Aquestive Therapeutics, Inc. vs Iono Pharma, LLC - IPR2025-00874

Director Discretionary Decision: Deny

Petitioner’s Brief Opposing Discretionary Denial

‘437 PCT File History – PCT/US20l7/06076l, filed November 9, 2017.

A copy of the ‘437 Provisional Application (EX1013) highlighted to show where material from the Almoazen Paper (EX1022) appears.

Schobel Provisional, Provisional Application, serial no. 62/331,996, filed May 5, 2016, to Schobel U.S. 11,191,737.

Motosue, et al, “Risk factors for severe anaphylaxis in the United States”, Ann Allergy Asthma Immunol 119 (2017) 356-361.

Dribin, et al., “Anaphylaxis definition, overview, and clinical support tool: 2024 consensus report—a GA2LEN project”, https://doi.org/10.1016/j.jaci.2025.01.021

U.S. Patent No. 12,023,309.

U.S. Patent No. 11,273,131.

Excerpts of quarterly report for the period ending 6-30-2025 filed with the SEC by Aquestive Therapeutics.

Aquestive 6-16-2025 Press Release.

Excerpts of 2023 annual report filed with the SEC by Aquestive Therapeutics.

Excerpts of 2024 annual report filed with the SEC by Aquestive Therapeutics.

Excerpts of quarterly report for the period ending 3-31-2025 filed with the SEC by Aquestive Therapeutics.

Excerpts of quarterly report for the period ending 6-30-2025 filed with the SEC by Aquestive Therapeutics.

Prescription Drug User Fee Amendments, https://www.fda.gov/industry/fda-user-fee-programs/

5-27-2016 email from Steve Wargacki to Ramona McCudden re: Possible candidate source.

6-3-2016 email from Ramona McCudden to Steve Wargacki re: MonoSol Rx (2).

6-16-2016 email from Ramona McCudden to Steve Wargacki re: MonoSol Rx (1).

10-23-2016 email from Steve Wargacki to Ramona McCudden re: email from Almoazen.

Declaration of Romona Mccudden, Recruiting Specialist at Petitioner Aquestive Therapeutics, Inc.

Petitioner’s First Updated Exhibit List

Patent Owner's Preliminary Response

EX2021 - U.S. Provisional No. 62/331,993

EX2022 - U.S. Provisional No. 62/929,737

EX2024 - Aquestive Therapeutics June 16, 2025, Press Release

EX2025 - FDA GSRS UNII Substance Record — Dibutepinephrine (UNII: 3ZU4LVA3G9)

EX2026 - F. Estelle R. Simmons, First-aid treatment of anaphylaxis to food: Focus on epinephrine, 113 Journal of Allergy and Clinical Immunology 837 (2004)

EX2027 - Keith J. Simons and F. Estelle R. Simons, Epinephrine and its use in anaphylaxis: current issues, Current Opinion in Allergy and Clinical Immunology 354 (2010)

EX2028 - Jacqueline A. Pongracic and Jennifer S. Kim, Update on epinephrine for the treatment of anaphylaxis, Current Opinion in Pediatrics 94 (2007)

EX2029 - Phil Lieberman, Use of epinephrine in the treatment of anaphylaxis, Current Opinion in Allergy and Clinical Immunology 313 (2003)

EX2030 - Xiaochen Gu et al., Is Epinephrine Administration by Sublingual Tablet Feasible for the First-Aid Treatment of Anaphylaxis? A Proof-of-Concept Study, Biopharmaceutics & Drug Disposition (2002)

EX2031 - F. Estelle R. Simons et al., Can Epinephrine Inhalations Be Substituted for Epinephrine Injection in Children at Risk for Systemic Anaphylaxis? 106 Pediatrics 1040 (2000)

EX2032 - U.S. Patent Publication No. 2018/0104195

EX2033 - Dipivefrin: “Uses, Interactions, Mechanism of Action.” DrugBank Online. Retrieved September 4, 2025

EX2034 - FDA News Release, FDA Approves First Nasal Spray for Treatment of Anaphylaxis

EX2035 - HCP Live, Positive Phase 3 Results Announced for Sublingual Epinephrine Treatment

EX2036 - Fortune Business Insights, Epinephrine Market Size, Share & Industry Analysis

EX2037 - Stock Titan, Aquestive Therapeutics Announces that FDA Will Not Require an Advisory Committee Meeting to Discuss New Drug Application for Anaphlym

EX2038 - Healio, FDA accepts new drug application for sublingual epinephrine film

EX2039 - Clinical Trial Arena, Aquestive maps out FDA approval for sublingual anaphylaxis drug

EX2001

EX2002

EX2003

EX2004

EX2005

EX2006

EX2007

EX2008

EX2009

EX2010

EX2011

EX2012

EX2013

EX2014

EX2015

EX2016

EX2017

EX2018

EX2019

EX2020

Patent Owner's Discretionary Denial Brief

EXPUNGED

Notice: Notice filing date accorded

Notice: Patent Owner's Mandatory Notice

Notice: Patent Owner's Power of Attorney

Almoazen '437 Patent, U.S. Patent No. 11,021,437 B2.

Truelove 1, U.S. Patent No. 3,809,714

Ashraf, “Considerations in Developing Sublingual Tablets – An Overview"

Fuchs, U.S. Patent No. 4,136,145.

Almoazen '437 Patent File History, U.S. App. Ser. No. 16/347,625.

Truelove 2, U.S. Patent No. 3,825,583.

Truelove 4, “Prodrug Approaches to , , , Novel Epinephrine Prodrug”

Truelove 3, U.S. Patent No. 3,868,461.

The Merck Index, 12th Ed., 1996, p. 613.

USP certificate for epinephrine, dated 14 Aug 2017.

EpiPen Information

Almoazen ‘437 Patent Provisional Application, Ser. No. 62,421,316.

Almoazen PCT Application, WO2018/089570 A1 (PCT/US2017/060761).

Florence, “Physicochemical Principles of Pharmacy”.

Bodor, U.S. Patent No. 4,145,441.

Rawas-Qalaji, U.S. Patent Application Publication No. US 2007/0202163 A1.

Ettmayer, “Lessons Learned from Marketed and Investigational Prodrug".

Rautio, “Prodrugs: design and clinical applications”.

Silverman, “Prodrugs and drug delivery systems”.

Schobel, U.S. Patent No. 11,191,737 B2.

Almoazen Paper, “Development of a fast dissolving film of epinephrine ...".

Baldessarini, “Hydrolysis of diester prodrugs of apomorphine”.

Kristoffersson, “Drug latentiation of terbutaline”.

Christrup, “Improvement of buccal delivery ... using the prodrug approach”

Lieberman, “The diagnosis and management of anaphylaxis practice parameter"

den Daas, “Improvement of the oral bioavailability . . . ester prodrugs".

Hansen 1991, “Ketobemidone prodrugs for buccal delivery”.

Hansen 1992, “Ketobemidone prodrugs for buccal delivery ...".

Markup of EX1001 showing EX1022 contribution.

Roche, “Design of biopharmaceutical properties through prodrugs ...".

Markup of EX1022 showing material found in EX1001.

Morrison and Boyd, “Organic Chemistry”, Sections 18.1-18-4.

Streitwieser, “Introduction to Organic Chemistry”, excerpts.

Stepensky, “Long-Term Stability Study of L-Adrenaline Injections ...".

Rautio II, “Prodrugs—from Serendipity to Rational Design”.

Senel, “Drug permeation enhancement via buccal route ...".

Kohn, “Clinical Comparison of Dipivalyl Epinephrine and Epinephrine ...".

Journal of Medicinal Chemistry (JMC) Manuscript Requirements

Declaration of Jarkko Rautio, Ph.D.

Declaration of Nicholas A. Meanwell, Ph.D.

Notice: Power of Attorney

Petition: as filed