`1.
`
`2.
`
`3.
`
`CFAD Fails to Explain How the References Disclose or Suggest
`the Features of Claim 1 .................................................................. 12
`
`CFAD Fails to Explain Why One of Ordinary Skill Would Have
`Combined the Asserted References ............................................... 15
`
`CFAD Resorts to Non-Analogous Art and Conclusory Allegations
`of Obviousness ............................................................................... 19
`
`Ground 2: Claims 2 and 3 Are Not Obvious Over Ross_GB
`(Ex. 1003), Ross_US2006 (Ex. 1005), the ’862 Patent (Ex. 1004), and
`Bredenberg (Ex. 1006) ........................................................................ 23
`
`CFAD Fails to Explain How the References Disclose or Suggest
`the Features of Claims 2 and 3 ....................................................... 25
`
`CFAD Fails to Explain Why One of Ordinary Skill Would Have
`Combined the Asserted References ............................................... 26
`
`CFAD Resorts to Conclusory Allegations of Obviousness ........... 28
`
`i
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`Ground 3: Claim 4 Is Not Obvious Over Ross_US2006 (Ex. 1005)
`and Bredenberg (Ex. 1006) ................................................................. 31
`
`C.
`
`
`
`D. Ground 4: Claims 4 and 5 Are Not Obvious Over Ross_GB
`(Ex. 1003) and Actiq_Excerpt (Ex. 1008) .......................................... 32
`
`E.
`
`F.
`
`G.
`
`Ground 5: Claim 6 Is Not Obvious Over Ross_GB (Ex. 1003),
`Actiq_Excerpt (Ex. 1008), and Bredenberg (Ex. 1006) ...................... 34
`
`CFAD’s Grounds Rely on Improper Hindsight .................................. 35
`
`CFAD Fails to Adequately Address Evidence of Secondary
`Considerations ..................................................................................... 36
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Commercial Success ...................................................................... 37
`
`Failure of Others ............................................................................ 39
`
`Long-Felt Need .............................................................................. 39
`
`Skepticism ...................................................................................... 40
`
`Unexpected Results ........................................................................ 41
`
`V.
`
`CFAD’s Claim Construction Analysis Is Deficient ...................................... 42
`
`VI. CFAD Improperly Relies on Material That It Fails to Establish Is Statutory
`Prior Art ......................................................................................................... 44
`
`A.
`
`B.
`
`CFAD Fails to Establish that Bredenberg (Ex. 1006) Is Statutory Prior
`Art ........................................................................................................ 46
`
`CFAD Fails to Establish that the Actiq_Excerpt (Ex. 1008) is
`Statutory Prior Art ............................................................................... 47
`
`VII. CFAD Advances Redundant Grounds of Rejection ...................................... 49
`
`VIII. Conclusion ..................................................................................................... 50
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`
`CASES
`
`A.R.M., Inc. v. Cottingham Agencies Ltd.,
`IPR2014-00671, Paper 10 (Oct. 3, 2014) ..................................................... 45, 49
`
`Page(s)
`
`Actavis, Inc. v. Research Corp. Techs., Inc.,
`IPR2014-01126, Paper 22 (Jan. 9, 2015) ............................................................ 45
`
`Apple Inc. v. ITC,
`725 F.3d 1356 (Fed. Cir. 2013) .......................................................................... 37
`
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys., Inc.,
`725 F.3d 1342 (Fed. Cir. 2013) .......................................................................... 35
`
`Circuit Check Inc. v. QXQ Inc.,
`795 F.3d 1331 (Fed. Cir. 2015) .......................................................................... 19
`
`Coal. For Affordable Drugs III LLC v. Jazz Pharms., Inc.,
`IPR2015-01018, Paper 17 (Oct. 15, 2015) ......................................................... 45
`
`Coal. For Affordable Drugs IV LLC v. Pharmacyclics, Inc.,
`IPR2015-01076, Paper 33 (Oct. 19, 2015) ......................................................... 45
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 11, 18
`
`Dell, Inc. et al. v. Selene Commc’n Techs., LLC,
`IPR2014-01411, Paper 23 (Feb. 26, 2015) ......................................................... 48
`
`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) ............................................................................ 22
`
`FriendFinder Networks Inc. v. WAG Acquisition, LLC,
`IPR2015-01033, Paper 8 (Oct. 19, 2015) ........................................................... 47
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Graham v. John Deere Co. of Kan. City,
`
`383 U.S. 1 (1966) ................................................................................................ 11
`
`Page(s)
`
`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, 37
`
`Jiawei Tech. (HK) Ltd. et al. v. Richmond,
`IPR2014-00938, Paper 20 (Dec. 16, 2014)......................................................... 42
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 11
`
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) .......................................................................... 45
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................ 10, 11, 17
`
`L-3 Comm. Holdings, Inc. v. Power Survey, LLC,
`IPR2014-00832, Paper 9 (Nov. 14, 2014) .......................................................... 45
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 22
`
`Liberty Mut. Ins. Co. v. Progressive Cas. Ins. Co.,
`CBM2013-00009, Paper 68 (Feb. 11, 2014) ............................................... 48, 49
`
`Monarch Knitting Mach. Corp. v. Sulzer Moral GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 41
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .................................................................... 22, 41
`
`Panduit Corp. v. Dennison Mfg. Co.,
`774 F.2d 1082 (Fed. Cir. 1985) .......................................................................... 39
`
`iv
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`Pfizer, Inc. v. Apotex, Inc.,
`
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 21, 22
`
`Page(s)
`
`Prism Pharma Co. v. Choogwae Pharma Corp.,
`IPR2014-00315, Paper 14 (July 8, 2014) ............................................................. 4
`
`Schott Gemtron Corp. v. SSW Holding Co., Inc.,
`IPR2014-00367, Paper 62 (May 26, 2015) ......................................................... 19
`
`Square, Inc. v. Unwired Planet, LLC,
`CBM2014-00156, Paper 22 (Feb. 26, 2015) ................................................ 46, 47
`
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ............................................................................ 22
`
`Star Sci., Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .......................................................................... 37
`
`Std. Innovation Corp. v. Lelo, Inc.,
`IPR2014-00148, Paper 41 (Apr. 23, 2015) ......................................................... 46
`
`Syntex (USA) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) .......................................................................... 39
`
`Zetec, Inc. v. Westinghouse Elec. Co., LLC,
`IPR2014-00384, Paper 10 (July 23, 2014) ......................................................... 43
`
`STATUTES
`
`35 U.S.C.
`§ 103(a) ......................................................................................................... 10, 11
`§ 311(b) ............................................................................................................... 44
`§ 313 ...................................................................................................................... 1
`§ 325(d) ........................................................................................................... 4, 10
`§ 326(b) ............................................................................................................... 49
`
`v
`
`

`

`TABLE OF AUTHORITIES
`(continued)
`
`OTHER AUTHORITIES
`
`37 C.F.R.
`§ 42.1(b) .............................................................................................................. 49
`§ 42.104(b)(3) ..................................................................................................... 42
`§ 42.104(b)(3)–(5) .............................................................................................. 43
`§ 42.107 ................................................................................................................. 1
`
`Page(s)
`
`
`
`vi
`
`

`

`Case IPR2015-01797
`
`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.
`
`vii
`
`

`

`Case IPR2015-01797
`
`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.
`
`[Reserved]
`
`2017. Declaration of Dr. Larry Dillaha, M.D., signed Sept. 17, 2012, in U.S.
`Patent Application No. 11/698,739.
`
`2018.
`
`[Reserved]
`
`2019.
`
`[Reserved]
`
`2020.
`
`Information Disclosure Sheet, filed July 22, 2013, in U.S. Patent
`Application No. 13/895,111. (Initialed by Examiner).
`
`2021.
`
`[Reserved]
`
`2022.
`
`[Reserved]
`
`2023.
`
`[Reserved]
`
`2024.
`
`[Reserved]
`
`2025.
`
`[Reserved]
`
`2026.
`
`[Reserved]
`
`2027. Chen et al., 2002. “Identification of the enzymatic mechanism of
`nitroglycerin bioactivation.” PNAS 99(12): 8306–8311.
`
`2028.
`
`[Reserved]
`
`2029.
`
`[Reserved]
`
`2030.
`
`[Reserved]
`
`
`
`viii
`
`

`

`
`I.
`
`Introduction
`
`Case IPR2015-01797
`
`U.S. Patent No. 8,835,459 (“the ’459 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. 8,486,972 (at issue in IPR2015-
`
`01800) 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. In
`
`1
`
`

`

`
`fact, at least one asserted reference teaches away from the claimed inventions. To
`
`Case IPR2015-01797
`
`make matters worse, CFAD sidesteps its obligations to construe critical claim
`
`terms and to show that the asserted references qualify to serve as the basis for an
`
`inter partes review. 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. 2017. 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 38–39 (sales
`
`data).
`
`2
`
`

`

`
`
`Case IPR2015-01797
`
`Developing Subsys® was no easy task. Its solid-form competitors (e.g.,
`
`lozenges and buccal tablets) require release and dispersal before absorption from
`
`dissolved form—a relatively slow process that increases the likelihood of
`
`swallowing the drug, which decreases bioavailability and relief of breakthrough
`
`pain. See, e.g., Ex. 1001, col. 2, ll. 1–11. 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 ’459 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
`
`“matter[s] of routine”—Insys created and developed Subsys® through clinical
`
`trials. Claims 1–3 of the ’459 patent recite specific combinations of three
`
`particular ingredients (fentanyl, ethanol, and propylene glycol), as well as specific
`
`pharmacokinetic parameters. Similarly, Claims 4–6 are directed to sublingual
`
`fentanyl spray formulations with specific pharmacokinetic parameters. Extensive
`
`3
`
`

`

`
`clinical trials have shown that the claimed inventions provide, among other things,
`
`Case IPR2015-01797
`
`significant pain relief in as few as five minutes. See, e.g., Ex. 2017.
`
`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
`
`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 ’459 patent. To the extent allegedly new
`
`secondary references were not expressly considered, they are deficient for other
`
`reasons (e.g., they are not analogous art or involve solid-form fentanyl
`
`preparations, which present different challenges than those faced by the inventors
`
`at least with respect to formulation, desired pharmacokinetic profile, and efficacy).
`
`As explained in detail below, and pursuant to 35 U.S.C. § 325(d), the Board should
`
`deny the Petition in its entirety.
`
`4
`
`

`

`
`A. Ross_US2006 (Ex. 1005) Was Considered by the Office
`Grounds 1–3 of the Petition rely on U.S. Patent Application Publication
`
`Case IPR2015-01797
`
`2006/0062812 by Calvin Ross, et al. (“Ross_US2006”; Ex. 1005). (Pet. at 4–5.)
`
`CFAD alleges that it discloses aspects of sublingual fentanyl spray formulations
`
`having certain pharmacokinetic parameters as recited in claims 1–4 of the ’459
`
`patent. (Pet. at 24–49.) However, the Examiner already considered
`
`Ross_US2006—in fact, it served as the basis of a rejection during prosecution of
`
`the ’459 patent. Ex. 1016, p. 4 (item C). In response, Applicant amended the
`
`claims to recite specific concentrations of fentanyl, ethanol, and propylene glycol
`
`not taught in Ross_US2006. Ex. 1017, p 2. The Examiner then issued a Notice of
`
`Allowance dated May 1, 2014. Ex. 1019.
`
`B.
`
`Substantially the Same Information as That Contained in Ross_GB
`(Ex. 1003) Was Considered by the Office
`
`Grounds 1, 2, 4, and 5 of the Petition rely on Great Britain Patent
`
`Publication GB2399286A by Calvin Ross, et al. (“Ross_GB”; Ex. 1003). (Pet.
`
`at 7.) Ross_GB is a Great Britain patent publication by Calvin Ross, et al. (Pet.
`
`at 3–4.) CFAD alleges that it discloses aspects of sublingual fentanyl formulations
`
`as recited in claims 1–6 of the ’459 patent. (Pet. at 24–59.) Though CFAD
`
`concedes that aspects of Ross_US2006 and Ross_GB “are very similar” (Pet.
`
`at 32), it nevertheless suggests that “[t]he Examiner would not have allowed any of
`
`the claims of the ’459 patent if he had known of Ross_GB” (Pet. at 10), which in
`
`5
`
`

`

`
`turn suggests that the Examiner never considered the material from Ross_GB. But
`
`Case IPR2015-01797
`
`the Examiner did in fact consider the material from Ross_GB.
`
`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. See Ex. 2020, p. 6. Second, the
`
`Examiner 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 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].
`
`6
`
`

`

`
`
`Case IPR2015-01797
`
` 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, “The concentration of polar organic solvent is in the
`
`range preferably of between 6 and 50%, more preferably 20-45%[,]
`
`especially 35-42%.” Ex. 1003, p. 5, ll. 22–23. Ross_US2006 recites
`
`the same. Ex. 1005, ¶ [0042].
`
` Ross_GB states, “The preferred polar organic solvent is ethanol.”
`
`Ex. 1003, p. 5, ll. 7–8. Ross_US2006 recites the same. Ex. 1005,
`
`¶ [0038].
`
` 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
`
`7
`
`

`

`
`
`Case IPR2015-01797
`
`glycol.” Ex. 1003, p. 7, ll. 11–14. Ross_US2006 recites the same.
`
`Ex. 1005, ¶ [0057].
`
` 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].
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` Ross_GB states, “[T]he formulations of the invention are preferably
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`administered sublingually as a spray.” Ex. 1003, p. 3, ll. 29–30.
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`Ross_US2006 discloses “[t]he formulations of the invention may be
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`used in analgesia and for the treatment of pain. They are preferably
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`administered sublingually as a spray.” Ex. 1005, ¶ [0022].
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` Ross_GB recites “monitor[ing] patients for evidence of
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`self[-]medication.” Ex. 1003, p. 1, l. 15. Ross_US2006 recites the
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`same. Ex. 1005, ¶ [0007].
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` Ross_GB recites “a formulation comprising 400 μg fentanyl.”
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`Ex. 1003, p. 10, l. 9. Ross_US2006 recites the same. Ex. 1005,
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`¶ [0031].
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` Ross_GB recites “the target dose is 400 μg per actuation.” Ex. 1003,
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`p. 11, ll. 9, 18, 26; p. 12, l. 2. Ross_US2006 recites the same.
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`Ex. 1005, ¶¶ [0096]–[0099].
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`Rather than admitting that information cited in Ross_GB also exists in the
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`already-considered-and-applied Ross_US2006, CFAD presents Ross_GB as if it
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`contains distinct and complementary disclosures that “one of ordinary skill in the
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`art would have been motivated to combine [with] the teachings of Ross_US2006.”
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`(Pet. at 33.) As shown above, CFAD’s position is incorrect. CFAD’s arguments
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`hinge on disclosures in Ross_GB that also appear in Ross_US2006.
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`C. CFAD’s Newly Presented References Are Deficient
`Though some of CFAD’s secondary references (U.S. Patent 5,370,862 (“the
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`’862 patent”; Ex. 1004), Bredenberg (Ex. 1006), and Actiq_Excerpt (Ex. 1008))
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`may not have been considered by the Examiner during prosecution of the ’459
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`patent, they are deficient for other reasons. For example, CFAD relies on
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`Actiq_Excerpt for its disclosure related to Actiq®. But information relating to
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`Actiq® was considered during prosecution. In fact, the ’459 patent discusses
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`Actiq® and shows how it is different from the inventions of the ’459 patent. See,
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`e.g., Ex. 1001, col. 61, l. 37–col. 65, l. 24. In addition, none of these other
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`references concern sublingual liquid formulations of fentanyl. Rather, the ’862
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`patent concerns an aerosol nitroglycerin spray for treating angina (see infra Section
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`IV.A.3), while Bredenberg and Actiq_Excerpt concern solid-form fentanyl citrate
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`Case IPR2015-01797
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`(see, e.g., infra Sections IV.B and IV.D). In addition, CFAD fails to demonstrate
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`that two of these references, Bredenberg and Actiq_Excerpt, qualify as printed
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`publications upon which inter partes review proceedings may be based. See infra
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`Section VI.
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`D. Conclusion
`In sum, nearly all of the references asserted in the Petition, or references
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`disclosing the same or substantially the same information, were considered by and
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`discussed with the Examiner during prosecution of the ’459 patent. While certain
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`secondary references were not expressly considered, these additional references are
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`deficient, at least because they pertain to non-analogous art and have not been
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`shown to qualify as printed publications. Therefore, the Board should exercise its
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`discretion under 35 U.S.C. § 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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`Case IPR2015-01797
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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 five grounds of rejection against the ’459 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: Claim 1 Is 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 sublingual formulation comprising from about
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`0.001% to about 15% by weight fentanyl, a free base, or a pharmaceutically
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`acceptable salt thereof, from about 20% to about 60% by weight ethanol, and from
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`about 4% to about 6% by weight propylene glycol, the formulation providing a
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`mean Tmax of about 1.28+/-0.60 hours when a dose is administered sublingually to
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`humans. CFAD asserts that claim 1 is obvious over the combination of Ross_GB,
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`Ross_US2006, and the ’862 patent. CFAD’s analysis is deficient for a number of
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`reasons. In particular, CFAD fails to show how the references disclose each and
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`every feature recited in claim 1 (see infra Section IV.A.1), fails to explain why one
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`of ordinary skill would have been motivated to combine the asserted references in
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`the manner proposed (see infra Section IV.A.2), and resorts to non-analogous art
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`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 Claim 1
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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 26–27.) CFAD also points to two generic disclosures of
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`propylene glycol in Ross_GB (Pet. at 27–28.), the first mentioning propylene
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`glycol among a list of many possible polar organic solvents (Ex. 1003, p. 5, ll. 1–5)
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`and the second mentioning propylene glycol among a list of many possible
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`moisturizing agents (Ex. 1003, p. 7, ll. 11–14). In addition, CFAD cites the ’862
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`patent, which is directed to an aerosol nitroglycerin product, allegedly comprising
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`propylene glycol in a general range of 2% to 30% by weight, with a specific
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`formulation comprising propylene glycol at 7.28% by weight. (Pet. at 28.)
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`Finally, CFAD argues that the claimed Tmax element is obvious in view of
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`Ross_US2006’s Table 2. (Pet. at 30–34.)
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`The asserted references, however, fail to disclose elements of claim 1 of the
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`’459 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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`mentions propylene glycol among many possible polar organic solvents and
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`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 28–29.)
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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 rang