UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ADAPT PHARMA OPERATIONS LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owners.
`__________________
`
`Case IPR2019-00694
`U.S. Patent No. 9,629,965
`__________________
`
`DECLARATION OF THOMAS J. BEGRES
`
`Opiant Exhibit 2203
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ADAPT PHARMA OPERATIONS LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owners.
`__________________
`
`Case IPR2019-00694
`U.S. Patent No. 9,629,965
`__________________
`
`DECLARATION OF THOMAS J. BEGRES
`
`Opiant Exhibit 2203
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`
`
`DECLARATION OF THOMAS J. BEGRES
`
`
`
`
`I.
`
`I, Thomas J. Begres, declare as follows:
`
`OVERVIEW
`
`1.
`
`I am over the age of 18 and otherwise competent to make this
`
`declaration. This declaration is based on my personal knowledge and experience.
`
`I understand that this declaration is being submitted in support of the Response of
`
`Patent Owners Adapt Pharma Operations Limited and Opiant Pharmaceuticals,
`
`Inc., to petitions for inter partes review filed by Nalox-1 Pharmaceuticals, LLC
`
`challenging claims 1–29 of U.S. Patent Nos. 9,211,253, claims 1–45 of U.S. Patent
`
`No. 9,468,747, and claims 1–30 of U.S. Patent No. 9,629,965.
`
`II. BACKGROUND
`
`2.
`
`I am the Senior Director of Clinical and Medical Affairs at Emergent
`
`BioSolutions, Inc. (“Emergent”), which is now the parent company of Adapt
`
`Pharma.1 Previously, I worked as the head of Clinical Affairs for Adapt Pharma. I
`
`started in that role at Adapt Pharma in early 2015, before the launch of Adapt
`
`Pharma’s only commercial product, Narcan® Nasal Spray. I remained in that role
`
`until after Emergent acquired Adapt Pharma in 2018, when Emergent promoted me
`
`to my current title. I refer to Adapt Pharma and Emergent collectively in this
`
`declaration as “Adapt.”
`
`
`1 By “Adapt Pharma,” I mean Patent Owner Adapt Pharma Operations Limited and
`its affiliates.
`
`
`
`2
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
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`Page 2
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`
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`DECLARATION OF THOMAS J. BEGRES
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`
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`3.
`
`In my role as Senior Director of Clinical and Medical Affairs at
`
`Adapt, I am the “clinical face” of Narcan® Nasal Spray in the United States and
`
`Canada. Among other things, I provide clinical information to healthcare
`
`providers and others regarding naloxone, including Narcan® Nasal Spray. I
`
`regularly interact with numerous medical professionals around North America,
`
`including medical directors of fire and emergency medical services (“EMS”)
`
`agencies and medical directors of state or local programs that provide direction on
`
`the use of medications (including naloxone) by pre-hospital providers. During
`
`these interactions, medical professionals often share with me their experiences with
`
`treating opioid overdoses with naloxone, including Narcan® Nasal Spray. I am in
`
`a noncommercial unit at Adapt, meaning I am not responsible for any marketing or
`
`direct sales.
`
`4.
`
`In addition to my full-time job at Adapt, I am also a full-time
`
`firefighter-paramedic for the Scio Township Fire Department, which operates near
`
`Detroit, Michigan. I have been trained to provide—and do provide—both fire
`
`suppression services and EMS. I am also a licensed firefighter instructor and a
`
`licensed paramedic instructor, and I regularly teach firefighting and EMS courses,
`
`which include instruction on the administration of naloxone to treat opioid
`
`overdose. It took me approximately 2,500 hours of training to obtain these
`
`
`
`3
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`
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`licenses. Throughout my 21-year career as a firefighter-paramedic, I have treated
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`DECLARATION OF THOMAS J. BEGRES
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`hundreds of persons suffering from opioid overdose.
`
`5.
`
`As a firefighter-paramedic, I am an “advanced life support” provider.
`
`In the United States, there are essentially two types of EMS providers: “advanced”
`
`life support providers (often called “paramedics”), and “basic life support”
`
`providers (often called “EMTs”). Advanced life support providers receive
`
`extensive medical training and are authorized to administer a variety of
`
`medications. Basic life support providers receive limited training and are generally
`
`not authorized to administer medications.
`
`6.
`
`In addition to my firefighter-paramedic training, I also have a
`
`Bachelor of Science in nursing and a Master of Science in Family Nurse
`
`Practitioning. I am a licensed registered nurse practitioner in Michigan, and I have
`
`over a decade of experience working as a registered nurse in hospital emergency
`
`departments. I started my nursing career at Detroit Receiving Hospital Emergency
`
`Department in the late 1990s, which is a Level 1 Trauma Center, meaning it is
`
`equipped to treat the most serious emergencies. While working as a nurse, I
`
`treated hundreds of persons suffering from opioid overdose.
`
`7.
`
`As a result of the training and experience I have described above, I am
`
`knowledgeable about the administration of opioid antagonists to treat opioid
`
`overdoses by medically trained personnel, first responders, and in the community.
`
`
`
`4
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`IPR2019-00694
`Page 4
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`
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`I have clinical experience with administering opioid antagonists to overdose
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`DECLARATION OF THOMAS J. BEGRES
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`patients. I am also familiar with recommended practices and procedures for the
`
`treatment of opioid overdoses in hospital and pre-hospital settings, and with
`
`potential adverse effects associated with the administration of opioid antagonists
`
`and withdrawal from opioid intoxication.
`
`8.
`
` In addition to the experience I have just described, from 1990 to
`
`1995, I served as a police officer in South Central Los Angeles. In that role, I
`
`regularly encountered individuals who had overdosed on opioids. At that time
`
`(which was before I began my medical career), police officers in my area were not
`
`equipped to treat opioid overdoses. If we encountered a person experiencing an
`
`opioid overdose, we would radio dispatch and request EMS, then wait for EMS to
`
`arrive. Today, in contrast, officers of the Los Angeles Police Department carry
`
`Narcan® Nasal Spray to treat opioid overdose.
`
`III. PRACTICE OF ADMINISTERING NALOXONE TO TREAT OPIOID
`OVERDOSE AS OF MARCH 16, 2015
`
`9.
`
`As of March 16, 2015, I had administered naloxone hundreds of times
`
`to treat opioid overdose. The following paragraphs describe my practice when
`
`administering naloxone to treat opioid overdose, which has not changed materially
`
`since I first received training to administer naloxone over twenty years ago.
`
`10.
`
`I have been trained to administer naloxone via a variety of routes,
`
`including intravenously, intraosseously (i.e., into the bone marrow), by
`
`
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`5
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`
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`intramuscular or subcutaneous injection, via an endotracheal tube, and intranasally.
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`DECLARATION OF THOMAS J. BEGRES
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`In my work as a firefighter-paramedic, whenever possible, I have always chosen to
`
`administer naloxone intravenously. Intravenous injection is the National Highway
`
`Traffic Safety Administration’s recommended method of naloxone administration
`
`for EMS providers like me. It allows me to administer very precise amounts of
`
`naloxone and to increase the dose slowly over time, i.e., to “titrate” the dose to
`
`clinical effect. In addition, because overdose patients commonly suffer from
`
`multiple afflictions, installing an intravenous line allows me easily to administer
`
`other medications in addition to naloxone.
`
`11. When I treat a patient with naloxone, the patient is almost always still
`
`breathing, albeit sub-optimally. If I arrive at the scene and the patient is no longer
`
`breathing, then in most cases the therapeutic window for naloxone administration
`
`has passed, and I do not administer naloxone. Only very rare occasions where I
`
`arrive at the scene and the patient has just stopped breathing only moments before
`
`my arrival will I consider administering naloxone to a patient who is no longer
`
`breathing (in which case I follow my ordinary naloxone administration and dosing
`
`practice). This has always been my practice, and it is how I train other EMS
`
`providers. The other medical professionals whom I have observed administer
`
`naloxone also follow this practice.
`
`
`
`6
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`Page 6
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`
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`12. When treating an opioid overdose with naloxone, my clinical
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`DECLARATION OF THOMAS J. BEGRES
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`objective is to administer the minimum amount of naloxone necessary to restore
`
`the patient’s ability to breathe on their own. I was taught this clinical objective in
`
`my paramedic training over two decades ago, and it remains my clinical objective
`
`when administering naloxone today. When I teach other EMS practitioners how to
`
`treat opioid overdose, I teach them this clinical objective. There are several
`
`reasons why this is and always has been my clinical objective when administering
`
`naloxone.
`
`13. First, fully reversing the effect of an opioid in an opioid-dependent
`
`patient increases the risk of withdrawal symptoms, and the greater the amount of
`
`naloxone administered, the greater the risk of and severity of the withdrawal
`
`symptoms. In my work as a medical provider, I have seen patients go through
`
`withdrawal and have talked to them about their symptoms. Withdrawal symptoms
`
`include nausea, vomiting, diarrhea, bone-chilling pain, and profuse sweating to the
`
`point of immobilization. Patients have likened withdrawal to feeling 1,000 times
`
`worse than the flu, with symptoms emerging within five minutes.
`
`14. Although withdrawal symptoms are usually not life-threatening in
`
`themselves (except for vomiting, which can be deadly if the patient aspirates on his
`
`or her vomit), they are extremely unpleasant for the patient, and can drive the
`
`patient to engage in extremely dangerous and even life-threatening behavior. For
`
`
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`7
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`example, it is quite common for patients who suffer from opioid withdrawal
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`DECLARATION OF THOMAS J. BEGRES
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`following administration of naloxone to take more opioids to relieve their
`
`withdrawal symptoms. This can lead to another, potentially fatal overdose. I have
`
`personally seen this happen. For example, a few years ago I arrived at a residence
`
`on Robinson Street where a patient had overdosed on opioids. Upon
`
`administration of naloxone, the patient became fully awake and began visibly to
`
`exhibit withdrawal symptoms. The patient refused further medical treatment, so I
`
`left his residence and returned to service. A few hours later, I was called back to
`
`his residence to find that he had re-overdosed on opioids. Unfortunately, no one
`
`called 911 in time to treat him, and he died.
`
`15.
`
`Second, patients who experience full reversal of the narcotic effects of
`
`an opioid are frequently agitated or combative. This sort of behavior presents a
`
`danger not only to the health and safety of the patient but also to the caregiver and
`
`bystanders. I have personally witnessed this type of behavior a number of times in
`
`my career. In one case, I treated an unconscious patient with intravenous naloxone
`
`in the presence of a police officer. Once the patient woke up, he became extremely
`
`upset and combative. He ripped out the intravenous line from his arm and sprayed
`
`blood on the police officer and me. When the police officer tried to restrain him,
`
`the patient dislocated his elbow.
`
`
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`8
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`DECLARATION OF THOMAS J. BEGRES
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`
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`16. Third, naloxone can have dangerous side-effects, even in patients who
`
`are not opioid-dependent. For example, naloxone is known to cause life-
`
`threatening pulmonary edema (a condition caused by excess fluid in the lungs that
`
`makes it difficult to breathe). In addition, naloxone can induce seizures. I have
`
`personally witnessed a patient experience a seizure after the administration of
`
`naloxone. In order to stop the seizure, I had to administer benzodiazepines, which
`
`create additional potential for dangerous side effects.
`
`17. Fourth, fully reversing the effects of the opioid could have unintended
`
`and undesirable consequences if the patient has also ingested other narcotics. For
`
`example, some patients take a “speedball,” which is a combination of heroin (an
`
`opioid) and cocaine. In such a situation, the depressant effect of the opioid may
`
`offset (to some extent) the stimulant effect of the cocaine. Administering naloxone
`
`in that situation reverses the depressant effect of the opioid but will not reverse the
`
`stimulant effect of the cocaine. Reversing just the effects of the opioid in such a
`
`situation can lead to a sudden increase in the clinical effect of the cocaine, which in
`
`turn can lead to a cocaine overdose.
`
`18. As a firefighter-paramedic, when I treat an opioid overdose in the
`
`field, I am required to follow an “EMS protocol.” An EMS protocol is a written
`
`procedure for treating a patient exhibiting a particular set of symptoms. Where I
`
`work as a firefighter-paramedic, the EMS protocol for treating opioid overdose
`
`
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`9
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`
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`permits me to give an initial dose of between 0.4 and 2 mg of naloxone via
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`DECLARATION OF THOMAS J. BEGRES
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`intravenous injection, intramuscular injection, subcutaneous injection, or
`
`intranasally. That has been the EMS protocol in my region since long before
`
`March 16, 2015.
`
`19. Although the EMS protocol applicable in my region would permit me
`
`to administer as much as 2 mg of naloxone in an initial dose, I have always started
`
`with a dose of 0.4 mg via injection. In my experience, a 0.4 mg injection dose of
`
`naloxone is sufficient to restore fully a patient’s breathing approximately 90
`
`percent of the time, and has at least some positive effect on a patient’s breathing
`
`even in the 10 percent of cases where I ultimately decide to administer more
`
`naloxone. If after several minutes a patient has not responded sufficiently to the
`
`initial 0.4 mg dose of naloxone, my practice is to administer a second 0.4 mg dose.
`
`That is how I was trained to administer naloxone, and it is how I train other EMS
`
`practitioners to administer naloxone. The other medical practitioners I have
`
`observed administer naloxone over the years, including paramedics, nurses, and
`
`physicians, all followed the same practice.
`
`20.
`
`In addition to administering naloxone, EMS providers sometimes
`
`provide mechanical ventilation to patients to assist with breathing. But mechanical
`
`ventilation has its drawbacks. For example, if not performed correctly, it can force
`
`air into a patient’s stomach rather than their lungs, which can lead to gastric
`
`
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`evacuation and the contents of the stomach being aspirated into the patient’s lungs.
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`DECLARATION OF THOMAS J. BEGRES
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`It is also inconvenient for EMS practitioners to provide for an extended period of
`
`time. Further, it is not always possible to provide mechanical ventilation. For
`
`example, if a patient is in a car seat or in a small bathroom stall, it may not be
`
`physically possible to provide mechanical ventilation in the patient’s current
`
`location, and it may not be safe to move the patient (for example, if the patient is in
`
`a car on the side of the road, or if moving the patient will take considerable time).
`
`At other times, we may not have enough EMS personnel at the scene of the
`
`overdose to provide mechanical ventilation.
`
`21. For these reasons, I have always administered an initial dose of
`
`naloxone that I expect to restore a patient’s ability to breathe adequately, regardless
`
`of whether or not the patient is also receiving mechanical ventilation. That dose,
`
`when administered via injection, is 0.4 mg. The EMS protocol for the
`
`administration of naloxone in my area does not change depending on whether or
`
`not we are able to provide mechanical ventilation. I do not alter my practice of
`
`administering an initial 0.4 mg injection dose, followed by a second 0.4 mg
`
`injection dose only if needed, depending on whether or not I am able to provide
`
`mechanical ventilation. I am not aware of any medical practitioners who alter the
`
`amount of naloxone they administer depending on whether or not they are able to
`
`provide mechanical ventilation.
`
`
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`11
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`IV. SKEPTICISM OF NARCAN® NASAL SPRAY
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`DECLARATION OF THOMAS J. BEGRES
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`22. Narcan® Nasal Spray contains a 4 mg dose of naloxone. I was
`
`initially very surprised to learn of this dose in mid-2015 and considered it to be
`
`problematic at the time. I was concerned about the risk of side effects, including
`
`pulmonary edema and withdrawal symptoms, which could result from such a large
`
`dose of naloxone.
`
`23.
`
`It is part of my job at Adapt to meet with people around the country to
`
`discuss naloxone and Narcan® Nasal Spray. In the first year after Narcan® Nasal
`
`Spray launched in the United States, healthcare providers and members of the harm
`
`reduction community repeatedly expressed skepticism to me when they first
`
`learned of the 4 mg dosage of Narcan® Nasal Spray. Some of those healthcare
`
`providers included Dr. Mark Eckstein (Medical Director of Los Angeles Fire
`
`Department), Dr. David Slattery (Medical Director of Las Vegas Fire & Rescue),
`
`Dr. Michael Mills (Medical Director of West Virginia State EMS), Dr. Michael
`
`Dailey (Medical Director of New York State EMS), Dr. Ross Megargel (Medical
`
`Director of Delaware State EMS), Dr. Sharon Stancliff (Medical Director of Harm
`
`Reduction Coalition), and Dr. Robert Dunn (Medical Director of Detroit Fire
`
`Department). In particular, they expressed concerns about the risks of withdrawal
`
`and pulmonary edema. They also expressed concerns that a 4 mg dose could cause
`
`
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`12
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`
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`patients to become agitated or violent, which could be unsafe for patients and
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`DECLARATION OF THOMAS J. BEGRES
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`healthcare providers.
`
`24. Although many people, including me, were initially skeptical of
`
`Narcan® Nasal Spray’s 4 mg dose, our views have changed over time. I, for one,
`
`am no longer as concerned about the risk of withdrawal and other side effects from
`
`a 4 mg intranasal dose as I once was. One of the reasons for this is that Narcan®
`
`Nasal Spray has now been on the market for a few years, and I have not received
`
`case reports of the withdrawal and other side effects in the frequency and severity
`
`that I was expecting. Many of the healthcare providers and individuals in the harm
`
`reduction community who initially expressed skepticism to me also appear to have
`
`changed their minds, as they eventually came to support the distribution and use of
`
`Narcan® Nasal Spray by the groups that they oversee and/or the populations that
`
`they serve.
`
`V. OTHER NALOXONE PRODUCTS ON THE MARKET
`
`25. The MAD kit is comprised of a syringe, a pre-filled vial of naloxone
`
`solution, and a separate Mucosal Atomizer Device (“MAD”). The pre-filled vial
`
`contains 2 mg of naloxone in 2 mL of fluid. I am familiar with and have used this
`
`type of system to administer naloxone intranasally to patients experiencing opioid
`
`overdose. I have also used the MAD to administer other medications intranasally.
`
`
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`13
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`
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`26. The MAD kit is not sold as a single, assembled device. Rather, it is
`
`sold in pieces that must be assembled before use. The following instructions
`
`illustrate how to assemble a MAD kit:
`
`
`
`See Ex. 2080 (Harm Reduction Coalition).
`
`27.
`
`I have trained EMS providers and law enforcement on how to
`
`assemble and use the MAD kit. I have also observed medical professionals and
`
`first responders assemble and attempt to administer MAD kits in the field. I
`
`regularly see these individuals have trouble assembling and using MAD kits.
`
`28.
`
`I have seen people make a number of mistakes when assembling the
`
`components of the MAD kit. For example, I have seen people drop and break the
`
`glass vial that contains the naloxone solution. I have seen many people forget to
`
`take all three caps off of the vial and the back of the Luer-lock hub on the syringe
`
`before attempting to combine them. I have also seen people break the MAD when
`
`attempting to screw it onto the syringe by using too much force. These issues are
`
`
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`not limited to trainees—I have seen trained medical professionals make the same
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`DECLARATION OF THOMAS J. BEGRES
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`mistakes during assembly, especially in emergency situations.
`
`29.
`
`I have also seen people have trouble administering naloxone using a
`
`properly assembled MAD kit. Proper administration requires careful technique.
`
`To administer naloxone using the MAD kit, one must apply enough force to create
`
`a mist to coat evenly the nasal mucosa. If not enough force is applied, the fluid
`
`will disperse from the nasal atomizer in a stream (similar to the stream from a
`
`squirt gun), rather than in a mist. Further, because proper use of the MAD kit calls
`
`for administering ½ of the contents of the vial (i.e., 1 mL of the 2 mL solution) into
`
`each nostril, one must quickly stop exerting pressure after spraying half of the
`
`vial’s contents, switch nostrils, and then resume pressure. This can be very tricky
`
`to do in practice, particularly in emergency situations.
`
`30. The difficulty in assembling and using the MAD kit is particularly
`
`problematic for basic life support providers or law enforcement officers who do
`
`not frequently practice these skills, and are therefore not able to remember how to
`
`assemble and administer the MAD kit properly. I have spoken to numerous
`
`individuals who have chosen not to deploy the MAD kit to the groups they oversee
`
`and/or populations they serve, given the complexity of the kit.
`
`31.
`
`I am also familiar with the Evzio® auto-injector. Evzio® is currently
`
`sold in a carton that contains two Evzio® autoinjectors (each containing a 2 mg
`
`
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`15
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`dose of naloxone) and a “trainer” device to allow individuals to practice using it.
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`DECLARATION OF THOMAS J. BEGRES
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`Evzio®’s manufacturer, Kaléo, originally launched Evzio® as a 0.4 mg dose in
`
`February 2014. After Adapt launched Narcan® Nasal Spray, however, Kaléo
`
`quintupled the dose of Evzio® to 2 mg. The Evzio® device “talks to you,” i.e., it
`
`provides audio instructions and a countdown to help people administer it.
`
`32.
`
`In the course of my work, I have heard people express several types of
`
`concerns about the Evzio® autoinjector. I share these concerns.
`
`33. First, people who do not speak English, who are hard of hearing, or
`
`who are using the device in a noisy environment, may not be able to hear or
`
`understand the audio instructions. These people may not be able to follow the
`
`instructions and may not administer Evzio® correctly.
`
`34.
`
`Second, because the Evzio® device contains a needle and a battery, it
`
`cannot be discarded in ordinary trash. Instead, it must be discarded in a special
`
`disposal box for biohazard waste. This makes disposal inconvenient.
`
`35. Third, many people are terrified of needles and are afraid of
`
`administering injections, even with autoinjectors, and may not administer an
`
`injection even to a loved-one in a life-threatening situation. In my experience, it is
`
`common for people to refrain from using auto-injectors in life-threatening
`
`emergencies because of a fear of administering an injection. For example, in my
`
`work as a firefighter-paramedic, I was once called to a school to treat a child who
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`16
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`Opiant Exhibit 2203
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 16
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`was experiencing a severe anaphylactic reaction. When I arrived at the scene, a
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`DECLARATION OF THOMAS J. BEGRES
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`teacher at the school approached me who had an EpiPen® (an auto-injector
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`product used to treat anaphylactic reactions) in hand. Although she could have
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`used the EpiPen® on the child before I arrived, she had not done so because of her
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`fear of administering an injection. To take another example, I was once called to a
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`cider mill where a child was experiencing an allergic reaction to a bee sting, and
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`the child’s mother had been unable to bring herself to administer the child’s
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`EpiPen® for the same reasons.
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`36. Fourth, people sometimes make mistakes when using auto-injectors.
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`For example, one common type of mistake is to invert the auto-injector. Instead of
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`injecting the patient, the needle punctures the hand of the caregiver. Another
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`common type of mistake is to withdraw the auto-injector before the injection is
`
`complete. Many people do not realize that it can take several seconds for an auto-
`
`injector to inject a complete dose. Withdrawing the device early means that part of
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`the dose is wasted and the patient does not receive the full dose.
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`*
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`*
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`*
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`*
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`*
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`In signing this declaration, I recognize that the declaration will be filed as
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`evidence in a contested case before the Patent Trial and Appeal Board of the
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`United States Patent and Trademark Office. I also recognize that I may be subject
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`to cross-examination in the case and that cross-examination will take place within
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`
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`17
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`Opiant Exhibit 2203
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 17
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`
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`Opiant Exhibit 2203
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 18
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`
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