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 IPR2019-00688
`U.S. Patent No. 9,468,747
`__________________
`
`SECOND DECLARATION OF KENNETH A. WILLIAMS, M.D.
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 1
`
`

`

`I.
`II.
`
`III.
`
`IV.
`
`V.
`
`DECLARATION OF KENNETH A. WILLIAMS
`
`TABLE OF CONTENTS
`
`B.
`
`C.
`
`OVERVIEW .................................................................................................... 4
`LEGAL STANDARDS ................................................................................... 5
`A.
`Obviousness ........................................................................................... 5
`B.
`Objective Indicia of Nonobviousness ................................................... 8
`SUMMARY OF MY FIRST DECLARATION AND SCOPE OF MY
`SECOND DECLARATION ............................................................................ 9
`THE POSA WOULD HAVE CHOSEN AN INTRANASAL
`NALOXONE DOSE OF 2 MG OR LESS .................................................... 12
`A.
`The POSA’s Goal Would Have Been To Mimic the Established
`Clinical Practice of Administering a Low Initial Dose of
`Naloxone ............................................................................................. 14
`The POSA Would Have Accounted for the Serious Withdrawal
`and Adverse Effects of Naloxone Administration in Opioid-
`Dependent Individuals ......................................................................... 17
`Dr. Donovan and Dr. Hochhaus, Who Have No Clinical
`Experience, Misconstrued the POSA’s Clinical Goal ........................ 22
`1.
`The Problem Dr. Donovan and Dr. Hochhaus Opine the
`POSA Would Have Sought To Solve Did Not Exist ................ 22
`Dr. Donovan and Dr. Hochhaus Conflate the Prior Art’s
`Discussion of a Total Dose of Naloxone with an Initial
`Dose of Naloxone...................................................................... 29
`The Prior Art Did Not Recognize Re-dosing as a Problem To
`Be Solved ............................................................................................ 32
`1.
`Lay Persons Can Readily Re-dose When Necessary ................ 32
`2.
`The Clinical Prior Art Did Not Identify Re-dosing as a
`Problem To Be Solved .............................................................. 35
`NARCAN® NASAL SPRAY SATISFIED A LONG-FELT BUT
`UNMET NEED ............................................................................................. 42
`A.
`There Was a Long-Felt but Unmet Need for a Needle-Free
`Community-Use Naloxone Product .................................................... 42
`
`2.
`
`D.
`
`2
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 2
`
`

`

`DECLARATION OF KENNETH A. WILLIAMS
`
`
`B.
`
`Naloxone Products Available as of March 16, 2015, Did Not
`Meet the Long-Felt Need .................................................................... 52
`1.
`Evzio® Did Not Satisfy the Long-Felt But Unmet Need ......... 52
`2.
`Unapproved MAD Kits Did Not Satisfy the Long-Felt
`but Unmet Need ........................................................................ 54
`Intranasal Products that Did Not Receive FDA Approval
`Did Not Satisfy the Long-Felt but Unmet Need ....................... 58
`Narcan® Nasal Spray Satisfied the Long-Felt but Unmet Need ........ 59
`C.
`VI. NARCAN® NASAL SPRAY WAS INITIALLY THE SUBJECT OF
`SIGNIFICANT SKEPTICISM ...................................................................... 61
`VII. NARCAN® NASAL SPRAY HAS RECEIVED SIGNIFICANT
`THIRD-PARTY PRAISE .............................................................................. 62
`
`3.
`
`
`
`3
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 3
`
`

`

`
`
`I, Kenneth A. Williams, M.D., declare as follows:
`
`I.
`
`OVERVIEW
`
`1.
`
`I am over the age of 18 and 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 Response of Patent Owners Opiant Pharmaceuticals,
`
`Inc. (“Opiant”) and Adapt Pharma Operations Limited (“Adapt”) to petitions for
`
`inter partes review (“IPR”) filed by Nalox-1 Pharmaceuticals, LLC (“Nalox-1”),
`
`challenging U.S. Patent Nos. 9,211,253 (“the ’253 patent”), 9,468,747 (“the ’747
`
`patent”), and 9,629,965 (“the ’965 patent”).
`
`2.
`
`This is my second declaration in this proceeding. Earlier this year, I
`
`submitted a declaration in support of Opiant’s preliminary responses to Nalox-1’s
`
`petitions challenging the ’253, ’747, and ’965 patents. See IPR2019-00685,
`
`Exhibit 2001; IPR201900688, Exhibit 2001; IPR201900694, Exhibit 2001. I refer
`
`to that declaration hereinafter as “my first declaration.”
`
`3.
`
`In preparing this declaration, I have reviewed the ’253, ’747, and ’965
`
`patents and their file histories; the petitions for inter partes review filed by Nalox-1
`
`challenging those patents; the exhibits submitted in support of Nalox-1’s petitions,
`
`including the declarations and deposition transcripts of Maureen Donovan, Ph.D.
`
`and Günther Hochhaus, Ph.D; Patent Owner Opiant Pharmaceuticals, Inc.’s
`
`
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 4
`
`

`

`DECLARATION OF KENNETH A. WILLIAMS
`
`
`preliminary responses to Nalox-1’s petitions and the exhibits submitted in support
`
`thereof; and the Board’s orders instituting trial on the petitions. I have considered
`
`the materials cited herein, as well as in my first declaration. I have also relied on
`
`my professional judgment and expertise.
`
`4.
`
`I understand that each of the three IPR proceedings at issue has its
`
`own set of exhibit numbers. I will therefore refer to the exhibits by name; a chart
`
`of the relevant exhibit numbers in each proceeding and the short names I use to
`
`refer to different documents is attached to the end of this declaration.
`
`5.
`
`I am being compensated at the rate of $500 per hour for my time spent
`
`working on this matter. My compensation is not contingent on my findings,
`
`testimony rendered, or on the outcome of this proceeding.
`
`II. LEGAL STANDARDS
`
`A. Obviousness
`
`6.
`
`I understand that a patent claim is “obvious,” and thus invalid, if the
`
`differences between the subject matter sought to be patented and the prior art are
`
`such that the subject matter as a whole would have been obvious at the time the
`
`invention was made to a person having ordinary skill (“POSA”) in the art to which
`
`said subject matter pertains. I understand that factual determinations relevant to
`
`the obviousness inquiry include (a) the scope and content of the prior art, (b) the
`
`differences between the claimed invention and the prior art, (c) the level of
`
`5
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 5
`
`

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`DECLARATION OF KENNETH A. WILLIAMS
`
`ordinary skill in the art, and (d) any objective indicia of non-obviousness, such as
`
`unexpected properties, long-felt and unmet need, failure of others, skepticism, and
`
`copying.
`
`7.
`
`I understand that there is no basis for concluding that an invention
`
`would have been obvious to the POSA solely because it is a combination of
`
`elements that were known in the art at the time of the invention. Rather, the
`
`challenger must show that there is a reason, suggestion, or motivation in the prior
`
`art that would lead the POSA to combine the references, with a reasonable
`
`expectation of success. I understand that for an invention to be obvious, the POSA
`
`who is following the reference or references that purportedly make it obvious must
`
`have had a reasonable expectation of success in applying the teachings of the
`
`references to arrive at the claimed invention.
`
`8.
`
`I understand that the determination of obviousness must be done
`
`based on the knowledge possessed by the POSA at the time when the invention
`
`was made. In other words, it is impermissible to use hindsight after viewing the
`
`claimed invention to determine questions of obviousness. Relatedly, I understand
`
`that the inventor’s path itself never leads to a conclusion of nonobviousness; that is
`
`hindsight. What matters is the path that the POSA would have followed, as
`
`evidenced by the pertinent prior art.
`
`6
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 6
`
`

`

`DECLARATION OF KENNETH A. WILLIAMS
`
`9.
`
`I further understand that a showing that a reference teaches away from
`
`elements of the claimed invention may disprove a motivation to combine that
`
`reference with others to render the claimed invention obvious. I have been
`
`informed that a prior art reference teaches away from the claimed invention if the
`
`POSA, upon reading the reference, would be discouraged from following the path
`
`set out in the reference, or would be led in a direction divergent from the path that
`
`was taken by the claimed invention. I understand that in general, a reference will
`
`teach away if it suggests that the line of development flowing from the reference’s
`
`disclosure is unlikely to be productive of the result sought by the claimed
`
`invention.
`
`10.
`
`I have been asked to assume that the relevant date for my analysis is
`
`March 16, 2015, the filing date of the ’253 patent. The opinions set forth herein
`
`are from the perspective of the POSA as of that date.
`
`11.
`
`I understand that for the purpose of assessing the inventions claimed
`
`in this proceeding, “prior art” includes U.S. patents or published patent
`
`applications that name another inventor and that were effectively filed before
`
`March 16, 2015, as well as printed publications available to the public before
`
`March 16, 2015.
`
`7
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 7
`
`

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`DECLARATION OF KENNETH A. WILLIAMS
`
`B.
`
`Objective Indicia of Nonobviousness
`
`12.
`
`I understand that in determining whether a claimed invention is
`
`obvious, the Board will consider a group of factors referred to as “objective indicia
`
`of nonobviousness.” I understand that these factors include (but are not limited to)
`
`commercial success, long-felt but unmet need, skepticism, and third-party praise.
`
`13.
`
`I understand that evidence that there was a long-felt but unmet need
`
`for the solution offered by the invention can also support a finding of
`
`nonobviousness. I understand that recognition of a problem in an existing product
`
`or process may create incentives for researchers to develop a solution to that
`
`problem, but that if the defect nonetheless persists for a long time in the face of
`
`those incentives, this supports an inference that the solution was not obvious. I
`
`understand that a problem and a need for the solution to that problem can be shown
`
`by, among other things, failed efforts by others working in the same field to solve
`
`the problem, and that satisfaction of a long-felt need can be shown by, among other
`
`things, the commercial success of an embodiment of the claimed invention. I
`
`understand that for a competing product to satisfy a long-felt need, the product
`
`must actually have been put on the market as of the relevant date, and that it is not
`
`enough that a patent or publication discloses a product that purports to solve the
`
`long-felt need.
`
`8
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 8
`
`

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`DECLARATION OF KENNETH A. WILLIAMS
`
`
`14.
`
`I understand that skepticism in the relevant field regarding the
`
`invention can also support of a finding of nonobviousness. I understand that
`
`skepticism can include surprise or doubt expressed by competitors or experts in the
`
`field as to the concept of the invention either before or after the invention was
`
`conceived and disclosed.
`
`15.
`
`I understand that third-party praise of the invention can also support a
`
`finding of nonobviousness. I understand that third-party praise includes
`
`expressions of praise for, or approval of, the invention, including an invention’s
`
`commercial embodiment.
`
`III. SUMMARY OF MY FIRST DECLARATION AND SCOPE OF MY
`SECOND DECLARATION
`
`16.
`
`In my first declaration, I set forth my qualifications, as well as certain
`
`opinions that are relevant to this matter. See Williams POPR Decl. ¶¶ 1–47. I
`
`incorporate into this declaration the entirety of my first declaration (including my
`
`statement of qualifications and all of my opinions) as if I had fully stated them
`
`here. Stated in summary form below, the opinions I expressed in my first
`
`declaration are as follows.
`
`17. First, I opined that the person of ordinary skill in the art (“POSA”)
`
`would include a team of people having a variety of qualifications. That team
`
`would have included an individual with clinical expertise in the administration of
`
`opioid antagonists to treat opioid overdoses. Williams POPR Decl. ¶¶ 13–19. As
`
`9
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 9
`
`

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`DECLARATION OF KENNETH A. WILLIAMS
`
`set forth in the qualifications section of my first declaration, I have over three
`
`decades of experience in emergency medicine and I have treated thousands of
`
`patients experiencing opioid overdose, including with naloxone. Id. ¶¶ 2–12. I
`
`readily meet the definition of the POSA team member with clinical expertise.
`
`18.
`
`I now know from their depositions that not only do neither Dr.
`
`Donovan nor Dr. Hochhaus meet the requirements of the POSA clinician, but also
`
`that they did not consult with anyone who had such qualifications before
`
`submitting their declarations. Donovan Tr. 6:8–8:20; Hochhaus Tr. 168:6–18. I
`
`find that surprising, as clinical expertise would have been critical to the POSA
`
`seeking to formulate a community-use product to treat opioid overdose. This is so
`
`because in choosing the dose, the POSA would have needed to undertake a careful
`
`balancing between clinically effective dosing and the known withdrawal and
`
`adverse effects of naloxone administration in relevant clinical settings. A clinician
`
`with relevant experience would have been well aware of, and understood, this
`
`balancing process. Persons with formulation and pharmacology skills alone would
`
`not be sufficient for purposes of completing the POSA team. Indeed, as I set forth
`
`below, in my opinion, Dr. Donovan and Dr. Hochhaus’s lack of clinical expertise,
`
`particularly in the area of opioid overdose treatment, has contributed to some
`
`fundamental misunderstandings about the use of naloxone that undermine their
`
`opinions. See infra, Part IV.C.
`
`10
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 10
`
`

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`DECLARATION OF KENNETH A. WILLIAMS
`
`19.
`
`Second, I opined that the POSA would have known that the active
`
`ingredient naloxone had long been in use to treat individuals suffering an opioid
`
`overdose. The standard clinical practice among physicians and pre-hospital
`
`medicine providers as of March 16, 2015, was to administer the minimum amount
`
`of naloxone necessary to restore adequate respiration and airway protection. This
`
`dose was typically 0.2 mg to 0.4 mg via injection (intravenous, intramuscular, or
`
`subcutaneous) and 0.4 mg to 2 mg intranasal (1 mg per nostril). Williams POPR
`
`Decl. ¶¶ 20–25. I expand on this opinion further below in Part IV.A.
`
`20.
`
`Third, I opined that the POSA would have known to administer the
`
`minimum amount of naloxone necessary to restore adequate respiration and airway
`
`protection because of the well-documented potential harmful consequences of
`
`administering too much naloxone to opioid users in the relevant clinical settings.
`
`Williams POPR Decl. ¶¶ 26–36. I also reviewed the clinical literature relevant to
`
`the administration of naloxone as of the priority date. I address those
`
`consequences and the literature in detail in my first declaration. Id. ¶¶ 37–41. I
`
`expand on these opinions below in Parts IV.B and IV.D.
`
`21.
`
`Finally, I opined that the POSA would not have understood Wyse to
`
`teach a dose of 4 mg naloxone, delivered intranasally. To the contrary, Wyse
`
`teaches away from high doses of naloxone, precisely because of the potential for
`
`adverse consequences. Williams POPR Decl. ¶¶ 42–46.
`
`11
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 11
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`

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`DECLARATION OF KENNETH A. WILLIAMS
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`22.
`
`I have now been asked to supplement the opinions I expressed in my
`
`first declaration regarding the administration of naloxone, and whether the POSA
`
`would have found it obvious to administer an initial 4 mg intranasal dose of
`
`naloxone in view of clinical practices and the available relevant literature. I have
`
`also been asked to respond to certain opinions of Dr. Donovan and Dr. Hochhaus.
`
`In addition, I have been asked to opine on whether Narcan® Nasal Spray satisfied
`
`a long-felt but unmet need; skepticism that has been expressed regarding Narcan®
`
`Nasal Spray and its 4 mg dose; and third-party praise that Narcan® Nasal Spray
`
`has received.1
`
`IV. THE POSA WOULD HAVE CHOSEN AN INTRANASAL
`NALOXONE DOSE OF 2 MG OR LESS
`
`23. Decades of clinical experience have shown that a 0.4 mg dose of
`
`naloxone administered via intravenous, intramuscular, or subcutaneous injection,
`
`or a 2 mg or less intranasal dose administered with a mucosal atomizer device
`
`(“MAD”), is sufficient to restore adequate respiration and airway protection in
`
`most opioid overdose patients who have not progressed to cardiac arrest. Williams
`
`POPR Decl. ¶¶ 20–25, 37–41. This is in part why, as of the priority date, not a
`
`1 I understand that Dr. Stuart Jones will be opining that Narcan® Nasal Spray is an
`
`embodiment of the claims of the ’253, ’747, and ’965 patents.
`
`12
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 12
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`

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`DECLARATION OF KENNETH A. WILLIAMS
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`single clinical prior art reference addressed, much less studied, the use of an initial
`
`dose of naloxone greater than 2 mg, via any route of administration. In my clinical
`
`practice, I have only ever administered initial doses of naloxone under 2 mg, and I
`
`have observed the efficacy and safety of this regimen in my over-thirty-years of
`
`clinical practice.
`
`24. Decades of clinical experience have also shown that the higher the
`
`dose of naloxone, the greater the likelihood and intensity of the withdrawal
`
`symptoms and other adverse effects that I referenced in my first declaration.
`
`Williams POPR Decl. ¶¶ 26–36. I have observed first-hand the withdrawal
`
`symptoms and other adverse effects of naloxone administration experienced by
`
`opioid-dependent individuals, and I use low initial doses of naloxone to avoid
`
`those effects. I train EMS providers and doctors who work with me to do the
`
`same.
`
`25.
`
`Thus, as I explain in more detail below, the POSA’s goal would have
`
`been to choose a naloxone dose that was clinically proven to be safe and effective
`
`and that would minimize the risk of withdrawal and other adverse effects. For the
`
`intranasal route, the POSA would have known that the appropriate dose would be
`
`at or below 2 mg. The POSA’s conclusion would have been supported both by
`
`clinical experience and by numerous clinical prior art studies.
`
`13
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 13
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`

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`DECLARATION OF KENNETH A. WILLIAMS
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`A.
`
`The POSA’s Goal Would Have Been To Mimic the Established
`Clinical Practice of Administering a Low Initial Dose of Naloxone
`
`26. Nalox-1 contends that the POSA would have selected an intranasal
`
`naloxone dose greater than 2 mg. I disagree. The POSA would have actively
`
`avoided using an intranasal dose higher than 2 mg.
`
`27. Nalox-1’s contention rests on a fundamental misunderstanding of how
`
`opioid overdose manifests physiologically. In practice, opioid overdose does not
`
`usually manifest as sudden and total cessation of breathing. Rather, the typical
`
`patient’s breathing gradually slows down to a suboptimal rate—what clinicians
`
`refer to as “respiratory depression.” Although respiratory depression can lead
`
`eventually to cessation of breathing, hypoxia, brain injury, and cardiac arrest if it
`
`progresses and is left untreated for a prolonged period-of-time, the layperson
`
`caregiver usually has a reasonable amount of time to treat the overdose victim
`
`before injury occurs. Typically, at the time of treatment by a layperson caregiver,
`
`an overdose patient has not fully stopped breathing; rather, he or she still has some,
`
`albeit suboptimal, respiratory function and airway protection (i.e., a gag reflex to
`
`prevent aspiration from vomiting).
`
`28.
`
`That is precisely why the well-accepted practice as of the priority date
`
`in the United States was not to start by administering a large initial dose of
`
`naloxone to treat opioid overdose. Initial doses above the routinely used
`
`amounts—i.e., a 0.4 mg injection or 2 mg intranasally—would have been far more
`
`14
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 14
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`

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`DECLARATION OF KENNETH A. WILLIAMS
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`naloxone than is required to treat almost all opioid overdose patients. Thus, the
`
`well-settled clinical practice for medical providers was to start with a low dose,
`
`such as a 0.4 mg or less intravenous or other route injection dose, and then titrate
`
`(by giving a continuous infusion or dose, or additional small doses at brief regular
`
`intervals) if the patient’s symptoms did not abate sufficiently to provide adequate
`
`respiration. For layperson caregivers, who typically would not be able to inject
`
`naloxone intravenously and therefore could not titrate, the practice was to
`
`administer 0.4–2 mg intranasally (or in some systems, 0.4 mg intramuscularly,2
`
`see, e.g., Enteen at 3; Seal at 3) and then to provide a repeat dose in 3–5 minutes if
`
`there was not an adequate response to the initial dose.
`
`29. Nor, as of the priority date, did the practice of administering a low
`
`initial dose of naloxone change if the naloxone was being administered by a lay
`
`2 Multiple studies had shown that lay persons trained to give a 0.4 mg
`
`intramuscular injection dose of naloxone were able to use it successfully to treat
`
`opioid overdose in the vast majority of cases. See Enteen at 3, 6–7, 9 (“Among
`
`trained participants who report using [0.4 mg intramuscular injection] naloxone,
`
`nine in 10 report positive outcomes”); Seal at 3, 6 (study participants using 0.4 mg
`
`intramuscular injection naloxone reported successful reversals of all overdose
`
`events).
`
`15
`
`Opiant Exhibit 2202
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 15
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`

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`DECLARATION OF KENNETH A. WILLIAMS
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`person in a community setting. I address at length in my first declaration the use of
`
`the system combining a syringe filled with a naloxone composition intended for
`
`parenteral administration and the MAD. Williams POPR Decl. ¶ 24. I will refer to
`
`that system hereinafter as the “MAD kit.” I further explain in my first declaration
`
`that the practice, as of the priority date, was to administer a 0.4–2 mg dose of
`
`naloxone intranasally using that kit. Id. Most typically, the formulation
`
`administered contained 2 mg of naloxone in 2 mL of liquid, half of which was
`
`administered into each nostril of the patient (i.e., 1 mL of liquid containing 1 mg of
`
`naloxone into each nostril). The nose is only capable of retaining about 0.2 mL of
`
`fluid in each nostril, meaning that most of that liquid could not be retained by the
`
`nasal cavity and would either drain down the patient’s throat or out of their nose,
`
`leading to reduced naloxone absorption. Thus, in practice, the MAD kit delivered
`
`an unpredictable dose of naloxone that was substantially lower than the 2 mg
`
`contained in the most typical MAD kit. As I note below and in my first
`
`declaration, substantial clinical evidence demonstrated that this was nonetheless a
`
`safe and effective dose when used in the community setting. See infra Part IV.C;
`
`Williams POPR Decl. ¶¶ 37–41.
`
`30. My opinion that the well-accepted practice as of March 2015 was to
`
`start with a low dose of naloxone is also corroborated by the fact that in 2014,
`
`Evzio®, a naloxone auto-injector, received FDA approval for use by lay people
`
`16
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 16
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`

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`DECLARATION OF KENNETH A. WILLIAMS
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`
`administering naloxone. When it came on the market in 2014, Evzio® had a 0.4
`
`mg dose, consistent with the prevailing view that 0.4 mg was the appropriate initial
`
`injection dose. The FDA considered that dose to be safe and effective, including
`
`for use by lay people, and I agree fully with that assessment. A 0.4 mg dose of
`
`naloxone, given by any of the accepted routes, is sufficient to treat the vast
`
`majority of opioid overdoses.
`
`31. The practice of starting with a naloxone injection dose of 0.4 mg or
`
`less, or an intranasal dose of 2 mg or less, also did not change depending on the
`
`route, type, potency, or amount (dose) of opioid used, if known. The POSA would
`
`have thus known that the well-established practices regarding the administration of
`
`naloxone do not change depending on what type of opioid(s) the patient has
`
`overdosed on.
`
`B.
`
`The POSA Would Have Accounted for the Serious Withdrawal
`and Adverse Effects of Naloxone Administration in Opioid-
`Dependent Individuals
`
`32.
`
`In my first declaration, I explained that the POSA would have
`
`recognized that increasing an initial dose of naloxone given to opioid overdose
`
`patients would increase the risk and severity of withdrawal and other adverse
`
`effects. Williams POPR Decl. ¶ 35. The POSA would also have recognized that
`
`these harms—which include vomiting (that can lead to choking and aspiration if
`
`there is insufficient airway protection), acute respiratory distress syndrome,
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`17
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`IPR2019-00688
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`DECLARATION OF KENNETH A. WILLIAMS
`
`
`pulmonary edema, agitation and violence, drug-seeking behavior, refusal of
`
`medical care, and others—are more likely to occur when a large amount of
`
`naloxone is delivered rapidly into an opioid overdose patient’s bloodstream. These
`
`harms are particularly problematic in a community use setting because most lay
`
`persons are not trained or equipped to handle them when they occur.
`
`33. The POSA, seeking to develop a community-use naloxone product,
`
`would therefore have sought to balance prompt treatment of respiratory depression
`
`against the risks of administering too much naloxone too quickly. See, e.g., Clarke
`
`at 4 (“Opioid overdose is a challenging condition that requires a difficult balancing
`
`act between over and under treatment with naloxone.”). This balancing would
`
`have led the POSA to prefer a slower, more gradual increase in naloxone blood
`
`concentration over time, one that mimics well-settled clinical practice. Wyse
`
`expressly teaches this goal:
`
`The serum levels in the 2 mg Naloxone Nasal Spray group
`
`demonstrated a later peak with a slower increase over the
`
`initial 15 minutes as compared to high levels seen after IV
`
`administration. The slower increase in blood serum levels
`
`is likely to be effective at reversing the hypoventilation
`
`while potentially decreasing the common side effects of
`
`severe agitation, nausea, vomiting, and the occasional
`
`seizure after IV administration.
`
`Wyse at 16:33–40.
`
`18
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 18
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`DECLARATION OF KENNETH A. WILLIAMS
`
`
`34.
`
`In order to achieve this objective, the POSA would have selected a
`
`dose of naloxone that had been shown to be clinically sufficient to restore adequate
`
`breathing in most patients who are exhibiting respiratory depression while
`
`minimizing the risk of withdrawal and other harms. In selecting that dose, the
`
`POSA would have recognized and accepted that a small subset of patients might
`
`require a repeat dose of naloxone, but that even in that small subset of patients, the
`
`initial dose of naloxone would have positive effects and advance the ultimate
`
`objective of restoring adequate respiration and airway protection.
`
`35. Dr. Hochhaus and Dr. Donovan discount the dangers of withdrawal
`
`and other adverse effects of naloxone by citing a single article, Kerr 2008.3
`
`
`3 In support of their opinions, Dr. Donovan and Dr. Hochhaus also selectively
`
`quote statements from Dr. Gregory W. Terman and an FDA official at the FDA’s
`
`2012 meeting on naloxone. 685 Hochhaus Decl. ¶ 62; 688 Hochhaus Decl. ¶ 64;
`
`694 Hochhaus Decl. ¶ 64; 685 Donovan Decl. ¶ 55; 688 Donovan Decl. ¶ 56; 694
`
`Donovan Decl. ¶ 55. As I explain below, Dr. Donovan and Dr. Hochhaus have
`
`taken those statements out of context and excerpted them in a way that distorts
`
`their meaning. Those statements do not support the conclusion that the
`
`administration of too much naloxone to a person experiencing an opioid overdose
`
`does not have serious adverse consequences. See infra Part IV.C.2.
`
`19
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`IPR2019-00688
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`Hochhaus ’685 Decl. ¶ 62; Hochhaus ’688 Decl. ¶ 64; Hochhaus ’694 Decl. ¶ 64;
`
`DECLARATION OF KENNETH A. WILLIAMS
`
`
`Donovan ’685 Decl. ¶ 55; Donovan ’688 Decl. ¶ 56; Donovan ’694 Decl. ¶ 55.
`
`But Kerr 2008 was referring to adverse event reporting following the standard
`
`clinical practice of administering naloxone in incremental doses—not to the safety
`
`of administering large initial doses. See generally Kerr 2008. Dr. Donovan and
`
`Dr. Hochhaus are correct that Kerr 2008 notes that “seizure, pulmonary edema,
`
`asystole, cardiac arrest” are “reportedly rare,” id. at 381, but this does not mean
`
`those side effects do not occur, or that they are not dangerous when they do occur.
`
`Indeed, I have personally treated individuals who have experienced seizures,
`
`pulmonary edema, and violent agitation as a result of naloxone administration.
`
`The POSA would not have risked these life-threatening effects for no reason by
`
`administering a dose of naloxone that was higher than necessary. Moreover, Kerr
`
`2008 highlights that, “[s]igns of opioid withdrawal (confusion, headache, nausea or
`
`vomiting, aggressiveness, tachycardia, sweating and tremor) are more likely to
`
`occur” with larger doses of naloxone. Id. This is also true. I treat patients
`
`suffering from these withdrawal effects of excessive naloxone administration on a
`
`weekly basis. This phenomenon would have further deterred the POSA from
`
`selecting an unnecessarily high dose of naloxone.
`
`36. To reach their opinions, Dr. Donovan and Dr. Hochhaus ignore the
`
`prior art that expressly teaches away from using an initial dose of naloxone greater
`
`20
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 20
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`than 2 mg by any route of administration in order to avoid withdrawal symptoms
`
`DECLARATION OF KENNETH A. WILLIAMS
`
`
`and other adverse effects. For example, they ignore the teaching of the seminal
`
`textbook in the field, Goldfrank’s, teaching away from high doses of naloxone
`
`because withdrawal symptoms depend on dose. See Williams POPR Decl. ¶ 21
`
`(discussing Goldfrank’s at 580). They ignore, as another example, the guidelines
`
`issued by the World Health Organization in 2014 on the treatment of opioid
`
`overdoses. See WHO Guide. These guidelines were developed by a WHO
`
`Steering Group and Guideline Development Group (“GDG”) after an extensive
`
`review of relevant medical literature. On the question of dose, the WHO Guide
`
`informed that the POSA that, “[i]n most cases 0.4-0.8 mg is an effective dose.” Id.
`
`at 12. Further, “[t]he GDG notes that higher initial doses above 0.8 mg IM/