On this record, and upon review of Petitioner’s arguments and supporting evidence, we determine that Petitioner sufficiently explains why one of ordinary skill in the art would have looked to Meezan ’962’s disclosure when seeking to enhance the bioavailability of the therapeutic agents in the compositions disclosed in Gwozdz.

For the reasons stated supra with regard to claims 8–10 and 15, Petitioner’s assertion that Patent Owner never showed any unexpected results with respect to the amount of ethanol and benzyl alcohol is not sufficiently supported by the evidence of record.

We are not persuaded that Petitioner and Dr. Peppas have provided sufficient argument and supporting evidence to explain why one of ordinary skill in the art would have reasonably expected success in achieving the bioavailabilities recited in claims 34–36 of the ’876 patent when combining the teachings of Gwozdz and Meezan ’962.

Petitioner argues that, since neither Gwozdz nor Meezan ’962 provide specific dosing regimens for benzodiazepines/diazepam, one of ordinary skill in the art would look to the similar reference of Cartt ’784, titled “Nasal Administration of Benzodiazepines,” for these teachings.

On this record, and upon review of Petitioner’s arguments and supporting evidence, we determine that Petitioner sufficiently explains why one of ordinary skill in the art would have looked to Cartt ’784’s disclosure when seeking dosing regimens for the compositions disclosed in Gwozdz and Meezan ’962.

Patent Owner may file a preliminary response to the petition no later than three months from the date of this notice.

Patent Owner may also file an election to waive the preliminary response to expedite the proceeding.

Patent Owner is advised of the requirement to submit mandatory notice information under 37 C.F.R. § 42.8(a)(2) within 21 days of service of the petition.

The parties are advised that under 37 C.F.R. § 42.10(c), recognition of counsel pro hac vice requires a showing of good cause.

Such motions shall be filed in accordance with the “Order -- Authorizing Motion for Pro Hac Vice Admission” in Case IPR2013-00639, Paper 7, a copy of which is available on the Board Web site under “Representative Orders, Decisions, and Notices.” The parties are reminded that unless otherwise permitted by 37 C.F.R. § 42.6(b)(2), all filings in this proceeding must be made electronically in the Patent Review Processing System (PRPS), accessible from the Board Web site at http://www.uspto.gov/PTAB.

Aquestive fails to show why EX1013—a document that is cited only in support of a non-instituted ground—(and Dr. Peppas’ discussion thereof, EX1041, ¶¶171-191, 264-362, Appendix A (pp. 197-224), and EX1050) is relevant to the instituted grounds.

Aquestive’s reliance on Genzyme Therapeutic and/or Ariosa Diagnostics is disingenuous given that neither of those decisions involved the lack of notice, and resultant prejudice, that is present here.

The declaration does not provide any “personal knowledge” as required by FRE 901(b)(1), or any other evidence that EX1069 is what Aquestive purports it to be—a manual available to, and followed by, medical technicians in Florida prior to the priority date.

Separately, Dr. Wermeling’s experience in drug development does not qualify him to provide expert opinions on economics and/or regulatory procedures.

Aquestive block cites portions of Dr. Wermeling’s testimony in support of the alleged “expertise”—but, a closer look at the testimony reveals that he (1) is merely “familiar with economic principles” (EX2031, 8:19-22) and otherwise collaborated with trained economists for his written work (id., 10:2-14); (2) has never worked at, or received any formal certifications related to, FDA practice and procedure (id., 10:22-11:7); (3) has limited experience with pricing (id., 77:2-7) and could not make any pricing decisions on his own (id., 79:24-80:81:5), and; (4) is only “pretty familiar” with the 505(b)(2) pathway and would need to consult the “regulatory person at the company” for the answer to a complex question on the same (id., 85:6-86:13).

Committee Note to 2000 Amendment to Rule 703 (“[W]hen an expert reasonably relies on inadmissible information to form an opinion or inference, the underlying information is not admissible simply because the opinion or inference is admitted.”); Malletier v. Dooney & Bourke, Inc., 525 F. Supp.

807(a)(2); see Committee Note to 2019 Amendments (“proponent must show that the hearsay statement is more probative then any other evidence the proponent can obtain”).

Contrary to PO’s assertion, the narratives provided by PO’s expert in paragraphs 2, 5, 7 and 67 of his declaration is not relevant to the subject recited in the challenged claims of the ‘876 patent.

For example, PO’s expert opines, with insufficient personal knowledge, regarding the appropriate level of skill possessed by a POSA as of the invention date of the subject matter recited in the ’876 patent (e.g., ¶¶ 28-33), and the alleged secondary considerations PO attempts points to in an attempt to support patentability (e.g., ¶¶ 36, 48, 50-51).

PO’s expert, in paragraphs 34, 68-70, 75 and 114, offers his views on an ultimate question of law -- what constitutes sufficient incorporation by reference.

Nonetheless, EX2001 and EX2004 “are offered for what they describe, and not to prove the truth of the matter asserted,” and thus are not hearsay as defined under FRE 801(c).

13 IPR2019-00451 U.S. Patent No. 9,763,876 K. Limiting Request Under FRE 105 None of Petitioner’s exhibits should be limited.

EX1069 is hearsay because it is an out-of-court statement offered to prove the truth of the matter asserted, namely—as Petitioner states— related to Petitioner’s argument for a motivation to combine alcohols and rebuttal to Patent Owner’s showing of long-felt need.

EX1081 appears to be a webpage showing “Diazepam Prices and Coupons.” EX1081 is hearsay because it is an out-of-court statement offered to prove the truth of the matter asserted—purportedly, related to Dr. Wermeling’s argument of lack of secondary considerations and commercial success.

Dr. Wermeling does not set forth the principles used nor does he demonstrate the methods or 10 (finding improper incorporation by reference of block cites to expert declaration without sufficient explanation of those portions).

French et al., Pharmacopeial Standards and Specifications for Bulk Drugs and Solid Oral Dosage Forms, Journal of Pharmaceutical Sciences, December 1967, Vol.

EX1050 Table of Various Diazepam Solutions Described in or Modified From Sonne’s Example 11 (“DS11”) EX1065 Maggio, Provisional Patent Appl’n Serial No. 60632038 EX1069 Florida Regional Common EMS Protocols Field Guide, Jones and Barlett Publishers, MA (2005) EX1080 Valium® Tablet Label, Roche, January 2008 EX1081 Drug Prices from Internet

The exhibit’s probative value is substantially outweighed by its confusion of the issues to be decided, its waste of the Board’s and the Petitioner’s time, and the danger that it will lead to unfair prejudice if used later in the proceeding or on appeal.

The exhibit’s probative value is substantially outweighed by its confusion of the issues to be decided, its waste of the Board’s and the Petitioner’s time, and the danger that it will lead to unfair prejudice if used later in the proceeding or on appeal.

The exhibit’s probative value is substantially outweighed by its confusion of the issues to be decided, its waste of the Board’s and the Petitioner’s time, and the danger that it will lead to unfair prejudice if used later in the proceeding or on appeal.

Paragraphs 2, 5, 7, 67 of Exhibit 2012 are not relevant to any instituted ground and their probative value is substantially outweighed by its confusion of the issues to be decided, its waste of the Board’s and the Petitioner’s time, and the danger that it will lead to unfair prejudice if used later in the proceeding or on appeal.

The exhibit’s probative value is substantially outweighed by its confusion of the issues to be decided, its waste of the Board’s and Petitioner’s time, and the danger that it will lead to unfair prejudice if used later in the proceeding or on appeal.

EX2031, 89:23-90:6. While Dr. Wermeling does not dispute that Neurelis’ formulation, Valtoco®, works to treat epileptic seizures, he nonetheless acknowledged that it behaves differently than other nasal formulations do when acute and ...

Nonetheless, Dr. Wermeling admits that Neurelis went a different route from other intranasal formulators and intentionally designed a slower absorbing intranasal formulation, completely counterintuitive to the need for a fast-absorbing ...

- PO argued the challenged claims exclude - New argument for a new theory that water and a POSA would therefore not be should have appeared, if anywhere, in motivated to use Meezan’s alkyl glycosides.

solution does not disclose particulate - New argument in support of new formulations and a POSA therefore would not theory, not appearing in petition or in consider Cartt ‘784, Ex. 1015 in connection EX1041 [Peppas].

POSA definition which included experience Contradicts use of Peppas, confirming in transmembrane/transmucosal, e.g., this is not supplementation of his intranasal, rectal, buccal development.

A & B); EX1150, ¶¶178- 27 and elaborates on why there was no 207. demonstration of criticality or unexpected - The reply does not identify anything in results based on the data in Figs. 1–3, Tables the opposition to which this responds— 4-1, 11-1, 11-2, and 11-3 relied on by the classic improper bolstering.

EX1150, ¶¶65-81, 92- PO’s expert, Dr. Gizurarson regarding 109. alleged commercial success and purported - No explanation why these factors and problems with formulating intranasal references were not in EX1041 solutions.

For the limited purpose of providing the Director of the United States Patent and Trademark Office with the information specified in 37 C.F.R. §90.2(a)(3)(ii), the issues on appeal include the Board’s determination that claims 1-36 of U.S. Patent No. 9,763,876 (“’876 Patent”) were shown to be unpatentable under 35 U.S.C. §103 in view of the grounds of unpatentability identified in the Board’s Final Written Decision.

The issues on appeal also include any Board finding or conclusion supporting or related to this determination, as well as all other decisions adverse to Patent Owner in any Board order, decision, ruling, or opinion.

These issues include, but are not limited to, the following: (1) whether the Board erred in applying the wrong standards and burdens to conclude that the claims of the ’876 Patent were not entitled to benefit of the priority filing date of U.S.

Publication No. 2006/0046962 to Meezan, and PCT Publication No. WO 2009/1209033 to Gwozdz; (3) whether the Board misconstrued dependent claims of the ’876 Patent to require a generic “alkyl glycoside”, thereby overlooking uncontested express support in the ’558 Provisional for those claims; and (4) whether the Board violated administrative- law requirements by introducing its own new and erroneous legal theories without providing Patent Owner adequate opportunity to respond.

Dated: October , 2020 Respectfully submitted, Jeffrey W. Guise, Lead Counsel Reg. No. 34,613

Found on those six SIGMA catalog pages are approximately 150 different compounds divided among four discrete sub-classes: (i) anionic, (ii) cationic, (iii) zwitterionic (amphoteric) and (iv) nonionic (polar).

); see Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (“It is not sufficient for purposes of the written description requirement of § 112 that the disclosure, when combined with the knowledge in the art, would lead one to speculate as to the modifications that the inventor might have envisioned, but failed to disclose.”).

Ex parte Maziere, 27 USPQ2d 1705 (BPAI 1993), cited by PO (POR24), is inapplicable –it was directed to foreign (not provisional) applications and is contrary to public policy reasons against incorporation-by-reference of essential material from non-patent documents.

Many benzodiazepines, including diazepam, are so slightly soluble in water that a therapeutically effective amount cannot be dissolved in a volume of aqueous solvent that is amenable to nasal insufflation as an aerosol or non-aerosol spray.” Cartt’784.Ex.1015¶[0139]-[0144](emphasis supplied).

Referring to the ‘876 Patent’s Figs. 1–3, Tables 4-1, 11-1, 11-2, and 11-3, and the same data from an EPO prosecution, the Board stated that “Petitioner’s assertion that Patent Owner never showed any unexpected results is not sufficiently supported by the evidence of record.” Decision17-21,24-27.

U.S. Patent No. 9,763,876 Pursuant to 37 C.F.R. § 42.8(a)(3), the undersigned on behalf of and acting in a representative capacity for Petitioner Aquestive Therapeutics, Inc., hereby submits the following mandatory change-of-information notices in connection with the petition for inter partes review identified in the caption.

In particular, John T. Gallagher (Reg. No. 35,516) has been added as an additional back-up counsel; he should be served with all documents.

First Back-Up Counsel for Petitioner Aquestive Therapeutics, Inc.

US 2008/0070904, Pharmaceutical Compositions of Benzodiazepines and Method of Use Thereof, Serial No. 11/897,028, published March 20, 2008 (Jamieson) 1013 Sonne, U.S. Patent No. 6,193,985, Tocopherol Compositions For Delivery Of Biologically Active Agents, issued February 27, 2001 (Sonne) 1014 Gwozdz et al., WO 2009/120933, Pharmaceutical Solutions And Method For Solubilizing Therapeutic Agents, published October 1, 2009, International Filing Date March 27, 2009 (PCT/US2009/038518) (Gwozdz) Cartt et al., U.S. Patent Application Publication No.

21 (1992) 165-l72 (Edman II) 1033 French et al., Pharmacopeial Standards and Specifications for Bulk Drugs and Solid Oral Dosage Forms, Journal of Pharmaceutical Sciences, December 1967, Vol.

1045 Maitani, et al., Design of ocular/lacrimal and nasal systems through analysis of drug administration and absorption, Journal of Controlled Release, Volume 49, Issues 2–3, 15 December 1997, Pages 185-192.

1144 Ahmad S, Ellis J, Kamwendo H, et al. Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open label trial.

Wermeling, D.P., Intranasal delivery of antiepileptic medications for treatment of seizures, Neurotherapeutics, April 2009, Volume 6, Issue 2, pp 352–358 1152 Declaration of Michael I, Chakansky, dated and served February 19, 2020 pursuant to 37 C.F.R. § 42.64(b)(2), filed

Howard LeWine, M.D., “Quick Injection Helps Stop Epileptic Seizures,” Harvard Health Blog, Feb. 23, 2012; p. 1 “Managing Epilepsy Well Network and Selected Self-Management Programs; Putting Collective Wisdom to Work for People with Epilepsy,” Prevention Research Centers (PRC), CDC , Nov. 2016, pp.1-17 K.M.

Fiest, et al., “Prevalence and Incidence of Epilepsy, A Systematic Review and Meta-Analysis of International Studies,” NEUROLOGY 88, Jan. 17, 2017, pp.296-303 SIGMA Chemical Company Catalog (1988) E. Bechgaard et al., “Solubilization of Various Benzodiazepines for Intranasal Administration, A Pilot Study,” Pharmaceutical Development and Technology 2:293-296 (1997) A. Hussain et al. “Nasal Absorption of Propranolol in Humans,” Journal of Pharmaceutical Sciences 69:1240 (1980) S. Lau and J. Slattery, “Absorption of Diazepam and Lorazepam Following Intranasal Administration,” International Journal of Pharmaceutics, 54:171-174 (1989) M. Schols-Hendriks et al., “Absorption of Clonazepam After Intranasal and Buccal Administration,” British Journal of Clinical Pharmacology 39:449-451 (1995) 2011 Dr. Nicholas Peppas Deposition Transcript, October 24, 2019.

2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 Declaration of Dr. Sveinbjorn Gizurarson, Ph.D. J. Riss et al., “Benzodiazepines in Epilepsy: Pharmacology and Pharmacokinetics,” Acta Neurologica Scandinavica 118:69-86 (2008) D. Wermeling, U.S. Patent No. 6,610,271, issued August 26, 2003 C. Cole et al., “Community Survey of Carer’s: Individual Epilepsy Guidelines (IEG) for Rescue Medication,” Seizure 18:220-224 (2009) D. Terry et al., “Acceptance of the Use of Diazepam Rectal Gel in School and Day Care Settings,” Journal of Child Neurology 22:1135- 1138 (2007) Diastat® Label (2005) “UCB announces NAYZILAM® (midazolam) nasal spray now approved by FDA to treat intermittent, stereotypic episodes of frequent seizure activity in people living with epilepsy in the U.S.,” UCB Press Release, https://www.biospace.com/article/releases/ucb- announces-nayzilam-midazolam-nasal-spray-now-approved-by-fda- to-treat-intermittent-stereotypic-episodes-of-frequent-seizure-activity- in-people-living-with-epilepsy-in-the-u-s-/ (2019) (Accessed October 31, 2019) J. French and T. Pedley, “Initial Management of Epilepsy,” New England Journal of Medicine 359:166-176 (2008) G. Corbo et al. “Measurement of Nasal Mucociliary Clearance,” Archives of Disease in Childhood 64:546-550 (1989) “How does the nose work?

The nasal mucosa,” https://www.fitonasal2act.com/how-does-the-nose-work/the-nasal- mucosa/ (Accessed November 5, 2019) N. Mygind, “Nasal Allergy,” 9 (Blackwell Scientific Publications, 1979) “Neurelis Files New Drug Application With The FDA For VALTOCO™ (Diazepam Nasal Spray), An Investigational Treatment For Pediatric, Adolescent And Adult Epilepsy Patients,” https://www.neurelis.com/neurelis-news/neurelis-files-new-drug- application-fda-valtocotm-nasal-spray-investigational-treatment- pediatric (2018) (Accessed November 1, 2019) “Neurelis Receives FDA Orphan Drug Designation for NRL-1 in the Treatment of Acute Repetitive Seizures,” https://www.neurelis.com/neurelis-news/fda-orphan-drug-designation (2015) (Accessed November 1, 2019) Affidavit of Robert Cleary (Dated November 21, 2019) Affidavit of Ronald Figueroa (Dated November 21, 2019) Transcript of Telephone Conference on Feb. 11, 2020 “Intranasal Technology, Inc.

Licenses Aegis Therapeutics' Intravail Drug Delivery Technology” (Business Wire) (April 13, 2005) Handbook of Pharmaceutical Excipients (Pharmaceutical Press and American Pharmacists Association, Publishers) (Fifth Edition, 2006) J. Wyse, U.S. Patent No. 9,192,570 issued November 24, 2015 Daniel P. Wermeling Deposition Transcript, February 26, 2020 “ITI Announces Formation of Scientific Advisory Board Led by the Dean of the University of Iowa’s College of Pharmacy,” ITI Press Release (2006) [SERVED BUT NOT FILED] Declaration of Dr. Sveinbjorn Gizurarson, Ph.D. [SERVED BUT