If the oral argument is held by video conference, Petitioner respectfully requests that the video conference provide the ability for the participants to display demonstrative exhibits and documents of record to all participants.

If the oral argument is held in person at USPTO headquarters in Alexandria or elsewhere, Petitioner respectfully requests that the Board make available audio- visual equipment, including a projector to be connected to a laptop and an ELMO, to display demonstrative exhibits and documents of record.

That a POSITA would have been motivated to combine the applied references and would have had a reasonable expectation of success in so doing.

Any issues raised by Patent Owner in its Request for Oral Argument.

Patent Owner’s contentions (Paper 26) alleging the presence of new or improper arguments in Petitioner’s Reply and/or in Wermeling Declaration.

of Health and Human Services re: IND 112621; NRL-1 (diazepam intranasal solution), Dec. 27, 2016, pp 1-2.

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?

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

Pursuant to the scheduling order (Paper 9, 6), Patent Owner (“Neurelis”) requests oral argument on all pending issues, including whether to terminate the review, whether to strike the reply of the Petitioner (Aquestive) or the declaration of its expert Dr. Wermeling, and any motion to exclude.

Because most of its participants are on the West Coast, Neurelis respectfully requests an afternoon (Eastern) argument.

Neurelis anticipates that eight (8) individuals (including counsel) will attend for Neurelis, if in-person attendance becomes feasible.

Date: March 31, 2020 Respectfully submitted,

/Jeffrey W. Guise / Jeffrey W. Guise, Reg. No. 34,613 Counsel for Neurelis

Petitioner, Aquestive Therapeutics, Inc. submits the following objections to evidence of the Patent Owner, Neurelis, Inc. Exhibit 2028: “Intranasal Technology, Inc.

Licenses Aegis Therapeutics' Intravail Drug Delivery Technology” (Business Wire) (April 13, 2005)

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.

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

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.

Patent Owner Neurelis, Inc. (Neurelis) submits the following mandatory change-of-information notices for IPR2019-00451.

Related Matters (37 C.F.R. §42.8(b)(2)) – Revised Petitioner (Aquestive) filed two additional inter partes review petitions (IPR2019-00449 and IPR2019-00450) against the involved patent, but both were denied.

Neurelis has an application (15/470,498) that claims benefit under 35 U.S.C. 120 to the application that issued as the involved patent.

Neurelis has filed a tort suit against Aquestive citing the Aquestive petitions as evidence of a pattern of tortious behavior against Neurelis.

Respectfully submitted, /Richard Torczon/ Richard Torczon Reg. No. 34,448 Case IPR2019-00451 Patent No. 9,763,876

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,” 2024 2025 2026 2027 2028 2029 2030 2031 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

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

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.

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.”).

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”.