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`PAPER NO. 21
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_______________________
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`AQUESTIVE THERAPEUTICS, INC.
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`Petitioner
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`v.
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`NEURELIS, INC.
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`Patent Owner
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`_______________________
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`IPR2019-00451
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`U.S. Patent No. 9,763,876
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`______________________
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`PETITIONER’S REPLY
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`TO PATENT OWNER’S RESPONSE TO THE PETITION
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`IPR2019-00451
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`U.S. Patent No. 9,763,876
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`TABLE OF CONTENTS
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`I.
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`PRELIMINARY STATEMENT ...................................................................... 1
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`II.
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`PO CANNOT CLAIM PRIORITY TO ITS ‘558 PROVISIONAL
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`APPLICATION (EXHIBIT 1008) AND DIDN’T POSSESS INVENTION ........... 1
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`A.
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`Petitioner Satisfied Its Initial Burden Of Going Forward With Evidence Of
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`Unpatentability and Lack of Written Support in ‘558 Provisional - The Burden
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`Then Shifted To PO To Demonstrate That The ‘876 Patent Demonstrated
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`Criticality and Is Entitled To Claim Priority To The ‘558 Provisional ..................... 3
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`B.
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`The ‘558 Provisional Fails To Satisfy The Written Description Requirement
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`Of Section 112 for the Essential Alkyl Glycosides ................................................... 4
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`C. Rule 57 Governs ............................................................................................... 9
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`III. CLAIM CONSTRUCTION ............................................................................. 9
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`A.
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`B.
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`“consisting of” – includes water ....................................................................... 9
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`“pharmaceutical solution” includes solutions where the benzodiazepine is
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`partially dissolved. ...................................................................................................11
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`IV. POSA – INCLUDES TRANSMEMBRANE EXPERIENCE .......................12
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`V. MOTIVATION TO COMBINE .....................................................................12
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`A. A POSA would have been motivated to combine Gwozdz and Meezan’96213
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`1. A POSA would have combined disclosures to increase solubility with
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`disclosures to increase penetration...........................................................................13
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`2. No concern about precipitating out. ...............................................................14
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`B. A POSA would have been motivated to combine Gwozdz, Meezan’962 and
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`Cartt’784. .................................................................................................................15
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`VI. THE PRIOR ART – GWOZDZ, MEEZAN’962 & CARTT’784 .................16
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`A. Gwozdz (Exhibit 1014) ..................................................................................16
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`1. Alkyl glycosides. ............................................................................................16
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`2.
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`Benzyl alcohol ................................................................................................17
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`B. Meezan’962 (Exhibit 1011) ............................................................................19
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`C. Cartt‘784 (Exhibit 1015) ................................................................................21
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`VII.
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`THE ‘876 PATENT CLAIMS ARE INVALID..........................................22
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`A. Claims 1-7, 13 & 14 with combined amounts of benzyl alcohol and ethanol
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`are obvious. ..............................................................................................................23
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`B. Claims 8, 9, 10, 15, 28, 30-33 are obvious, notwithstanding the separate
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`ranges for benzyl alcohol and ethanol (or dehydrated ethanol). ..............................23
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`C. Claims 11 & 12 are obvious. ..........................................................................25
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`D. Claim 16 is obvious. .......................................................................................25
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`E. Claims 24-26 are obvious. ..............................................................................25
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`F.
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`Claims 27 & 29 are obvious. ..........................................................................26
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`G. Claims 34-36 are obvious. ..............................................................................26
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`H. Claims 17-23 are obvious. ..............................................................................27
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`VIII. SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS DON’T
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`SUPPORT THE VALIDITY OF THE CLAIMS OF THE ‘876 PATENT ............27
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`A. The History of Intrasnasal Development is Replete with Successful Solutions
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`As Well As The Intranasal Use of Benzodiazepine IV Solutions for Treating
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`Seizures. ...................................................................................................................28
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`B. Many Non-Formulation Issues Contributed to Lack of Commercialization. 29
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`C. No nexus between the ‘876 patent claims and Valtoco. ................................30
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`IX. CONCLUSION ..............................................................................................31
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`CERTIFICATE OF COMPLIANCE ..................................................................32
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`CERTIFICATE OF SERVICE ............................................................................33
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`Cases
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`TABLE OF AUTHORITIES
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`Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010) ................... 8
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`Dynamic Drinkware v. LLC v. National Graphics, Inc., 800 F.3d 1375 (Fed. Cir.
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`2015) ...................................................................................................................... 4
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`E.I. du Pont de Nemours & Co. v. Synvina C.V., 904 F.3d 996 (Fed. Cir. 2018) ...23
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`Ex parte Maziere, 27 USPQ2d 1705 (BPAI 1993) .................................................... 9
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`Fujikawa v. Wattanasin, 93 F.3d 1559 (Fed. Cir. 1996) ........................................... 7
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`Litton Sys., Inc. v. Whirlpool Corp., 728 F.2d 1423 (Fed. Cir. 1984) ....................... 5
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`Lockwood v. Am. Airlines, Inc., 107 F.3d 1565 (Fed. Cir. 1997) .............................. 8
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`New Railhead Mfg., L.L.C. v. Vermteer Mfg. Co., 298 F.3d 1290 (Fed. Cir. 2002) . 4
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`Power Oasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299 (Fed. Cir. 2008) .............. 5
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`Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320 (Fed. Cir. 2000) ................... 7
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`Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316 (Fed. Cir. 2008) ................. 4
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`I.
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`PRELIMINARY STATEMENT
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`Petitioner relied on the declaration of Dr. Peppas (Exhibit 1041) in support
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`of its Petition (Paper 3). Dr. Peppas is a world-renowned expert in many fields of
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`drug delivery. But Patent Owner (“PO”) argues that he has no hands-on
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`experience working with benzodiazepines. Patent Owner’s Response, Paper 16, p.
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`6 (“POR”). Therefore, while Petitioner fully stands behind Dr. Peppas and his
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`declaration, Petitioner has also engaged the services of Dr. Wermeling, who is also
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`renowned and who has had first-hand experience working with benzodiazepines
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`and the development of intranasal sprays. See Declaration of Daniel P.
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`Wermeling, Pharm.D., Exhibit 1150 (“WermelingDec.Ex.1150”).
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`II.
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`PO CANNOT CLAIM PRIORITY TO ITS ‘558 PROVISIONAL
`APPLICATION (EXHIBIT 1008) AND DIDN’T POSSESS
`INVENTION
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`To benefit from its ‘558 provisional application (Exhibit 1008), PO has the
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`burden of demonstrating that [150]-[152] of the ‘558 provisional provides written
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`description for the use of alkyl glycosides as an essential element of all the claims
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`of the ‘876 patent. PO has failed to meet this burden. See Decision.Reh’g.Paper-
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`14,pp.3-4.
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`First, PO wrongly argues that it is Petitioner’s burden to demonstrate an
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`absence of sufficient written description support for alkyl glycosides in the ‘558
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`provisional. See POR18-21.
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`Second, PO argues that it has met its burden via the ‘558 provisional’s
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`incorporation by reference of a list of over 150 compounds found in the SIGMA
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`catalogue (amongst the multitude of absorption enhancers expressly described
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`within the provisional). See POR10-11,20-21. Petitioner’s expert Dr. Wermeling
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`opines that a POSA would have no reason to think alkyl glycosides were being
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`singled out.
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`Third, PO argues that the Board misapplied Rule 57 in its findings that the
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`‘876 patent is not entitled to the benefit of the ‘558 provisional’s filing date. See
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`POR11-12,21-23. However, the very language of Rule 57 denies even the right to
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`incorporate “essential” alkyl glycosides listed in the SIGMA catalogue by
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`reference. Moreover, PO failed to “show how the written description in the earlier
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`[priority] applications supports the challenged claims”, despite the Board’s request.
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`Decision.Req.Reh’g,Pap.14,p.4.
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`A. Petitioner Satisfied Its Initial Burden Of Going Forward With
`Evidence Of Unpatentability and Lack of Written Support in ‘558 Provisional -
`The Burden Then Shifted To PO To Demonstrate That The ‘876 Patent
`Demonstrated Criticality and Is Entitled To Claim Priority To The ‘558 Provisional
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`PO wrongly argues that the Petition “facially failed” to consider the entire
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`disclosure of the ‘558 provisional, and therefore “was facially defective and
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`insufficient to provide a reasonable likelihood of unpatentability from the start.”
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`See POR17,21. However, Petitioner was only required to show lack of support in
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`‘558 provisional for essential and material claim element “alkyl glycosides” –
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`which it showed for all claims. See Petition, Paper 3 (“Petition”), 18-20.
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`Petitioner then fulfilled its burden of showing that Gwozdz (Exhibit 1014) is
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`entitled to the effective date of its provisional, March 28, 2008, and therefore
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`qualified as prior art under 35 U.S.C. § 102(e)(1). See Petition6-7. PO does not
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`dispute that Gwozdz is entitled to this effective filing date.
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`Then Petitioner established the reasonable likelihood that Gwozdz combined
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`with Meezan’962 and/or Cartt’784 rendered at least one challenged claim
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`unpatentable. Petition5,23-87; see e.g., Decision10-17,21-24,31-34.
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`PO failed to carry its burden that it is entitled to the effective filing date of
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`its ‘558 provisional; therefore, PO cannot claim “that [Gwozdz] is not prior art
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`because the asserted claim is entitled to the benefit of a filing date prior to the
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`alleged prior art.” See Dynamic Drinkware v. LLC v. National Graphics, Inc., 800
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`F.3d 1375, 1379 (Fed. Cir. 2015) (quoting Tech. Licensing Corp. v. Videotek, Inc.,
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`545 F.3d 1316, 1327 (Fed. Cir. 2008)).
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`PO’s argument regarding the Board’s so-called misapplication of the parties’
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`respective burdens simply rehashes the arguments presented in PO’s Preliminary
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`Response (Paper 7), unsuccessful Request for Rehearing (Paper 10) and
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`unsuccessful request for Precedential Opinion Panel review to address, inter alia,
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`whether the Board improperly shifted the burden of proof to PO (Paper 17). The
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`Board correctly assigned the burden to PO.
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`In sum, the Board correctly determined that Petitioner satisfied its overall
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`burden to establish a reasonable likelihood of unpatentability. The burden then
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`shifted to PO, and PO has failed to meet this burden.
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`B. The ‘558 Provisional Fails To Satisfy The Written Description
`Requirement Of Section 112 for the Essential Alkyl Glycosides
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`For the ‘876 patent to claim priority to the ‘558 provisional, the specification
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`of the provisional must satisfy the written description requirement of Section 112.
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`Dynamic Drinkware, 800 F.3d at 1375-1378. (Fed. Cir. 2015); see New Railhead
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`Mfg., L.L.C. v. Vermteer Mfg. Co., 298 F.3d 1290, 1294 (Fed. Cir. 2002). There is
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`no presumption that the ‘876 patent is entitled to the benefit of the filing date of the
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`‘558 provisional. See Power Oasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299,
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`1305 (Fed. Cir. 2008). Accordingly, “care must be taken to ensure that the
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`disclosure filed as the [‘558] provisional application adequately provides (1) a
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`written description of the subject matter of the claim(s) at issue . . . and (2) an
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`enabling disclosure to permit [a POSA] to make and use the claimed invention . . .
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`without undue experimentation.” Litton Sys., Inc. v. Whirlpool Corp., 728 F.2d
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`1423, 1439 (Fed. Cir. 1984).
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`PO wrongly asserts that the disclosure found in [150]-[152] of the ‘558
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`provisional is adequate because the alkyl glycosides of the challenged claims can
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`be found among the various “biological detergents” identified in the SIGMA
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`catalog cited in Paragraph 152. POR10-11. PO’s superficial approach to the
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`written description requirement lacks merit. Petitioner’s Dr. Wermeling opines
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`that a POSA would not have understood that the ‘558 provisional was providing a
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`written description of alkyl glycosides. See WermelingDec.Ex.1150¶¶171-177.
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`Paragraphs [150]-[152] of the ‘558 provisional (Exhibit 1008) generically
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`refer to “absorption enhancers,” defines the term “enhancer” as “any material
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`which acts to increase absorption across the mucosa and/or increase
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`bioavailability,” and describes 15 classes falling within this broad “absorption
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`enhancer” class. WermelingDec.Ex.1100¶¶171,172.
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`For example, it is noted that the recited “enhancers” can include mucolytic
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`agents, degradative enzyme inhibitors, “compounds which increase permeability of
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`the mucosal cell membranes” [150], only identifying lysophospholipids and acyl
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`carnitines as preferred candidates [151]. WermelingDec.Ex.1100¶¶171-173.
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`Paragraph [152] also identifies six additional “enhancer” classes: (i)
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`chelating agents, (ii) surface active agents (especially non-ionic materials), (iii)
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`acyl glycerols, (iv) fatty acids and salts, (v) tyloxapol and (vi) the biological
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`detergents listed on six pages of the SIGMA catalog (Exhibit 2006).
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`WermelingDec.Ex.1100¶172.
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`Found on those six SIGMA catalog pages are approximately 150 different
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`compounds divided among four discrete sub-classes: (i) anionic, (ii) cationic, (iii)
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`zwitterionic (amphoteric) and (iv) nonionic (polar). Exhibit 2006, pp.316-321.
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`Within the “non-ionic” biological detergent sub-class are (i) about a dozen alkyl
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`glycoside species and (ii) over eighty non-alkyl glycoside species.
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`WermelingDec.Ex.1100¶175.
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`The ‘558 provisional provides absolutely no information regarding alkyl
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`glycosides, apart from generally listing them among approximately 150 other
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`biological detergents appearing in the SIGMA catalog.
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`WermelingDec.Ex.1100¶¶175-177. In fact, nothing in the ‘558 provisional would
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`reasonably lead a POSA to any particular sub-class, let alone specific species
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`(compounds) identified in the SIGMA catalog, nor does the ‘558 provisional
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`suggest that alkyl glycosides might be of special interest, or be significant to the
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`claims. Rather, the ‘558 Provisional directs the POSA to lysophospholipids and
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`acyl carnitines; all other enhancers being in a “kitchen sink” listing. See
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`WermelingDec.Ex.1100¶¶176.
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`The ‘558 provisional provides no blaze marks pointing to alkyl glycosides.
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`Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326-27 (Fed. Cir.
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`2000)(“[O]ne cannot disclose a forest in the original application and then later pick
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`a tree out of the forest and say here is my invention. In order to satisfy the written
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`description requirement, the blaze marks directing the skilled artisan to that tree
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`must be in the originally filed disclosure.”); Fujikawa v. Wattanasin, 93 F.3d 1559,
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`1571 (Fed. Cir. 1996) (“In the absence of such blazemarks, simply describing a
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`large genus of compounds is not sufficient to satisfy the written description
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`requirement as to particular species or subgenuses.”). PO was unaware – and did
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`not recognize – the significance of alkyl glycosides; otherwise, PO would have
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`specifically disclosed them or specifically incorporated them by reference (as
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`opposed to a general whole-sale reference to “biological detergents”).
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`PO provides merely a footnote for its bald assertion that the biological
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`detergents listed in SIGMA catalog as disclosed in [152] would have been
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`understood to have been limited to only non-ionic detergents. POR11,fn.5.
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`However, Dr. Wermeling and Dr. Gizurarson testified that nothing in [152]
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`associates the non-ionic surface active agents with the biological detergents listed
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`in the SIGMA catalog. See WermelingDec.¶176; Deposition Transcript of Dr.
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`Gizsurarson, Exhibit 1149 (“GizurarsonDep.”),51:18-52:9. Paragraph [152]’s
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`citation to the “biological detergents” listed in the SIGMA catalog is not restricted
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`to strictly non-ionic detergents. Moreover, each of [150]-[152] of the ‘558
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`provisional lists at least “ionic” and “non-ionic” enhancing agents.
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`WermelingDec.Ex.1100¶175(&fns.).
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`Had PO believed only non-ionic biological detergents were “appropriate for
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`administering to the nasal cavity” as now urged, the ‘558 provisional was required
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`to specifically incorporate or identify only the non-ionic compounds rather than
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`approximately 150 different biological detergents included in the Sigma catalog .
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`See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1352 (Fed. Cir. 2010)
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`(“A description that merely renders the invention obvious does not satisfy” the
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`written description requirement.); see Lockwood v. Am. Airlines, Inc., 107 F.3d
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`1565, 1572 (Fed. Cir. 1997) (“It is not sufficient for purposes of the written
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`description requirement of § 112 that the disclosure, when combined with the
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`knowledge in the art, would lead one to speculate as to the modifications that the
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`inventor might have envisioned, but failed to disclose.”). There is nothing in the
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`‘558 provisional directing a POSA generally to non-ionic biological detergents or
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`specifically to any of the approximately dozen alkyl glycosides appearing within
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`those six pages to the exclusion of almost 150 other biological detergents.
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`WermelingDec.¶¶176,177.
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`C. Rule 57 Governs
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`Section 1.57 of Title 37 of the Code of Federal Regulations expressly
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`provides for incorporation by reference of “essential” material in a United States
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`patent, but only if the reference is a US patent or a US patent application. 37
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`C.F.R. § 1.57 (c), (d). The SIGMA catalog is neither and does not satisfy Rule
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`57’s requirement for permissible incorporation by reference. Nor should it.
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`Ex parte Maziere, 27 USPQ2d 1705 (BPAI 1993), cited by PO (POR24), is
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`inapplicable –it was directed to foreign (not provisional) applications and is
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`contrary to public policy reasons against incorporation-by-reference of essential
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`material from non-patent documents. Moreover, the Board is not bound by the
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`M.P.E.P.’s interpretation.
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`III. CLAIM CONSTRUCTION
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`A. “consisting of” – includes water
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`Petitioner disagrees with PO’s claim construction of “consisting of” to the
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`extent that PO relies on it to exclude any other excipients, at least for claims
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`reciting “ethanol” and not “dehydrated ethanol”. POR12-13.
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`To begin, claim 1 recites “ethanol”, while dependent claim 28 recites
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`dehydrated ethanol. There is a difference between “ethanol” and “dehydrated
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`ethanol”. Moreover, the ‘876 patent refers to different embodiments as having
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`either “ethanol” or “dehydrated ethanol”, and Figure 4 refers to it as “dehydrated
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`alcohol, USP”. See also, WermelingDec.Ex.1100¶27. “In some embodiments, the
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`one or more alcohols are selected from the group consisting of: ethanol, . . . benzyl
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`alcohol, any isomers thereof, and any combinations thereof. . . . In some
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`embodiments, the alcohol or glycol is free of water (dehydrated, USP). In some
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`embodiments, the alcohol is ethanol (dehydrated, USP)”. ‘876 patent,7:33-42.
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`Therefore, “[a] POSA would understand that the ordinary meaning of the terms
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`‘ethanol’ and ‘dehydrated ethanol’ would be the meanings given in the U.S.
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`Pharmacopeia (“USP”). See Ex. 1078, pp. 0004-0005.”
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`WermelingDec.Ex.1100¶23.
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`A POSA would understand that the recitation of “ethanol” in the claims of
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`the ‘876 patent meant that the ethanol was required to meet USP standards that
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`ethanol “contains not less than 92.3% and not more than 93.8%, by weight,
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`corresponding to not less than 94.9% and not more than 96.0%, by volume, at
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`15.56o, of C2H5OH.” USP, Exhibit1078, pp.0004-0005 (emphasis supplied). A
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`POSA would understand the remaining 4-5% (by volume) to be mostly – if not
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`all – water. Indeed, the definition of “ethanol” essentially requires that there be
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`water present in an amount equal to 4-5% of the actual ethanol molecule.
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`WermelingDec.Ex.1100¶¶24-30.
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`Thus, a POSA would understand that the recitation of at least “ethanol” in
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`the “consisting of” portion of the claims requires the presence of some water.
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`See also, WermelingDec.Ex.1100¶¶28,29.
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`B. “pharmaceutical solution” includes solutions where the benzodiazepine is
`partially dissolved.
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`The ‘876 Patent’s claimed “solution” includes solutions where the
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`benzodiazepine is partially dissolved, i.e., containing drug particulates. As
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`originally filed, the ‘876 Patent contained a claim to a “pharmaceutical solution”
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`and then a depending claim reciting “wherein the benzodiazepine drug is
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`dissolved”. ‘876PatentFileHistory.Exhibit.1002.p.0098. Claim differentiation
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`requires that originally filed claim 1 recites dissolved and partially dissolved drug
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`particles, notwithstanding the recited term “solution”. See also,
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`Gwozdz.Ex.1014,5:17-25,p.14(claims1&8).
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`IV.
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` POSA – INCLUDES TRANSMEMBRANE EXPERIENCE
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`Petitioner disagrees with PO’s description of a POSA which relies on
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`GizurarsonDec.Ex.2012¶31. POR15-17. In particular, it is necessary to add
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`“transmembrane” to “intranasal” in respect of GizurarsonDec.Ex.2012¶¶31, in that
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`a POSA would have “relevant experience in developing intranasal and
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`transmembrane formulations.” This is because, in part, all the routes referred to in
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`GizurarsonDec.Ex.2012¶¶32 are transmembrane. See
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`WermelingDec.Ex.1100¶¶20-22.
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`V. MOTIVATION TO COMBINE
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`Regarding the motivation to combine Meezan’962 with Gwozdz, a POSA
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`would have looked to Meezan’962’s disclosure when seeking to enhance the
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`bioavailability of benzodiazepines as well as the rate and extent of absoprtion in
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`the compositions disclosed by Gwozdz. See PeppasDec.Ex.1041¶¶193-194,225-
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`226,257-260,364,424 and WermelingDecWermelingDec.Ex.1150¶¶79,99,113,157-
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`170. Moreover, a POSA would have then looked to Cartt’784’s disclosure when
`
`seeking dosing regimens for the compositions disclosed in Gwozdz. See
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`PeppasDec.Ex.1041¶¶257-260 and WermelingDecWermelingDec.Ex.1150¶¶157-
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`170. Moreover, Gwozdz also discloses solutions having particulates, similar to
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`Cartt’784. Gwozdz.Ex.1014.p.0005,lines17-23.
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`PO wrongly argues that Petitioner has failed to demonstrate a motivation to
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`combine Gwozdz and Meezan’962 (POR28-38) and to combine Gwozdz,
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`Meezan’962 and Cartt’784 (POR38-40).
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`A. A POSA would have been motivated to combine Gwozdz and Meezan’962
`
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`1. A POSA would have combined disclosures to increase solubility
`with disclosures to increase penetration.
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`
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`As noted by PO, Dr. Peppas had testified that a POSA in considering
`
`benzodiazepine formulations would have looked to both increasing drug solubility
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`and using penetration enhancers. See PeppasDec.Ex.1041¶¶121-168. PO
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`disagrees with Dr. Peppas. PO disingenuously argues that solutions involving
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`increasing solubility and solutions involving penetration enhancers are “mutually
`
`exclusive”. See POR27-28.
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`
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`Interestingly, the disclosure in one of Dr. Gizurarson’s own patent
`
`applications contradicts this “mutual exclusivity”. The application is directed to the
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`use of alkoxy-polyethylene glycol as a solubilizer for poorly soluble therapeutic
`
`agents. Nevertheless, Dr. Gizurarson, disclosed adding additional compounds to
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`his alkoxy-polyethylene glycol solubilizer, such as adding ethanol and benzyl
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`alcohol to enhance solubility, and adding surfactants, i.e., enhancing agents. Thus,
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`PO’s own expert has indicated that solubilizers and enhancing agents are not
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`“mutually exclusive”.
`
`GizurarsonPat.Appl.Pub.Ex.1070¶[0017],[0060],[0061],[0062].
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`2. No concern about precipitating out.
`
`
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`PO argues that a POSA would have been concerned that the substitution of a
`
`percentage of tocopherol with a percentage of benzyl alcohol would have caused a
`
`POSA to be concerned about the diazepam precipitating out. PO incorrectly
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`argues that Gwozdz does not allow for the use of the ternary co-solvent system
`
`(tocopherol+ethanol+ benzyl alcohol), even though it actually is disclosed in
`
`Gwozdz. POR27-30. See WermelingDecWermelingDec.Ex.1150¶¶129-145.
`
`
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`First, a POSA would have used Gwozdz’ disclosure of ternary co-solvent
`
`systems such as tocopherol+ethanol+benzyl alcohol, because such systems offer
`
`the potential for better solubility. Second, Gwozdz’ disclosure is not limited to
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`administration in one nostril, and administration in more than one nostril would
`
`allow for a lower concentration of drug in the solution being administered in each
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`nostril (thereby avoiding the potential for diazepam to precipitate out of the
`
`solution). WermelingDec.Ex.1150¶¶130-132.
`
`
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`PO’s expert, Dr. Gizurarson, agrees that a POSA would reduce the
`
`concentration and apply a lower concentration to both nostrils in order to avoid
`
`salting out while still achieving the desired therapeutic effect.
`
`GizurarsonDep.Ex.1149,38:9-18
`
`
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`Moreover, as disclosed in Cartt’784Ex.1015¶ [0031] a POSA would have
`
`known that intranasal solutions can be administered in one nostril; in both nostrils
`
`sequentially; or in one nostril, then the second nostril, and then the first nostril
`
`again (and, optionally, in the second nostril again), sequentially – in these cases,
`
`the concentration could be even further reduced. See
`
`WermelingDec.Ex.1150¶¶144-145.
`
`
`
`
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`
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`B. A POSA would have been motivated to combine Gwozdz, Meezan’962 and
`Cartt’784.
`
`PO wrongly argues that a POSA would not combine Cartt’784 with Gwozdz
`
`and/or Meezan’962, because the dosing regimens of “particle formulations” of
`
`benzodiazepines would not be transferable to Gwozdz or Meezan’962. POR26-
`
`27,38-40.
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`A POSA would have looked to Cartt’784 for its disclosure of dosing
`
`regimens (including dosing amounts and volume amounts) for benzodiazepines
`
`(including diazepam). Moreover, a POSA would have combined Cartt’784’s
`
`disclosure of intranasal benzodiazepine (diazepam) dosing regimens with Gwozdz’
`
`disclosure of intranasal benzodiazepine (diazepam) in ternary co-solvent systems,
`
`and further with Meezan’962’s disclosure of intranasal alkyl glycosides
`
`(penetration enhancers). See WermelingDec.Ex.1150¶¶157-170.
`
`
`
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`VI. THE PRIOR ART – GWOZDZ, MEEZAN’962 & CARTT’784
`
`A. Gwozdz (Exhibit 1014)
`
`PO argues that Gwozdz does not disclose the use of Meezan’962’s alkyl
`
`glycosides. POR24-25. PO wrongly argues that a POSA would not have had an
`
`expectation of success in combining ethanol, benzyl alcohol and alkyl glycosides.
`
`POR30-35.
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`1. Alkyl glycosides.
`
`PO irrelevantly argues that the antimicrobial properties of ethanol and
`
`
`
`
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`benzyl alcohol would be inactivated and/or reduced in the presence of alkyl
`
`glycosides, and, therefore, a POSA would be “less likely to look to a nonionic
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`surfactant to combine with a formulation that already included ethanol and benzyl
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`alcohol.” POR31.
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`
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`Both Dr. Wermeling and Dr. Gizurarson agree that ethanol is not known to
`
`be used as an antibacterial in benzodiazepine formulations for intravenous,
`
`intramuscular, intranasal, or rectal administrations. GizurarsonDep.Ex.149,78:15-
`
`21; WermelingDec.Ex.1150¶154. Moreover, the benzodiazepine formulation in
`
`the final package has to be aseptic; there are no bacteria to kill. Therefore, whether
`
`or not the antimicrobial properties are inactivated is irrelevant and a POSA would
`
`not be led away from considering nonionic surfactants. WermelingDec.
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`WermelingDec.Ex.1150¶155. Moreover, a POSA would not expect that the very
`
`small amounts of nonionic surfactants being used would be sufficient to inactivate
`
`the antimicrobial properties of high concentrations of ethanol and/or benzyl
`
`alcohol being used here. WermelingDecWermelingDec.Ex.1150¶156.
`
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`
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`Finally, a POSA would have recognized that Gwozdz’s formulation would
`
`have benefited from Meezan’962’s alkyl glycosides. See, e.g.,
`
`WermelingDec.Ex.1150¶¶15,149.
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`
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`2. Benzyl alcohol
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`PO argues that a POSA would not have an expectation of success in adding
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`benzyl alcohol to Gwozdz’ binary co-solvent system (tocopherol+ethanol) because
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`of concerns that benzyl alcohol would accelerate the auto-oxidation of fats.
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`POR33.1 PO is presumably referring to tocopherol as a fat. However, a POSA
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`would not be concerned for several reasons, not the least of which is the absence of
`
`oxygen in these single-use emergency rescue products. Pointedly, the reference
`
`relied on by PO states that benzyl alcohol “can also accelerate the autoxidation of
`
`fats.” HandbookEx.1031,p.0010. However, the reference does not provide any
`
`conditions necessary for such autoxidation to occur, nor does the reference indicate
`
`that tocopherols would autoxidize in the presence of benzyl alcohol. As Dr.
`
`Gizurarson testified, HandbookEx.1031 does not identify tocopherols as a subject
`
`for autoxidation and that he himself merely considers the statement in The
`
`Handbook to be a general “warning signal.” GizurarsonDep.Ex.1149,76:4-24.
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`Therefore, given Gwozdz’ express direction to use tocopherol+ethanol+benzyl
`
`alcohol (GizurarsonDep.Ex.1149,73:11-15), a POSA would not have been
`
`dissuaded from using benzyl alcohol.
`
`See WermelingDec.Ex.1150,¶134(fn2).
`
`
`Here, PO conspicuously ignores that all three co-solvents are specifically
`
`1
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`disclosed by Gwozdz – no modification is necessary.
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`WermelingDec.Ex.1150¶139;GizurarsonDep.Ex.1149,73:11-15.
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`PO argues that benzyl alcohol is a known irritant, so formulations containing
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`it would therefore be unacceptable. POR34-35. However, in the case of acute
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`health threats, such as epileptic seizures, any irritation due to benzyl alcohol was
`
`(and is) outweighed by the need to stop the seizures.
`
`WermelingDec.Ex.1150¶¶208-211; GizurarsonPat.Appl.Pub.Ex.1070¶0004. As
`
`noted above, diazepam IV formulations (which included ethanol and benzyl
`
`alcohol; see PDR.Ex.1042,p.0010) were successfully administered intranasally by
`
`EMS workers. See EMS.Ex.1069,p.0030.
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`
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`PO also relies on a statement by Dr. Wermeling in one of his patents that a
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`composition containing benzyl alcohol was not acceptable for intranasal use
`
`because it would be irritating. POR34. Dr. Wermeling addresses PO’s argument
`
`in his declaration, noting that his patent was directed to the use of lorazepam as a
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`sedative and to treat conditions of anxiety, situations which are neither non-life-
`
`threatening nor comparable to life-threatening situations. In life-threatening
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`situations, irritation would not only be acceptable, it would not ev
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