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 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) 2023 2024 2025 2026 2027 “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) [SERVED

Transcript of Telephone Conference on Feb. 11, 2020 Date: 13 February 2020 /Lorelei Westin/ Lorelei Westin, Reg. No. 52,353 Counsel for Neurelis, Inc.

Patent owner Neurelis Inc. will conduct examination by deposition of Daniel P. Wermeling.

Dr. Wermeling’s deposition will commence at 9:00AM (local time) on February 26, 2020, at the offices of Hoffmann & Baron, LLP, 4 Century Drive, Suite 300, Parsippany, NJ 07054-4606.

The deposition will be taken before a notary public or other officer authorized by law to administer oaths and will be recorded by stenographic means.

Neurelis will arrange for the reporter.

Dated: February 11, 2020 Respectfully submitted, /Lorelei Westin/ Lorelei Westin, Reg. No. 52,353 Counsel for Neurelis, Inc.

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

FRE 901 (authentication) Aquestive failed to provide evidence sufficient to establish the exhibit is what it is purported to be.

FRE 901 (authentication) Aquestive failed to provide evidence sufficient to establish the exhibit is what it is purported to be.

upon which trial was instituted is substantially outweighed by the danger of unfair prejudice, confusing the issues, or wasting time.

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.

U.S. Patent No. 9,763,876 Gudmundsdottir H, Sigurjonsdottir JF, Masson M, et al., Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans.

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.

U.S. Patent No. 9,763,876 Pursuant to 37 CFR § 42.53, Petitioner, Aquestive Therapeutics, Inc., by and through its counsel, will take the deposition of Dr. Sveinbjorn Gizurarson commencing on January 14, 2020 at 9:00 a.m. (local time), and continuing day to day until completed, at the law offices of Wilson Sonsini Goodrich & Rosati PC, 12235 El Camino Real, San Diego, CA 92130 or at such other time and location as the parties agree.

The deposition will be conducted before an officer authorized to administer oaths.

The deposition will be recorded by stenographic means.

The arrangement for the reporter will be made by counsel for Petitioner.

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

Petitioner, Aquestive Therapeutics, Inc. submits the following objections to evidence of the Patent Owner, Neurelis, Inc. Exhibit 2001: Epilepsy Fast Facts, CDC, 2019

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.

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.

On August 1, 2019, the PTAB denied institution of IPR2019-00449, see Paper

On September 27, 2019, the PTAB denied Petitioner’s Request for Rehearing of the denial of institution of IPR2019-00449, see Paper 10.

Therefore, Petitioner Aquestive Therapeutics, Inc. hereby requests a refund of $15,000.00 for the post- institution fee Petitioner paid for IPR2019-00449.

See copy of portion of fee payment receipt below:

The refund should be deposited into the deposit account from which it was paid, namely, Hoffmann & Baron LLP Deposit Account No. 08-2461, as provided for in the Petition, page 3, Paper 2 (“The undersigned further authorizes payment from and to the above referenced Deposit Account [i.e., 08-2461] for any additional fees or refund that may be due in connection with this petition and IPR proceeding.”).

On August 1, 2019, the PTAB denied institution of IPR2019-00449, see Paper

On September 27, 2019, the PTAB denied Petitioner’s Request for Rehearing of the denial of institution of IPR2019-00449, see Paper 10.

Therefore, Petitioner Aquestive Therapeutics, Inc. hereby requests a refund of $15,000.00 for the post- institution fee Petitioner paid for IPR2019-00449.

See copy of portion of fee payment receipt below:

The refund should be deposited into the deposit account from which it was paid, namely, Hoffmann & Baron LLP Deposit Account No. 08-2461, as provided for in the Petition, page 3, Paper 2 (“The undersigned further authorizes payment from and to the above referenced Deposit Account [i.e., 08-2461] for any additional fees or refund that may be due in connection with this petition and IPR proceeding.”).

On August 1, 2019, the PTAB denied institution of IPR2019-00450, see Paper

See copy of portion of fee payment receipt below:

The refund should be deposited into the deposit account from which it was paid, namely, Hoffmann & Baron LLP Deposit Account No. 08-2461, as provided for in the Petition, page 3, Paper 2 (“The undersigned further authorizes payment from and to the above referenced Deposit Account [i.e., 08-2461] for any additional fees or refund that may be due in connection with this petition and IPR proceeding.”).

Indeed, Aquestive relies on the wrong priority date as the entire basis for its obviousness analysis – depending solely on a lack of written description theory that even Aquestive’s expert, Dr. Peppas, could not substantiate during his

Epilepsy is a general term for conditions with recurring seizures, involving abnormal electrical activity in the brain that causes an involuntary change in body movement or function, sensation, awareness, and/or behavior.

Epilepsy actively affects over 3.4 million people in the United States (about 1.2% of the total population) and ranks as the second most burdensome neurological disorder worldwide in terms of disability-adjusted life years, with associated stigma, psychiatric co-morbidity and high economic costs.

While Dr. Peppas makes blanket assertions that “there simply is no criticality to (or unexpected results stemming from) the specific types or amounts of ... benzodiazepines” (EX1041, ¶51) and that “benzodiazepines ... have been known for decades, and their effects on the human body are generally predictable” (id., ¶63), he admitted in deposition testimony that he has zero experience working with benzodiazepines (directly or indirectly).

EX2023; see also EX2002 (granting Neurelis “Fast Track development program the investigation of NRL-1 for the management of selected, refractory patients with epilepsy, on stable regimens of AEDs, who require intermittent use of diazepam to control bouts of increased seizure.”).

1031 Ritschel, Handbook of Basic Pharmacokinetics, Chapter 36 (Bioavailability and Bioequivalence), Drug Intelligence Publications, Illinois, 1992 (Ritschel) Osborne et al., Skin Penetration Enhancers Cited in the Technical Literature, Pharmaceutical Technology, November 1997 (Osborne) Lindhardt et al., Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers, Blackwell Science Ltd Br J Clin Pharmacol, 52, 521-527, 2001 (Lindhardt) Kibbe, editor, Handbook of Pharmaceutical Excipients, Third Edition (2000), American Pharmaceutical Association, Washington DC (Kibbe) Illum, Nasal drug delivery-possibilities, problems and solutions, Journal of Controlled Release 87 (2003) 187-198 (Illum) Ivaturi et al., Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers, Acta Neurol Scand.

‘876 Patent defines “bioavailability” as: “Bioavailability” “it is intended that bioavailability be determined by a suitable pharmacodynamics method, such as comparison of area under the blood plasma concentration curve (AUC) for the nasally and intravenously administered drug.

General Teachings Sonne is directed to: “…the use of a tocopherol or a derivative thereof as a solvent…for substantially insoluble and sparingly soluble biologically active agents, especially in the manufacture of pharmaceutical compositions.

[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” (internal citations and quotations omitted) See also Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1344 (Fed.Cir.

A POSITA would therefore routinely experiment by varying the relative amounts of tocopherols, ethanol, and benzyl alcohol in order to optimize the sprayability, solubility, and viscosity – while simultaneously minimizing potential irritation.

1031 Ritschel, Handbook of Basic Pharmacokinetics, Chapter 36 (Bioavailability and Bioequivalence), Drug Intelligence Publications, Illinois, 1992 (Ritschel) Osborne et al., Skin Penetration Enhancers Cited in the Technical Literature, Pharmaceutical Technology, November 1997 (Osborne) Lindhardt et al., Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers, Blackwell Science Ltd Br J Clin Pharmacol, 52, 521-527, 2001 (Lindhardt) Kibbe, editor, Handbook of Pharmaceutical Excipients, Third Edition (2000), American Pharmaceutical Association, Washington DC (Kibbe) Illum, Nasal drug delivery-possibilities, problems and solutions, Journal of Controlled Release 87 (2003) 187-198 (Illum) Ivaturi et al., Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers, Acta Neurol Scand.

Epub 2009 May 14 (Ivaturi) O’Dell et al., School nurses’ experience with administration of rectal diazepam gel for seizures, J Sch Nurs., June 2007, 23(3):166-9 (O’Dell) Gizurarson et al., Intranasal Administration of Diazepam Aiming at the Treatment of Acute Seizures: Clinical Trials in Healthy Volunteers, Biological and Pharmaceutical Bulletin, Volume 22 (1999) Issue 4 Pages 425-427 (Gizurarson) Rowe et al., editors, Handbook of Pharmaceutical Excipients, Fourth Edition (2003), Monographs for “Alcohol” (i.e., ethanol), “Alpha Tocopherol”, “Benzyl Alcohol”, “Glycerin”,

“Olive Oil”, “Polyethylene Glycol”, “Propylene Glycol”, “Sesame Oil”, and “Triacetin”, American Pharmaceutical Association, Washington DC (Rowe) Edman [II] et al., Microspheres as a nasal delivery system for peptide drugs, Journal of Controlled Release, Vol.

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

“Bioavailability” ‘876 Patent defines “bioavailability” as follows: “it is intended that bioavailability be determined by a suitable pharmacodynamics method, such as comparison of area under the blood plasma concentration curve (AUC) for the nasally and intravenously administered drug.

Ritschel, Handbook of Basic Pharmacokinetics, Chapter 36 (Bioavailability and Bioequivalence), Drug Intelligence Publications, Illinois, 1992 (Ritschel) Osborne et al., Skin Penetration Enhancers Cited in the Technical Literature, Pharmaceutical Technology, November 1997 (Osborne) Lindhardt et al., Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers, Blackwell Science Ltd Br J Clin Pharmacol, 52, 521-527, 2001 (Lindhardt) Kibbe, editor, Handbook of Pharmaceutical Excipients, Third Edition (2000), American Pharmaceutical Association, Washington DC (Kibbe) Illum, Nasal drug delivery-possibilities, problems and solutions, Journal of Controlled Release 87 (2003) 187-198 (Illum) Ivaturi et al., Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers, Acta Neurol Scand.

The exception under 35 U.S.C. 103(c) is inapplicable because at the time of the invention of the Challenged Claims (i.e., March 27, 2009), Cartt’784 was owned by inventor Edward T. Maggio, possibly with an obligation to assign to Aegis Therapeutics, LLC.

‘876 Patent defines “bioavailability” as: “Bioavailability” “it is intended that bioavailability be determined by a suitable pharmacodynamics method, such as comparison of area under the blood plasma concentration curve (AUC) for the nasally and intravenously administered drug.

Therefore, a POSITA could easily and routinely experiment with varying the relative amounts of tocopherols, ethanol, and benzyl alcohol disclosed in Gwozdz in an attempt to optimize Gwodz’s teachings.

“These pharmaceutical solutions” may be administered intransally and can include “benzodiazepenes [sic] such as Diazepam, alpraxolam, bromazepam, chlordiazepoxidem, clonazepam, estazolam, flunitrazepam, flurazepam, lorazepam, lormetazepam, mexazolam, nitrazepam, oxazepam, temazepam, and triazolam”.

§ 42.53, Neurelis Inc., by and through its attorneys, will conduct examination by deposition of Nicholas Peppas.

Dr. Peppas’ deposition will commence at 9:00AM (local time) on October 24, 2019, at the offices of Hoffinann & Baron, LLP, 4 Century Drive, Suite 300, Parsippany, NJ 07054-4606.

The deposition will be taken before a Notary Public or other officer authorized by law to administer oaths and Will be recorded by stenographic means.

The arrangement for the reporter will be made by counsel for Neurelis Inc.

Dated: September 20, 2019 Respectfiilly submitted, mud/14 [/Mm Lorelei Westin Reg. No. 52,353

Case IPR2019-00449 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 Patent Owner Neurelis, Inc. (Patent Owner), hereby submits the following mandatory change-of-information notices in connection with the petition for inter partes review identified in the caption.

Date: 5 September 2019

Respectfully submitted, /Richard Torczon/ Richard Torczon Reg. No. 34,448 Case IPR2019-00449 Patent No. 9,763,876