The nasal mucosa - Fitonasal 2Act Page 1 of 2 How does the nose work?

Underneath the epithelium is a dense network of capillary blood vessels.

The nasal mucosa is essential to correct operation of the entire respiratory system.

The nose works as it does thanks to various defensive mechanisms: its epithelium and dense network of capillaries, its mucus, the vibrating cilia which move the mucus, the cells of the immune system and many substances capable of combating bacteria and viruses and harmful substances.

The nasal mucosa - Fitonasal 2Act Page 2 of 2 The mucus traps harmful substances (viruses, bacteria, dust, pollens, etc.) on the surface of the mucosa and the vibratory cilia move the mucus toward the pharynx to eliminate it.

In 2001, I founded Hananja ehf, an Icelandic entity accredited by the European Union and a specialty biopharmaceutical company focused on discovery and development of innovative treatments for life-threatening diseases, specifically nasal spray drug products.

The physiological constraints of active ingredient uptake due to the nasal anatomy, as well as the very low solubility of benzodiazepines requires a higher skill set and knowledge than a POSA with a bachelor’s degree “with several years of experience.”

While benzodiazepine formulations had been developed for intravenous administration by 2008, the need for medical professionals to administer these therapeutic products greatly limited their use for epileptic patients requiring an immediate cessation of the seizure symptoms outside of a hospital or clinic setting.

Lau attempted to overcome these challenges by first solubilizing the benzodiazepines in an organic non-aqueous vehicle, including triacetin, dimethyl sulfoxide, polyethylene glycol 400, Cremophor EL (polyoxyethylated castor oil), Lipal-9-LA (laureth-9(polyoxyethylene-9 lauryl ether), isopropyl adipate and azone 1- dodecylazacycloheptane-2-one.

1986 Chemical Warfare – analysis & emergency Ministry of defense, Denmark Employment 1991-: Assistant (1991), Associated (1993) and Full Time Professor (1996) at the Faculty of Pharmaceutical Sciences, University of Iceland CEO of Lyfjaþróun biopharmaceuticals.

VALTOCO, Neurelis’ lead product candidate, is a proprietary formulation of diazepam ® incorporating the unique combination of a vitamin E-based solution and Intravail absorption enhancement.

“VALTOCO was developed to provide an eective combination of reliability, safety, and tolerability in a simple, ready-to-use nasal spray.” The NDA for VALTOCO is supported by an extensive clinical and pre-clinical package including studies in healthy volunteers and patients with epilepsy.

This NDA submission also represents a highly meaningful milestone for the Neurelis team, many of which have been intimately engaged in advancing epilepsy rescue treatment options over the last two decades.

This lack of novel and innovative therapies is a signicant unmet need in the epilepsy community that needs to be addressed.” More About VALTOCO VALTOCO nasal spray is a proprietary formulation of diazepam, delivered via a nasal spray formulation, developed for the management of pediatric, adolescent, and adult patients who require intermittent use of diazepam to control bouts of increased seizure activity, also known as cluster or acute repetitive seizures.

Neurelis is leveraging its expertise in the development and commercialization of CNS compounds and strong relationships with leading researchers and clinicians in these markets to advance unique product candidates, such as VALTOCO, to address signicant unmet medical needs.

"We are pleased to have received Orphan Drug Designation from the FDA based on the potential clinical benet of NRL-1 to patients who experience acute repetitive seizures" stated Craig C. Chambliss, President and Chief Executive Ocer of Neurelis.

"Pediatric, adolescent, adult patients and their caregivers desire an eective, reliable, and well-tolerated treatment alternative to either rectal diazepam or an emergency room visit.

There are over 2.7 million people with epilepsy in the United States with approximately 200,000 new patients diagnosed each year.

Studies have shown that prolonged or repetitive seizures can cause neurological damage and dramatically increase the risk of changes in neuropsychological function or even death.

Neurelis leverages expertise in the development and commercialization of CNS compounds and strong relationships with leading researchers and clinicians in these markets to advance unique product candidates to address signicant unmet medical needs.

Diagnosis Hyperventilation Migraine Panic attack Psychogenic seizures Syncope Transient global amnesia Transient ischemic attack Important Clinical Features Anxiety and overbreathing evident; often perioral cyanosis, hand paresthesias, and carpo pedal spasm are present; environmental trigger may be evident Slow progression of neurologic symptoms; visual symptoms prominent; basilar migraine has unusual features, including confusion, stupor, bilateral blindness; headache may be minimal or absent Abrupt onset with intense feeling of dread or fear; often sense of impending death or inability to breathe; prominent autonomic features (e.g., tachycardia, sweating, nausea); lasts longer (5–30 min) than typical seizure; no loss of consciousness Psychiatric history; patient usually motionless with eyes closed at onset; fluttering eye movements and forceful eye closure common; out-of-phase, thrashing limb move- ments and pelvic thrusting common; urinary incontinence unusual; refractory to treatment Precipitating circumstances usually identifiable; prodrome of wooziness but no aura or unilateral symptoms; loss of consciousness brief (<20 sec), with rapid return to nor- mal; a few muscle jerks (“convulsive syncope”) can occur at end because of hypoxia Isolated amnesic syndrome; prolonged duration (several hours); no alteration of con- sciousness; no confusion, weakness, or aphasia; persistent memory gap during period of attack; recurrence unusual Sudden onset without progression of symptoms; variable symptoms related to brain and vascular anatomy; negative features (e.g., weakness, loss of sensation, aphasia) predominate Evaluation The neurologic examination is normal in most pa- tients with epilepsy.

Patients should be discouraged from participating in ac- tivities for which a history of seizures increases the risk of injury or death; these activities include driving, operating high-risk power equipment, n engl j med 359;2 www.nejm.org july 10, 2008 The New England Journal of Medicine Copyright © 2008 Massachusetts Medical Society.

T h e ne w e ngl a nd jou r na l o f m e dicine tively inexpensive phadenopathy; rela- acial features, lym- sutism, coarsened gival hyperplasia, hir- increased risk of gin- Reduces bone density; f netics‡ lead to nonlinear ki- ed; more likely to Not always well tolerat-

How- ever, clinical trials in newly diagnosed epilepsy have not shown any advantage associated with phenytoin,27 and it is generally preferable to initi- ate whichever antiepileptic drug is considered to n engl j med 359;2 www.nejm.org july 10, 2008 The New England Journal of Medicine Copyright © 2008 Massachusetts Medical Society.

* Type of Medication Cardiac Psychiatric Antineoplastic Antiinfective Other Increased Clearance (and Need for Higher Doses) with Phenytoin, Phenobarbital, Carbamazepine Decreased Clearance (and Need for Lower Doses) with Valproic Acid Mexiletine, quinidine, amiodarone, propranolol, meto- prolol, nifedipine, felodipine, nimodipine, digoxin, lovastatin, simvastatin, dicoumarol, warfarin Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, citalopram, paroxetine, buproprion, haloperidol, chlorpromazine, clozapine, olanzapine, risperidone, quetiapine Cyclophosphamide, busulfan, etoposide, methotrexate, teniposide, some vinca alkaloids Praziquantel, albendazole, doxycycline, nevirapine, efavirenz, delavirdine, indinavir, ritonavir, saquinavir Cyclosporine, tacrolimus, diazepam, alprazolam, prednisone, oral contraceptive pills, theophylline, methadone Nimodipine Amitriptyline, nortriptyline, clomip- ramine, paroxetine Zidovudine, possibly others Lorazepam, diazepam * Data are from Patsalos and Perucca.46 This list is not comprehensive.

Box 71 71, IS-127 Reykjavik, Iceland 3Dansk Toxicologi Center, ATV, Agern Alle 15, DK-2970 H~rsholm, Denmark Received November 1, 1996; Accepted April 9, 1997

Considerable effort has been put into the development of intravenous administrations, since dilution with intra- venous fluids or plasma may cause precipitation, result- ing in irritation of the vein endothelium, and possibly in thrombophlebitis, e.g., in the lungs and in the kindneys (3,4).

Clinical Dose (mg) Drug Clonazepam Desmethyldiazepam Diazepam Fluni trazepam Lorazepam Lormethazepam Midazolam Nitrazepam Triazolam 1 5a 5a 0.

This study demonstrates that it may be possible to produce formulations, using only acceptable excipients, to dissolve clinically relevant amounts of benzodiaz- epines in a volume not exceeding 300 pl.

M. G. Alessandri, V. Scalori, L. Giovannini, M. Mian, and A. A. E. Bertelli, Plasma and tissue concentration of Coenzyme Qlo in the rat after intravenous administra- tion by a microsphere delivery system or in a new type: of solution, Int.

v. Int’l Game Tech., 543 F.3d 657 (Fed. Cir. 2008)  Exela Pharma Sciences, LLC v. Lee, 781 F.3d 1349 (Fed. Cir. 2015)  Exxon Corp. v. Phillips Petroleum Co., 265 F.3d 1249 (Fed. Cir. 2001)  Harari v. Hollmer, 602 F.3d 1348 (Fed. Cir. 2010)  Magnivision, Inc. v. Bonneau Co., 115 F.3d 956 (Fed. Cir. 1997)  Ex parte Maziere, 27 USPQ2d 1705 (BPAI 1993)  McDonnell v. United States, 579 U.S. _, 136 S.Ct.

 Manual of Patent Examining Procedure §608.01(p), I.B Based on my professional judgment, I believe this case requires an answer to three or more precedent-setting questions of exceptional importance: 1.

The panel’s silence on rehearing about the rule error and its shift to requiring the patent owner to meet a burden of production when there is no possible dispute that the petitioner failed to even address the most pertinent

disclosure, thus failing to make out a facial case sufficient to shift any burden to the patent owner, simply compounds the error.

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Zip Code Country This offer is good only when this official form is used prior to January 1, 1989 We cannot accept requests by letter, purchase order or any other way, because of the increased handling involved.

4/9/2019 Epilepsy Fast Facts | CDC Tire Centers for Disease Control and Prevention .

These seizures are not caused by a temporary underlying medical condition such as a high fever.

These factors play a major role in determining both the severity of the person’s condition and the impact it has on his or her life.

Learn more about active epilepsy and find state-specific prevalence estimates on our Data and Statistics page.

Russ SA, Larson K, Halfon N. A national profile of childhood epilepsy and seizure disorder.

Neurelis, Inc. c/o Pacific Link Consulting, LLC Attention: Richard Lowenthal, MS, MSEL President, Pacific-Link Consulting 8195 Run of the Knolls Court San Diego, CA 92127 Dear Mr. Lowenthal: Food and Drug Administration Silver Spring MD 20993

We have reviewed your request and concluded that it meets the criteria for Fast Track designation.

Therefore, we are designating as a 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 seizures.

Please note that if the clinical development program you pursue does not continue to meet the criteria for Fast Track designation, the application will not be reviewed under the Fast Track program.

Sincerely, {See appended electronic signature page} Billy Dunn, MD Director Division of Neurology Products Office of Drug Evaluation I Center for Drug Evaluation and Research Reference ID: 4034029 Neurelis - EX. 2002 Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00450

Estimates of the prevalence and incidence of epi- lepsy worldwide vary considerably, likely reflecting differences in measurement and reporting, along with clinical characteristics such as etiology and seizure type.

Articles were included if they met the following criteria: (1) original research, (2) population-based (selecting the entire population or using probability-based sampling methods), (3) reported a prevalence or incidence of epilepsy (or raw numbers that allowed the calculation of an estimate).

Epilepsy prevalence or incidence estimates, raw numbers, and confidence in- tervals (CIs) (when provided) were recorded along with any strati- fied results by age, sex, or year of data collection.

Congruent with pre- the vious descriptive reports,35 we found that incidence of epilepsy was generally higher in the youngest and oldest age groups; however, there were insufficient studies to perform a meta-analysis.

Ideally, a multivariable meta- regression would have been employed to deal with the possible confounding effects of variables such as age and location, though this would have required a very large number of studies, and as such only strat- ified estimates are provided.

4/9/2019 Epilepsy Fast Facts | CDC Tire Centers for Disease Control and Prevention .

These seizures are not caused by a temporary underlying medical condition such as a high fever.

These factors play a major role in determining both the severity of the person’s condition and the impact it has on his or her life.

Learn more about active epilepsy and find state-specific prevalence estimates on our Data and Statistics page.

Russ SA, Larson K, Halfon N. A national profile of childhood epilepsy and seizure disorder.

4/9/2019 Epilepsy Fast Facts | CDC Tire Centers for Disease Control and Prevention .

These seizures are not caused by a temporary underlying medical condition such as a high fever.

These factors play a major role in determining both the severity of the person’s condition and the impact it has on his or her life.

Learn more about active epilepsy and find state-specific prevalence estimates on our Data and Statistics page.

Russ SA, Larson K, Halfon N. A national profile of childhood epilepsy and seizure disorder.

Some of these epilepsy self-management programs are available by phone, online, and on other electronic devices, eliminating barriers to care, such as lack of access to transportation, functional limitations, and stigma.

As with any chronic condition, many people with epilepsy can benefit f om learning skills and techniques that help them better manage their disorder and its effects on daily life.

/11/11 HOBSCOTCH (Home-Based Self-Management and Cognitive Training Changes Lives) is a program led by Dartmouth College that is designed to address memory and attention problems among people with epilepsy through a combination of in-person visits and phone calls that provide coaching.

It is also testing a web-based group format approach designed to reach people at high risk of negative health events, such as seizures, hospitalizations, accidents or traumatic injuries, or self-harm attempts.

Blixen C, A Perzynski, Kanuch S, et al. Training peer educators to promote self-management skills in people with serious mental illness (SMI) and diabetes (DM) in a primary health care setting.

4/19/2019 Harvard Health Blog Quick injection helps stop epileptic seizures - Harvard Health Blog - Harvard Health Blog - https://www.health.harvard.edu/blog - Quick injection helps stop epileptic seizures Posted By Howard LeWine, M.D.

A study published last week in the New England Journal of Medicine indicates that a hand-held auto-injector—much like the epi pens used by people with life-threatening allergies—could be used to treat seizures that don’t stop on their own.

Muscle trumps vein For the trial, more than 4,000 emergency medical technicians were trained to administer seizure-stopping drugs called benzodiazepines two ways: through an intravenous line inserted into a vein in the arm (the current standard treatment), and with a device that automatically injects the drug into the thigh.

Looking ahead This one study isn’t the green light for doctors to give auto-injectors filled with anti-seizure medication to all of their patients who have seizures.

This could spare these people and their families the agonizing wait for an ambulance to arrive in order to halt the seizure.