UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner.
`__________________
`
`Case No. IPR2019-00690
`U.S. Patent No. 9,468,747
`__________________
`
`DECLARATION OF KENNETH A. WILLIAMS, M.D
`
`Opiant Exhibit 2001
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 1
`
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner.
`__________________
`
`Case No. IPR2019-00690
`U.S. Patent No. 9,468,747
`__________________
`
`DECLARATION OF KENNETH A. WILLIAMS, M.D
`
`Opiant Exhibit 2001
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 1
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`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
`
`I, Kenneth A. Williams, M.D., do hereby declare as follows:
`
`I.
`
`OVERVIEW
`
`1.
`
`I am over the age of 18 and otherwise competent to make this
`
`Declaration. This Declaration is based on my personal knowledge as an expert in
`
`the fields of emergency and pre-hospital medicine. I understand that this
`
`Declaration is being submitted in support of the Preliminary Response of Patent
`
`Owner Opiant Pharmaceuticals, Inc. to a petition for inter partes review (“IPR”)
`
`filed by Nalox-1 Pharmaceuticals, LLC (“Nalox-1”), challenging certain claims of
`
`U.S. Patent No. 9,468,747 (“the ’747 patent”).
`
`II. BACKGROUND AND QUALIFICATIONS
`I am a practicing physician and am licensed in the State of Rhode
`2.
`
`Island and the Commonwealth of Massachusetts. I am a Professor of Emergency
`
`Medicine at The Warren Alpert Medical School of Brown University. I also serve
`
`as Director of Brown’s Division of Emergency Medical Services (EMS) and
`
`Program Director for Brown’s EMS Fellowships within the Brown Department of
`
`Emergency Medicine. I am also Medical Director for the LifePACT Critical Care
`
`Transport Team at Rhode Island Hospital and for Rhode Island Hospital’s
`
`Ambulance Services, which provide the only comprehensive critical care transport
`
`capability in Rhode Island and the only physician-staffed critical care transport
`
`service in New England. I also serve as the Medical Director for the Rhode Island
`
`
`
`2
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
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`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`Department of Health, Center for Emergency Medical Services, Division of
`
`Preparedness, Response, Infectious Disease & EMS and immediate past Chair of
`
`the Medical Director’s Council for the National Association of State EMS
`
`Officials.
`
`3.
`
`I am board-certified in both emergency medicine and emergency
`
`medical services, and have current certifications as an instructor in advanced
`
`cardiac life support and advanced trauma life support. I have been actively
`
`engaged in the practice of emergency medicine since 1984. Over the course of my
`
`career, I have treated thousands of patients experiencing opioid overdoses, and I
`
`have administered or ordered administration of naloxone to such patients on
`
`hundreds of occasions.
`
`4.
`
`In my role as Medical Director for the Rhode Island Department of
`
`Health Center for EMS, I am responsible for the protocols that govern the scope of
`
`practice for the over 4,000 EMS practitioners working in Rhode Island. Those
`
`protocols specify, among many other things, the standard of care for pre-hospital
`
`treatment of known or suspected opioid overdose, including (when appropriate) the
`
`administration of naloxone. The protocols and standing orders I am responsible for
`
`are the product of evidence-based literature review, incorporation of input from
`
`several committees, and review of other state and national EMS guidelines and
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`protocols.
`
`
`
`3
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`5.
`
`I received my undergraduate degree from Hampshire College in 1977,
`
`continued my education with Postgraduate Science Studies at the University of
`
`Massachusetts, Amherst, and received my medical degree from the University of
`
`Massachusetts Medical School in 1984. I also participated in additional training
`
`from the University of Massachusetts, Amherst in Medical Informatics, Artificial
`
`Intelligence and Knowledge Engineering, during the mid-1990s.
`
`6.
`
`I began my residency in Emergency Medicine at the University of
`
`Pittsburgh in 1984, served as Chief Resident between 1986 and 1987, and
`
`graduated in 1987. I received a resident research award from the Emergency
`
`Medicine Foundation in 1986.
`
`7.
`
`During my 30-plus year career in emergency medicine, I have served
`
`in numerous leadership and committee positions for various national, regional,
`
`state, and local organizations focused on the provision of emergency medicine and
`
`emergency medical services, including the Air Medical Physician Association, the
`
`Association of Air Medical Services, the Alliance for Critical Care Transport, the
`
`National Association of EMS Physicians, the American College of Emergency
`
`Physicians, the National Association of State EMS Officials, the Society for
`
`Academic Emergency Medicine, the National Registry of EMTs, the Prehospital
`
`Guidelines Consortium, and The New England Council for Emergency Medical
`
`Services, to name a few. Among other things, I am a member of the Board of
`
`
`
`4
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`Directors of the Rhode Island Medical Society, and I have served as President of
`
`the Air Medical Physician Association and as President of the Rhode Island
`
`chapter of the American College of Emergency Physicians.
`
`8.
`
`I have received numerous honors and awards for my work in
`
`emergency medicine, including an Exemplary Service Award from the University
`
`Emergency Medicine Foundation, a President’s Award and a Distinguished
`
`Physician Award from the Air Medical Physician Association, and the Rhode
`
`Island ACEP1 Exceptional Service Award. I am also a fellow of the Academy of
`
`Emergency Medical Services. I have received multiple awards for my teaching of
`
`emergency medicine at Brown’s Alpert Medical School.
`
`9.
`
`I have published dozens of articles, books, and book chapters on the
`
`practice of emergency medicine. My articles have appeared in peer-reviewed
`
`journals such as the Annals of Emergency Medicine, the Air Medical Journal,
`
`Resuscitation, The American Journal of Emergency Medicine, the Rhode Island
`
`Medical Journal, and Prehospital Emergency Care. In addition, I have given
`
`hundreds of presentations on emergency medicine to local, national, and
`
`international audiences. A complete list of my publications and presentations is
`
`contained in my CV, attached as Exhibit A.
`
`
`1 ACEP stands for the American College of Emergency Physicians.
`
`
`
`5
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`10. Between 2017 and 2019, I led a technical expert panel of experienced
`
`EMS field practitioners, EMS physician medical directors, experts in addiction
`
`medicine, pain medicine, toxicology/pharmacology, experts in GRADE2
`
`methodologies, and a patient advocate. The panel’s task was to develop and
`
`disseminate evidence-based guidelines and a model protocol for administration of
`
`naloxone by EMS practitioners to persons experiencing suspected opioid overdose,
`
`as well as training materials for EMS practitioners in implementing the guideline,
`
`creation of performance measures by which adherence to the clinical practice
`
`guideline and its impact could be assessed, and the development of a manuscript
`
`for publication. The project was developed in the fall of 2017 by the Medical
`
`Director’s Council of the National Association of State EMS Officials in
`
`collaboration with the National Association of EMS Physicians and the EMS
`
`Committee of the American College of Emergency Physicians, and was funded by
`
`
`2 GRADE refers to the Grading of Recommendations Assessment, Development
`
`and Evaluation methodology, which is used to summarize the evidence and assess
`
`the strength of the literature in order to develop treatment recommendations. It is
`
`emerging as the most widely used system for clinical practice guideline
`
`development, and has been endorsed as an optimal method for guideline
`
`development.
`
`
`
`6
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`the National Highway Traffic Safety Administration, Office of EMS, NHTSA
`
`OEMS, and the Health Resources and Services Administration, Maternal and Child
`
`Health Bureau’s EMS for Children Program. Our panel’s work included a
`
`systematic review and synthesis of the scientific literature relating to naloxone
`
`administration, including a number of the references I discuss below. See infra
`
`Part V. Our group published its conclusions in March 2019. See Williams, Ex.
`
`2031.
`
`11. During my typical work-week, I care for emergency department
`
`patients for 16 hours, transport critically ill or injured patients on our physician-
`
`staffed ambulances for 24 hours, and spend the balance of the week teaching,
`
`doing research, and completing administrative responsibilities.
`
`12.
`
`In addition to my work in emergency medicine, I am also a member of
`
`the United States Coast Guard Auxiliary and actively provide service alongside
`
`Coast Guard members based at Station Castle Hill, including search and rescue,
`
`medical, training, and other missions. I frequently teach first aid, including
`
`measures to treat opioid overdose, to Coast Guard members, high school and
`
`college students, medical students, physician assistant students, and others. One of
`
`my responsibilities as Medical Director for the Rhode Island Department of Health
`
`Center for EMS is advising the Department on treatment of opioid overdose
`
`
`
`7
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`patients (including training curricula and the use of naloxone) by the lay public,
`
`first responders (police, fire, and others), school nurses, security staff, and others.
`
`III. THE PERSON OF ORDINARY SKILL IN THE ART
`I have been informed that many issues in this proceeding, including
`13.
`
`the ultimate question of obviousness or non-obviousness of the patent claims at
`
`issue, are evaluated from the perspective of a hypothetical person of ordinary skill
`
`in the art (“POSA”). I also have been informed that this hypothetical POSA is
`
`presumed to be of ordinary creativity, but is at the same time presumed to be aware
`
`of all pertinent prior art. I also have been informed that the hypothetical POSA
`
`may reflect the skills, and have the motivations, of a multi-disciplinary team.
`
`14. For purposes of this Declaration, which I understand is being
`
`submitted at a preliminary stage of these proceedings, I have not been asked to
`
`provide an opinion about the appropriate definition of the POSA here, except in the
`
`following respects. If these proceedings continue and I am asked to provide
`
`further opinions, I may provide further opinions about the POSA at that later time.
`
`15.
`
`I have been informed that Nalox-1 contends that the POSA in this
`
`case would be a team of individuals having a variety of qualifications relating to
`
`drug development of intranasal formulations, and further contends that the POSA
`
`would have relevant clinical expertise, and would also have experience evaluating
`
`issues of safety and efficacy. For purposes of this Declaration, I have been asked
`
`
`
`8
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`to apply this understanding of the POSA and to comment on what clinical expertise
`
`would be relevant to developing, and evaluating the safety and efficacy, of an
`
`intranasal naloxone formulation intended to treat opioid overdoses, which is the
`
`subject of the ’747 patent at issue.
`
`16.
`
`In my opinion, relevant clinical expertise for the POSA would include
`
`knowledge of the administration of opioid antagonists to treat opioid overdoses by
`
`medically trained personnel, first responders, and in the community. Among other
`
`things, the POSA would have had clinical experience with administering opioid
`
`antagonists to overdose patients. The POSA also would have been familiar with
`
`clinical and epidemiological literature on opioid overdoses; 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. In
`
`my opinion, the “team” that is included in the hypothetical POSA would thus
`
`include a medical practitioner with knowledge and experience relating to the
`
`treatment of opioid overdoses.
`
`17.
`
`I have the expertise I have just described. Accordingly, in the
`
`Declaration that follows, I provide opinions regarding the knowledge and
`
`motivations of the POSA from this perspective.
`
`
`
`9
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`18.
`
` In my opinion, when it comes to the questions I address herein
`
`regarding intranasal naloxone dosing, the motivations of a hypothetical drug
`
`development team would be particularly influenced by this clinical perspective.
`
`19. For the purpose of this declaration, I have been asked to consider the
`
`state of the art as of March 16, 2015.
`
`IV. PRACTICE OF ADMINISTERING NALOXONE TO TREAT OPIOID
`OVERDOSE AS OF MARCH 16, 2015
`
`20. Opioid overdose is treatable with naloxone, an opioid antagonist
`
`which rapidly reverses the effects of opioids. Naloxone blocks or reverses the
`
`effects of opioids, which can include extreme drowsiness, slowed breathing, and/or
`
`loss of consciousness. Naloxone can be administered in a number of ways, the
`
`most common being intravenously, intramuscularly, and intranasally.
`
`21. When a patient is experiencing an opioid overdose, administration of
`
`naloxone counteracts potentially fatal depression of the central nervous system and
`
`respiratory depression. When administered to individuals with a tolerance to
`
`opioids, however, naloxone can induce withdrawal symptoms, particularly when
`
`administered in high doses. Goldfrank’s, Ex. 2011 at 580. The severity of the
`
`withdrawal symptoms will depend on the route of administration, the dose of the
`
`administered naloxone, and the degree and type of opioid dependence.
`
`22. The primary objective of administering naloxone is to restore
`
`adequate respiratory function and airway protection while minimizing the risk of
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`adverse secondary effects, including opioid withdrawal symptoms and patient
`
`agitation. Naloxone administration should be accompanied by indicated first aid
`
`measures. This combined treatment, first aid and properly dosed and administered
`
`naloxone, is because the optimal outcome when administering naloxone is not
`
`simply reversal of opioid-induced respiratory depression; it is the long-term safety,
`
`survival, and well-being of the patient and those around him or her.
`
`23. The standard clinical practice among physicians and pre-hospital
`
`medicine providers as of March 16, 2015, was to administer the lowest amount of
`
`naloxone necessary to restore adequate respiration without causing unnecessary
`
`harm. The preference among medical practitioners was therefore to “titrate” the
`
`dose, starting with an initial dose of 0.2 or 0.4 mg and, only if necessary,
`
`administer additional doses in small increments every few minutes until the
`
`patient’s symptoms abated sufficiently to assure adequate unsupported airway
`
`protection and respiratory function. This ensured that the patient received an
`
`adequate amount of naloxone, but reduced the risk that the patient would receive
`
`too much naloxone, which can lead to withdrawal symptoms, patient agitation,
`
`complications of reversal such as pulmonary edema or adult respiratory distress
`
`syndrome, refusal of further treatment, and other undesirable secondary effects,
`
`such as the resumption of sudden, extreme pain due to the loss of the opioid’s
`
`analgesic effect.
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`24.
`
`In the context of intranasal administration of naloxone, the standard
`
`practice as of March 16, 2015, was to administer 0.4–2 mg of naloxone using a
`
`syringe filled with a naloxone composition intended for parenteral administration,
`
`in combination with a device known as the “MAD”: the Mucosal Atomization
`
`Device. This combination system required assembly before use and was not FDA-
`
`approved. The figure below shows the unassembled components of the system in
`
`panel A and the assembled system in panel B:
`
`
`
`25. After administering the 0.4–2 mg intranasal dose of naloxone via the
`
`MAD, the practice as of March 15, 2016 (and also today) was to wait several
`
`minutes (while continuing indicated first aid) for the naloxone to take effect before
`
`administering an additional dose. Most patients will respond, and their symptoms
`
`will improve, after the first 0.4–2mg intranasal dose of naloxone, in which case no
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`further naloxone need be administered. Only if the patient does not respond and
`
`their condition does not improve after several minutes should a medical
`
`practitioner consider administering an additional dose of naloxone. This helps to
`
`ensure that the patient receives sufficient, but not too much, naloxone.
`
`V. HARMFUL CONSEQUENCES OF ADMINISTERING TOO MUCH
`NALOXONE
`
`26. As of March 16, 2015, it was well known that administering too much
`
`naloxone to a patient experiencing an opioid overdose could result in harmful
`
`consequences for the patient and bystanders, including serious withdrawal
`
`symptoms, agitation or violence, and unnecessary suffering. The POSA would
`
`have been aware of, and concerned about, these risks. The POSA, seeking to
`
`develop a naloxone product for use by persons without medical training, would
`
`have been motivated to select a naloxone dose that minimized these risks.
`
`27. First, the POSA would have known that naloxone administration can
`
`precipitate withdrawal symptoms such as agitation or irritability, anxiety, body
`
`aches, nausea or vomiting, diarrhea, piloerection, rhinorrhea, and sweating.
`
`Vomiting or aspiration in an opioid overdose situation can be life-threatening.
`
`Individuals in the midst of an overdose characterized by respiratory distress are
`
`typically lying down when naloxone is administered. Vomiting in such a situation
`
`can present serious risks, including choking. For example, one author warned that
`
`“[i]t is important to note that the patient may enter an acute withdrawal syndrome
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`after administration of naloxone, with consequent nausea and vomiting. The
`
`airway must, therefore, be guarded at all times.” van Dorp, Ex. 2027 at 128. The
`
`airway must be “guarded at all times” because vomitus in the mouth of a patient
`
`with depressed mental status can lead to choking. The risk of vomiting and
`
`choking is so significant that the protocol for administering NARCAN® Nasal
`
`Spray advises putting the patient in “recovery” position (on their side) after
`
`administering the naloxone so that if they throw up they are less likely to choke.
`
`NARCAN® Nasal Spray Prescribing Information, Ex. 2016 at 18. The POSA
`
`would have been particularly concerned about vomiting in the case of a product
`
`intended for use by lay persons because of the possibility that lay persons may not
`
`be trained on first aid measures such as how to prevent choking or to rescue a
`
`person who is choking. See, e.g., van Dorp, Ex. 2027 at 130 (“Acute withdrawal
`
`may occur with vomiting, hypertension, tachycardia and delirium. These require
`
`acute treatment to prevent further damage (such as aspiration). Training of family
`
`and friends of opioid addicts who receive take-home naloxone should, therefore,
`
`not be restricted to instructions how to administer naloxone in case of heroin
`
`overdose, but also be aimed at the acute treatment of the patient.”).
`
`28. Second, the POSA would have known that severe reactions to
`
`naloxone administration can occur, including acute respiratory distress syndrome
`
`(ARDS), hypertensive emergency, ventricular tachycardia and fibrillation, and
`
`
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`14
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`sudden death. See, e.g., Pallasch, Ex. 2018 at 603; Buajordet, Ex. 2006 at 21, 23;
`
`van Dorp, Ex. 2027 at 130; Sporer 2007, Ex. 2022 at 10. For example, in 1987,
`
`two physicians at the University of Illinois reported that a patient experienced
`
`sudden and severe pulmonary edema after receiving 1.6 mg naloxone
`
`intravenously over the course of three minutes. Schwartz, Ex. 2020 at 1295. The
`
`authors hypothesized that had they administered a lesser amount of naloxone over
`
`a longer period of time, they might have successfully treated the overdose without
`
`inducing pulmonary edema:
`
`It is plausible that had we begun with 0.4 to 0.8 mg
`naloxone over five minutes rather than 1.6 mg over three
`minutes, our patient might have experienced a controlled,
`partial reversal of the mental obtundation associated with
`codeine intoxication without experiencing the observed
`morbidity and possible mortality of pulmonary edema.
`
`Id. at 1296. The authors further noted that “[i]n recent years reports have appeared
`
`linking naloxone administration to adverse cardiovascular effects in patients,” id.
`
`at 1295, even at doses of 0.04 mg to 0.4 mg IV, see id. Thus, they warned that
`
`“[a]lthough naloxone is thought to be a safe drug with few complications, it should
`
`not be used indiscriminately, and the smallest doses necessary to elicit the desired
`
`response should be used.” Id. at 1294. See also, e.g., Pallasch, Ex. 2018 at 603
`
`(“Severe hypertension, cardiac arrhythmias, pulmonary edema, and fatal cardiac
`
`arrest have occurred in both healthy and medically compromised patients. . . .
`
`When naloxone is used to treat narcotic overdosage, it would appear prudent to
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`employ as low a dose as possible, monitor the blood pressure for at least 10
`
`minutes after naloxone administration, and have ready access to antihypertensive
`
`medication.”).
`
`29. Third, the POSA would have known that even people who are not at
`
`significant risk of opioid withdrawal, such as previously opioid-naïve persons who
`
`have been prescribed a few days’ or weeks’ worth of opioids to treat acute pain,
`
`can still experience harmful consequences if too much naloxone is administered.
`
`One would not, for example, want to completely reverse the effects of an opioid on
`
`a patient with bone pain from metastatic cancer, one who has just undergone major
`
`surgery or one who has recently suffered a fracture or other painful injury.
`
`30. Fourth, the POSA would have known that administration of too much
`
`naloxone can precipitate agitation and violent behavior, which “can place both the
`
`patient and medical personnel at risk for avoidable injury.” See Gaddis, Ex. 2010 at
`
`197; see also Baca, Ex. 2004 at 1827 (“Abrupt opioid withdrawal precipitated by
`
`naloxone can result in an angry or agitated patient. Sporer et al. (1996) [Ex. 2021]
`
`found that 7% required restraints.”); van Dorp, Ex. 2027 at 128 (“Another
`
`symptom of acute withdrawal may be patient violence,” so much so that in the
`
`hospital setting “adequate preparation for this situation in the form of restraints is
`
`needed.”); Kerr 2008, Ex. 1035 at 381 (“[A]fter heroin reversal patients are often
`
`restless and aggressive upon awakening . . . .”); Wermeling 2013, Ex. 1016 at 9
`
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`(“Rapid intravenous administration [of naloxone], while effective in reversal of
`
`narcosis, can result in a rapid emergence with possible agitation and violence.”).
`
`The POSA would have known that an agitated or violent withdrawing overdose
`
`victim can injure himself or herself, as well as bystanders and medical providers,
`
`and sedation or restraint may be warranted, both prolonging and complicating
`
`patient care. In addition, patients experiencing withdrawal are obviously less
`
`likely to attend to offers of opioid addiction treatment, detoxification, or other
`
`beneficial long-term care.
`
`31. The prior art is replete with examples of patient agitation and
`
`combativeness connected to the administration of naloxone to treat opioid
`
`overdose. For example, in a study of EMS-treated opioid overdose cases in King
`
`County, Washington, during 2004, patients received initial doses of naloxone
`
`ranging from 0.2 mg to 2 mg, a total amount of naloxone ranging from 0.2 to 4 mg
`
`(administered in multiple doses over time), and agitation or combativeness were
`
`observed in 15% of those patients. See Belz, Ex. 2005 at 468–69. The author
`
`advised that “[t]raining to manage the agitation and combativeness seen in 15% of
`
`our cases would need to be part of any program training EMTs to administer
`
`naloxone.” Id. at 471. As another example, in one case, a paramedic administered
`
`2.0 mg intravenous naloxone to a 35-year-old man, who
`
`abruptly became extremely violent and disconnected his
`intravenous line. Paramedics, fearing for their safety,
`17
`
`
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`Opiant Exhibit 2001
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 17
`
`
`
`DECLARATION OF KENNETH A. WILLIAMS, M.D.
`
`called their dispatcher for assistance. Because of his
`continued and escalating violent behavior, more than ten
`police and fire personnel were called to the scene to
`physically subdue the patient with limited success. A base
`station order by a resident physician for diazepam 5 mg
`IM had little effect.
`
`Gaddis, Ex. 2010 at 196. In a second case, a 31-year-old woman became “fully
`
`awake and combative” within 60 seconds of receiving 2 mg intravenous naloxone,
`
`but “[b]ecause she had been restrained before naloxone was administered, the
`
`patient posed no safety threat to herself, other patients, or personnel in the ED.”
`
`Id. at 197. Johns Hopkins doctors described another case of withdrawal-related
`
`agitation triggered by intravenous administration of 2 mg naloxone:
`
`[w]ithin 3 min the patient became very agitated and
`combative, requiring physical restraint. It was difficult to
`maintain venous access and radiography was impossible.
`A total of 4 mg morphine sulphate and 25 mg droperidol
`was given intravenously without subsequent change in her
`agitation. A further 5 mg of droperidol also failed to have
`an effect. After 47 min the patient’s state continued to
`hinder diagnostic evaluation and it was felt that her
`agitation could aggravate injuries she may have sustained.
`She was therefore intubated and ventilated following the
`administration of pancuronium (20 mg) . . . . Her family
`later confirmed that she had used large amounts of heroin
`shortly before the accident. It is likely that the
`administration of naloxone either precipitated acute opiate
`withdrawal or allowed the effects of another drug to
`predominate.
`
`Popper, Ex. 2019 at 446.
`
`
`
`18
`
`Opiant Exhibit 2001
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 18
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`32. The POSA, seeking to develop a naloxone product for use by
`
`laypersons, would have been very concerned about the risk of patient agitation
`
`resulting from the administration of too much naloxone. Unlike medical
`
`professionals and first responders such as police officers, lay persons are not
`
`trained to deal with aggressive behavior and may not even be aware of the risk that
`
`it might occur in the aftermath of an opioid overdose reversal. The POSA would
`
`have been motivated to select an initial naloxone dose that, while saving the
`
`patient’s life, would not unnecessarily put an unprepared and otherwise untrained
`
`friend, family member, or “good samaritan” at risk of harm.
`
`33. Fifth, the POSA would have known that administration of too much
`
`naloxone can lead to patients refusing medical care, and possibly even engaging in
`
`dangerous drug-seeking behavior in order to restore their “high” and mitigate their
`
`withdrawal symptoms. For example, Zuckerman 2014 reported that IV drug users
`
`“report that they would likely redose themselves with opioid medications to treat . .
`
`. withdrawal symptoms. Such behavior can be lethal. Death from overdose
`
`increases dramatically following recovery from nonfatal overdose; opioid
`
`withdrawal triggered by intranasal naloxone may be a powerful motivator to reuse
`
`and cause more harm than good.” Zuckerman, Ex. 2033 at 552; see also Stoove,
`
`Ex. 2023 at 351 (study finding “that experiencing a non-fatal overdose
`
`substantially increases the risk of subsequent overdose mortality”). Still another
`
`
`
`19
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`Opiant Exhibit 2001
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 19
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`author observed that “[t]he dosage of take-home naloxone to be administered to a
`
`heroin overdose victim has been a somewhat difficult issue” because “[a] large
`
`dose will resuscitate the victim more reliably, but at the expense of causing more
`
`intensely unpleasant withdrawal symptoms, leading possibly to dangerous
`
`immediate use of more heroin.” Baca, Ex. 2004 at 1826.
`
`34.
`
`I personally have witnessed some of these complications of opioid
`
`overdose reversal in my own work, including agitation, violent behavior, vomiting,
`
`and refusal of further treatment. I also have witnessed several instances in which a
`
`patient who received naloxone developed pulmonary edema and had to be admitted
`
`to the intensive care unit. It is also fairly common that patients who have received
`
`naloxone are unwilling to stay in our emergency room for a period of further
`
`observation or treatment.
`
`35. The POSA would have known that the higher the initial dose of
`
`naloxone, the greater the likelihood of the adverse consequences I have described
`
`above. In some cases, even a starting dose of 0.4 mg can precipitate these adverse
`
`consequences. See Sabzghabaee, Ex. 1051 at 312 (12 of 50 patients who received
`
`0.4 mg IV naloxone exhibited agitation); Goldfrank’s, Ex. 2011 at 581–82 (“A
`
`dose of naloxone 0.4 mg IV will reverse the respiratory depressant effects of most
`
`opioids and is an appropriate starting dose in nonopioid-dependent patients.
`
`However, this dose in an opioid-tolerant patient usually produces withdrawal,
`
`
`
`20
`
`Opiant Exhibit 2001
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 20
`
`
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`DECLARATION OF KENNETH A. WILLIAMS, M.D.
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`which should be avoided if possible.”). In my clinical practice, I have seen some
`
`patients experience withdrawal symptoms after receiving a single, 0.4 mg IV dose
`
`of naloxone.
`
`36. Given these risks, the preferred clinical practice as of March 16, 2015,
`
`was (and remains) to start with the lowest initial dose of naloxone that would be
`
`expected to reverse dangerous respiratory depression in order to avoid adverse
`
`complications. See, e.g., Baca, Ex. 2004 at 1827 (2005 review of literature on
`
`distribution of take-home naloxone “recommended that naloxone be given in
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