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 9,629,965
`__________________
`
`
`
`SUPPLEMENTAL DECLARATION OF STUART A. JONES, PH.D.
`
`
`__________________
`
`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 9,629,965
`__________________
`
`
`
`SUPPLEMENTAL DECLARATION OF STUART A. JONES, PH.D.
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`I.
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`INTRODUCTION ......................................................................................... 1
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`TABLE OF CONTENTS
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`II.
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`BACKGROUND & QUALIFICATIONS ................................................... 2
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`III. THE POSA WOULD HAVE FOLLOWED WYSE’S TEACH-
`AWAY CONCERNING BZK AND NALOXONE. ................................... 3
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`A.
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`B.
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`The POSA would have recognized that excipients can increase
`drug degradation through indirect mechanisms. ................................... 4
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`BZK’s surfactant properties could increase the naloxone
`degradation observed in Wyse. ............................................................. 7
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`IV. THE POSA WOULD NOT HAVE PERFORMED ADDITIONAL
`EXPERIMENTS TO DETERMINE THE “ROOT CAUSE” OF
`THE DEGRADATION OBSERVED IN WYSE. ..................................... 16
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`1
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`I, Stuart A. Jones, Ph.D., declare as follows:
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`I.
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`INTRODUCTION
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`
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`I am an expert in the field of drug development, including the fields of
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`intranasal drug formulation, drug delivery, dosage form design, formulation
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`manufacture, and pharmacokinetics.
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`
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`I understand that this declaration is being submitted in support of
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`Patent Owners Adapt Pharma Operations Limited and Opiant Pharmaceuticals, Inc.
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`(collectively, “Adapt”) in three proceedings before the Patent Trial & Appeal
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`Board—IPR2019-00685, IPR2019-00688, and IPR2019-00694—in which
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`Petitioner Nalox-1 Pharmaceuticals, LLC (“Nalox-1”) has challenged the
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`patentability of certain claims of U.S. Patent Nos. 9,211,253 (“the ’253 patent”),
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`9,468,747 (“the ’747 patent”), and 9,629,965 (“the ’965 patent”) (collectively, “the
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`Adapt patents” or “the challenged patents”).
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`
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`I am over the age of 18 and otherwise competent to make this
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`declaration. I am being compensated at my customary hourly rate of £320.00, as
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`well as reimbursement of reasonable business expenses. My compensation is not
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`contingent upon the outcome of these proceedings or the opinions I reach.
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`This is my second declaration in these proceedings. I submitted my
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`first declaration on December 23, 2019. See Declaration of Stuart A. Jones, Ph.D.,
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`Ex. 2201 (“First Jones Decl.”). I have been asked to supplement the opinions set
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`1
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`forth in my first declaration to respond to certain opinions offered in the
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`Supplemental Declaration of Maureen Donovan, Ph.D. (Nalox1201) (“Supp.
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`Donovan Decl.”). In this declaration, I apply the legal principles of obviousness
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`and the same definition of the the person of ordinary skill in the art (“POSA”) that
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`I set forth in my first declaration. First Jones Decl. (Ex. 2201) ¶¶ 29–44.
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`
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`In preparing this declaration, I have considered the documents cited in
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`my first declaration, the Supplemental Declaration of Dr. Donovan and the
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`documents she cited in it, and the additional documents identified herein. I
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`understand that each of the three IPR proceedings at issue has its own set of exhibit
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`numbers, but that the same exhibit numbers have been maintained for the same
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`exhibits across the three proceedings. I will therefore refer to the exhibits by
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`name; a chart of the relevant exhibit numbers in and the short names I use to refer
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`to different documents is attached to the end of this declaration.
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`
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`Having considered Dr. Donovan’s supplemental declaration, it
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`remains my opinion that none of claims 1–29 of the ’253 patent, claims 1–45 of
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`the’747 patent, or claims 1–30 of the ’965 patent (“the challenged claims”) would
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`have been obvious to the POSA.
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`II. BACKGROUND & QUALIFICATIONS
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`
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`In addition to the experience and qualifications described in my
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`previous declaration, see, e.g., First Jones Decl. (Ex. 2201) ¶¶ 1, 10–21, I have the
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`2
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`following experience and qualifications relevant to my response to Dr. Donovan
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`set forth in this supplemental declaration.
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` My research involves the use of surfactants to design drug delivery
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`systems. I also have studied how surface active excipients influence the
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`formulation characteristics and pharmacokinetics of intranasal medicines. I also
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`have expertise in chemistry, including the physical chemistry of drug-excipient
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`interactions, as well as expertise concerning the ability of metal complexes to
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`influence the physical and chemical stability of formulations. My research and
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`experience in these areas have been the subject of grants I have received and
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`studies published in peer-reviewed scientific journals, as described in my
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`curriculum vitae, previously submitted as Exhibit 2200.
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`
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`In addition to my research, I have been a reviewer for Langmuir, a
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`scientific journal published by the American Chemistry Society, including for
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`review articles attempting to understand surfactant behavior in formulations and
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`the use of surfactant micelles to enhance the delivery of drugs.
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`III. THE POSA WOULD HAVE FOLLOWED WYSE’S TEACH-AWAY
`CONCERNING BZK AND NALOXONE.
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`
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`In her Supplemental Declaration, Dr. Donovan opines for the first
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`time that BZK “does not act as an oxidizing agent in pharmaceutical formulations”
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`and therefore “could not have been responsible” for the naloxone degradation
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`observed in Wyse. Supp. Donovan Decl. (Nalox1201) ¶¶ 12, 15 & n.7, 16. Dr.
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`3
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`Donovan is incorrect. The POSA would not have concluded that a given excipient
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`cannot increase chemical degradation of an active ingredient just because that
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`excipient is not known to directly chemically react with the active ingredient in a
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`particular way. Even if an excipient does not chemically react with the active
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`ingredient at all, it can cause degradation through other mechanisms. The POSA
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`reading Wyse would have known that there are a variety of ways in which BZK
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`could have increased naloxone degradation, especially in light of BZK’s well-
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`known surfactant properties, and would not have disbelieved or discounted Wyse’s
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`teachings not to use BZK.
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`A. The POSA would have recognized that excipients can increase
`drug degradation through indirect mechanisms.
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` The POSA would have recognized that “[e]xcipients may affect drug
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`stability via various mechanisms.” Yoshioka & Stella 2002 (Ex. 2301) at 119.
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`Although “excipients may participate directly in degradation as reactants,”
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`excipients “may also exhibit catalyzing effects toward drug degradation.” Id.; see
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`also, e.g., Alsante 2007 (Ex. 2302) at 5 (“[N]on-active pharmaceutical ingredients
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`can also react with the API or catalyze degradation reactions.”); Pifferi 1999 (Ex.
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`2303) at 2 (observing that “[f]rom the chemical point of view, even the so-called
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`inertia of the excipients is to be accepted with reservations” because excipients
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`“may, when influenced by chemical and physical factors in the environment,
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`trigger some reactions leading to degradation”); Mollica 1978 (Ex. 2304) at 6
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`4
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`(explaining that “‘extrachemical’ or additional reactions can occur to the drug
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`formulated in solution, and they may be overlooked or not considered” and that
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`“[t]he effect of excipients … on stability can be significant”).
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` Dr. Donovan limited the analysis in her second declaration to
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`oxidative degradation of naloxone, and in particular to only one possible
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`mechanism in which BZK acts directly as an oxidizing agent to yield a particular
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`oxidative degradant of naloxone. See Supp. Donovan Decl. (Nalox1201) ¶¶ 13–17.
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`The POSA would have understood that oxidative degradation mechanisms can be
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`“complex,” and can therefore present many opportunities for one ingredient in a
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`formulation to cause or increase the degradation of another, including in indirect
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`ways. Baertschi 2005 (Ex. 2305) at 38 (“[O]xidative mechanisms can be quite
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`diverse and complex and oxidative degradation often does not follow typical
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`Arrhenius kinetic models.”); see also, e.g., Felton 2012 (Ex. 2306) at 11
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`(remarking that “an oxidation reaction is complicated”); Connors 1986
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`(Nalox1208) at 3 (“[O]ur overall mechanistic understanding of oxidative and
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`photochemical reactions is poor. . . . [M]any oxidative and photochemical reactions
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`involve very complex reaction pathways”).
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` With regard to BZK in particular, the POSA would have recognized
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`BZK as an excipient that can participate in a variety of chemical and physical
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`processes, and accordingly could affect drug stability in both direct and indirect
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`5
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`ways. As Dr. Donovan notes, see Supp. Donovan Decl. (Nalox1201) ¶ 16, BZK is
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`a quaternary ammonium compound. Such compounds would have been well
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`known to the POSA to “possess rich reactivity” as “starting material, reagent,
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`catalyst, and solvent,” and can serve “as reactive substrates, reagents, phase-
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`transfer catalysts, ionic liquids, electrolytes, frameworks, surfactants, herbicides,
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`and antimicrobials.” Bureš 2019 (Nalox1206) at 1, 17. BZK in particular was
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`known to be a surfactant, and was known to have effects on formulations that can
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`influence chemical degradation reactions, as discussed in greater detail below.
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`In view of this, the POSA would not have perceived it to be a
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`“shortcoming” of Wyse that Wyse did not explain the mechanism by which
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`naloxone degrades, nor would the POSA have disbelieved Wyse’s conclusions
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`because of doubt about whether BZK could directly chemically react with
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`naloxone, as Dr. Donovan contends. See Supp. Donovan Decl. (Nalox1201) ¶¶ 12,
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`15 & n.7, 16. Rather, the POSA would have understood that other mechanisms—
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`including indirect physical and/or chemical interactions involving BZK—could
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`explain Wyse’s results. And the POSA would have had no reason to perform time-
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`consuming experiments to ascertain the precise degradative mechanism actually
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`responsible for Wyse’s results.1
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`1 Knowing the exact mechanism by which BZK actually caused naloxone to
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`6
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`B.
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`BZK’s surfactant properties could increase the naloxone
`degradation observed in Wyse.
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` The POSA would have known that “[m]echanisms for the effect of
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`surfactants are complex and depend on various factors.” Yoshioka & Stella 2002
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`(Ex. 2301) at 127. One important factor is a surfactant’s tendency in aqueous
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`degrade in Wyse’s formulations is not necessary to my opinion that the POSA
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`would have followed Wyse’s admonition not to use BZK. Consistent with that, in
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`response to questioning at my deposition, I testified that I was not aware of
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`literature “suggest[ing] the mechanism by which naloxone would be degraded in
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`the intranasal formulations that are stipulated within Wyse,” Nalox1248 at 124:4–
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`10. I am still not aware of any literature that addresses which mechanism caused
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`the degradation in Wyse. I have identified here some of the ways in which BZK
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`could have increased naloxone degradation in Wyse’s experiments, but of course
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`my list of possibilities is not and need not be exhaustive. It remains my opinion
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`that the POSA would not need to have known the specific mechanism by which
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`naloxone was degraded to follow the teachings of Wyse, given Wyse’s
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`experimental results, Wyse’s numerous statements concluding that BZK was
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`involved, Wyse’s decision to use a different preservative not associated with
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`naloxone degradation, and the POSA’s knowledge that she or he need not even use
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`any preservative and in any event had other preservative options.
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`7
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`solution to assemble spontaneously into “micelles”—agglomerations of surfactant
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`molecules arranged to have a lipophilic (or oily) interior and a hydrophilic exterior
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`interface with the surrounding aqueous solution. See, e.g., Broxton 1984 (Ex.
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`2307) at 1 (“The study of the effects of micelles on organic reactions is currently of
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`great interest. In particular, there have been many reports of the catalysis of
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`organic reactions.”). Indeed, “[t]wo fundamental parameters of each surfactant
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`that must be considered before its application are surface activity and tendency to
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`self-assemble in solution and form aggregates, micelles, and vesicles . . . .” Bureš
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`2019 (Nalox1206) at 11–12.
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` Dr. Donovan’s supplemental declaration does not discuss BZK’s
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`surfactant properties. This omission is glaring because the POSA would have
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`known that surfactants can facilitate the degradation of drugs, and that “[t]he effect
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`of surfactants on the degradation” can be “difficult to interpret.” Yoshioka &
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`Stella 2002 (Ex. 2301) at 128 (reporting that the “[d]egradation of cefaclor (an a-
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`aminophenyl cep[h]alosporin) was enhanced by CTAB,” a well-known surfactant).
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`The POSA would also have known that surfactants are capable of increasing
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`reaction rates, including for oxidation reactions. See Samiey 2014 (Ex. 2308) at 5
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`(discussing examples in which surfactants exhibit “catalytic effects” in oxidation
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`reactions); Tsuji 1982 (Ex. 2309) at 1 (“Surfactants incorporated in the drug
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`dosage form are able to influence the drug stability and dissolution as a result of
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`8
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`drug-surfactant micellar interactions.”). For example, the prior art taught that
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`CTAB could enhance the degradation of drugs such as ceflacor and indomethacin,
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`and potentially other drugs.2 See Yoshioka & Stella 2002 (Ex. 2301) at 127–28
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`(further noting that CTAB’s enhancement of indomethacin degradation “has been
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`explained by increased concentration of the reactants upon micelle formation,”
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`while “[t]he dependence on salt concentration suggests a complex mechanism for
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`the effect of surfactants on degradation of cefaclor”).
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`2 CTAB and BZK are both quaternary ammonium compounds that the POSA
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`would have recognized as having similar properties, including with respect to their
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`ability to act as surfactants and preservatives. See Nalox1012 at 5–7 (excerpt from
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`the Handbook of Pharmaceutical Excipients for BZK); HPE Cetrimide (Ex. 2310)
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`at 1–3 (same for CTAB). CTAB and BZK differ in chemical structure by their
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`“head” group and substitution of the bromide counterion in CTAB for a chloride
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`counterion in BZK. The POSA would not have understood these differences to be
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`material. See Prapaitrakul 1985 (Ex. 2311) at 1 (finding that “with ionic
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`surfactants, the nature of the head group is of little consequence in determining the
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`magnitude of the intramicellar solubilities.”); see also, e.g., Matheson 1978 (Ex.
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`2312) at 1, 5; Geiger 1975 (Ex. 2313) at 2; Turro 1979 (Ex. 2314) at 4.
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`9
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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` The POSA would have appreciated that there are numerous
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`mechanisms by which BZK’s surfactant properties could have increased naloxone
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`degradation. Any of these mechanisms, alone or in combination, could have been
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`responsible for the “additional [naloxone] degradant” observed in Wyse. Dr.
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`Donovan’s discussion of BZK and reduction/oxidation chemistry, therefore, does
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`nothing to call Wyse’s teachings into question.
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` For one thing, the POSA would have known that the concentration of
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`oxygen plays a key role in promoting oxidative degradation. The chemical
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`pathway Dr. Donovan cites involves oxygen as a reactant, and therefore, a
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`contributor to oxidative degradation, albeit for morphine. Specifically, Dr.
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`Donovan postulates that the naloxone degradation observed by Wyse involved the
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`following oxidation reaction, as described in Connors 1986:
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`Connors 1986 at 9; Supp. Donovan Decl. (Nalox1201) ¶¶ 13–14. In this reaction,
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`free oxygen (O2) serves as the hydrogen acceptor. Thus, an increase in solubilized
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`oxygen would be expected to facilitate the reaction cited by Dr. Donovan and to
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`10
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`increase the speed with which naloxone is degraded. See also Quarry (Nalox1231)
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`at 1 (“It has been reported that pH and oxygen contribute to the degradation of this
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`class of compounds.” (emphasis added)); Yeh 1961 (Nalox1240) at 2 (“[T]he rate
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`of degradation of morphine is oxygen-dependent . . . .”).
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` Thus, the POSA would have understood BZK could enhance naloxone
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`degradation by, among other possibilities, facilitating the reaction between oxygen
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`and naloxone. Micelles, which surfactants like BZK can form spontaneously in
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`aqueous solution, were known to increase the solubility of oxygen in solution. See,
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`e.g., Handa 2014 (Ex. 2315) at 4 (noting the “far greater solubility of oxygen in
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`hydrocarbon media as found within micellar arrays than in the surrounding
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`water”). Increasing the solubility of oxygen increases the amount of free oxygen
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`available to participate in oxidation and thereby facilitates such reactions.
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`The POSA would have understood micelle-mediated oxygen solubilization to be
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`one potential explanation for Wyse’s “additional degradant” because the POSA
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`would have expected Wyse’s Example 5 formulations to contain BZK micelles.3
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`3 Surfactants such as BZK will form micelles in aqueous solution at concentrations
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`above the “critical micelle concentration,” or “CMC.” See, e.g., Bureš 2019
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`(Nalox1206) at 11–12. While the exact CMC depends on the formulation in which
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`BZK is dissolved, in the Wyse formulations containing BZK (and for that matter in
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`11
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`The POSA would have further recognized that oxygen readily penetrates micelles
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`in aqueous solution, and that the presence of micelles can increase significantly the
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`amount of oxygen in an aqueous solution by enhancing the solubility of oxygen
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`from the surrounding environment. See Parikh 2011 (Ex. 2317) at 2 fig.1.
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` BZK also could cause naloxone degradation through its interaction
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`with the container. The POSA would have known that polymer packaging,
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`delivery, administration, and manufacturing systems—i.e., container closures—
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`used with pharmaceutical products may include substances that can leach into and
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`affect a drug product over time. See, e.g., Jenke 2014 (Ex. 2318) at 2. More than
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`the formulations recited in the challenged claims), the POSA would understand the
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`concentration of BZK to be far above the CMC—likely by more than hundred-fold
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`at Wyse’s BZK concentration of 0.125%. For example, Okano 2000 reports that
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`micelles of “CMe2BzACl” (cetyldimethylbenzylammonium chloride, one of the
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`primary constituents of BZK, see, e.g., Okano 2000 at 1–2, Nalox1012 at 5) form
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`at a CMC of approximately 0.2 × 10–4 M in an NaCl solution. Okano 2000 (Ex.
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`2316) at 1, 3. The POSA would understand that Wyse’s formulation (which also
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`contains NaCl) had approximately 3.4 × 10–3 M BZK (based on an average
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`molecular weight for BZK of 360 g/mol, Nalox1012 at 5).
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`12
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`500 such leachable or extractable substances have been identified in polymeric
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`materials typically used in pharmaceutical drug products. See id.
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` The POSA also would have known that rubber stoppers were a known
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`source of leachables, and that “[d]ifferent formulation excipients have a significant
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`impact on leachables” from such stoppers. Yu 2010 (Ex. 2319) at 8. In one study,
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`for example, the inclusion of a surfactant (Tween 80) “significantly increased” the
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`amount of leachables as compared to other excipients. Id. Notably, the device
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`used by Wyse in his clinical studies was the “Aptar/Pfeiffer single spray device”
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`having a glass vial sealed by a rubber stopper “manufactured by West
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`Pharmaceuticals using PH 701/55/C Black Chlorobutyl Rubber.” Wyse
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`(Nalox1007) at 10:58–64; see also Sacha 2010 (Ex. 2320) at 13 (noting that
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`“rubber is used for many applications,” including “closures of vials and bottles,
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`seals and plungers for syringes and cartridges”); Yu 2010 (Ex. 2319) at 3 (“Glass
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`vials and rubber stoppers are widely used as container/closure systems for
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`biopharmaceutical product and drug formulations.”).
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` BZK is also known to be adsorbed and/or absorbed by polymers
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`including PVC, PVDF, nylon, etc., see, e.g., Guess 1962 (Ex. 2321) at 4–5, and
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`into plastics, see Hiom 2004 (Nalox1214) at 12. As noted in my first declaration,
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`the HPE teaches away from BZK because it is “[i]ncompatible with . . . some
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`rubber mixes, and some plastic mixes.” HPE (Nalox1012) at 6; First Jones Decl.
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`13
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`(Ex. 2201) ¶ 131. This teaching is consistent with the POSA’s understanding that
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`preservatives may interact with materials like plastic or rubber in container
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`closures, which can lead, among other things, to problems with stability. See Yu
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`2010 (Ex. 2319) at 3 (observing that “typical biopharmaceutical drug product
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`formulation ingreidents, such as . . . surfactants . . . can alter the physicochemical
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`properties of the drug formulation itself and also may have an impact on the
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`leaching of organic compounds from rubber stoppers”) (emphasis added); see also
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`Felton 2012 (Ex. 2306) at 15–17; First Jones Decl. (Ex. 2201) ¶ 131. Adsorption
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`onto a rubber or polymer seal or other device component could increase solvent
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`hydration and increase the potential for leachable compounds to be extracted into
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`solution. See Guess 1962 at 3–5. The leachable substances in polymers include,
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`for example, metal oxides, which have been shown to leach out into
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`pharmaceutical products. See Sacha 2010 (Ex. 2320) at 14, 17–19. These metal
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`oxides were known to catalyze oxidation reactions, see, e.g., Védrine 2017 (Ex.
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`2322) at 2 (“Metal oxides became prominent in the mid-1950s when they were
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`found to effectively catalyse a wide variety of reactions, in particular oxidation and
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`14
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`acid-base reactions.”), and if present, would have been expected to enhance the
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`oxidative degradation of naloxone in solution.4
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` Furthermore, glass vials can also release trace metals. Quarry 2002
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`(Nalox1231) at 1–6; see also Sacha 2010 (Ex. 2320) at 12–13; Borchert 1989 (Ex.
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`2323) at 1 (“Glass containers used in the pharmaceutical industry are durable, but
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`cannot be considered inert.”). “[T]race contamination of metal ions can catalyze
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`oxidative reactions by many orders of magnitude.” Connors 1986 (Nalox1208) at
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`3. Similar to rubber leachables, this process can be enhanced by surfactants like
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`BZK, and the POSA would have understood that this phenomenon could have also
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`been present in Wyse.
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`*
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`*
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`*
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`*
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`*
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`4 Dr. Donovan suggests that concerns regarding BZK’s incompatibility with rubber
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`have been resolved. Supp. Donovan Decl. ¶ 24 & n.21 (citing Hiom 2004 at 12).
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`I disagree. Hiom 2004 confirms that “adsorption [] followed by absorption . . . is a
`
`particular problem with preservatives,” including BZK. Hiom 2004 (Nalox1214)
`
`at 12. Hiom further observes that preservative loss “can be reduced by careful
`
`selection of elastomer type and by pre-soaking and autoclaving,” id., but never
`
`suggests that these strategies would prevent BZK-mediated leaching of impurities
`
`or the resulting downstream effects on a formulation.
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`15
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`
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`In short, irrespective of whether BZK can act directly as an oxidizing
`
`agent, the POSA would have known of multiple other mechanisms through which
`
`BZK could increase degradation of naloxone as reported by Wyse. The POSA
`
`would not have been “alerted to potential shortcomings, or found incomplete
`
`evidence” for Wyse’s conclusions, as Dr. Donovan suggests, Supp. Donovan Decl.
`
`(Nalox1201) ¶¶ 10, 12, but would have credited Wyse and not used BZK.
`
`IV. THE POSA WOULD NOT HAVE PERFORMED ADDITIONAL
`EXPERIMENTS TO DETERMINE THE “ROOT CAUSE” OF THE
`DEGRADATION OBSERVED IN WYSE.
`
` Dr. Donovan further asserts that “[a] Formulator POSA would have
`
`investigated the cause of the degradation observed in Wyse’s formulations,” and
`
`that “a Formulator POSA would have conducted further studies to determine
`
`whether BAC was incompatible with naloxone.” Supp. Donovan Decl.
`
`(Nalox1201) ¶ 18. I disagree. Given the variety and complexity of degradation
`
`mechanisms, including those described above, by which BZK could cause
`
`naloxone degradation, see supra ¶¶ 11–23, the POSA would have had no
`
`motivation to invest time and effort to investigate all of the ways in which BZK
`
`might facilitate naloxone degradation in a hypothetical future formulation.
`
`
`
`Instead, the POSA would have known that screening a range of
`
`excipients and ruling out excipients associated with increased naloxone
`
`degradation, as Wyse did, was an efficient and appropriate formulation
`
`
`
`16
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`development strategy. See First Jones Decl. (Ex. 2201) ¶ 57. Wyse observed
`
`naloxone instability across many formulations containing BZK, and concluded that
`
`BZK was not acceptable to use in intranasal naloxone formulations. See id. ¶¶ 67–
`
`92. And, as I explained above and previously, see id. ¶¶ 93–127, the POSA would
`
`have no reason to disbelieve Wyse’s conclusion that BZK increased naloxone
`
`degradation. As a result, the POSA would not have required additional
`
`information, or further study of the “root cause” of Wyse’s results, to follow
`
`Wyse’s conclusions.
`
`
`
` The POSA’s goal would have been to formulate a storage-stable
`
`naloxone nasal spray, not to find any conceivable way to use BZK as a
`
`preservative. The POSA would have recognized that preservatives were both
`
`unnecessary and disfavored in single-use products. First Jones Decl. (Ex. 2201) ¶¶
`
`128–66. And the POSA would have also recognized that there were a number of
`
`other preservatives that could be used that were not associated with naloxone
`
`degradation, including several that had been previously used in FDA-approved
`
`intranasal products. Wyse had shown that one of these, benzyl alcohol, was
`
`compatible with naloxone in long term stability studies, and Wyse selected it for
`
`his final formulation.
`
` The POSA would not have favored BZK over other preservatives and
`
`would not have considered BZK to be “superior[] . . . as an antimicrobial agent
`
`
`
`17
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`SUPPLEMENTAL DECLARATION OF STUART A. JONES
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`(e.g., as an anti-Pseudomonal agent),” as Dr. Donovan contends. Supp. Donovan
`
`Decl. (Nalox1201) ¶ 18. The POSA would have known that alternative
`
`preservatives were effective against Pseudomonas and other microorganisms, with
`
`known minimum concentrations to achieve this efficacy. See, e.g., First Jones
`
`Decl. (Ex. 2201) ¶¶ 173, 175, 178–80. I agree with Dr. Donovan’s testimony at
`
`her first deposition that even if a formulation required a preservative, the POSA
`
`would recognize that it merely needed to be “effective,” not the “most effective”
`
`preservative compared to a different one. See Donovan Tr. (Ex. 2065) at 157:9–
`
`11. And here, for a single-use nasal spray product, like the claimed invention, the
`
`POSA would have recognized that no antimicrobial preservative is required at all,
`
`and therefore its relative potency as compared to other preservatives would not be
`
`important for that reason as well. See First Jones Decl. (Ex. 2201) ¶¶ 143–66.
`
` Accordingly, the POSA would not have had reason to perform further
`
`experimentation to try to further explore the “root cause” of the degradation Wyse
`
`reported, but simply would have followed Wyse’s teaching not to use BZK in an
`
`intranasal naloxone formulation.
`
`*
`
`*
`
`*
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`
`
`I hereby declare that all statements made herein of my own knowledge are
`
`true and that all statements made on information and believe are believed to be
`
`true; and further that these statements were made with the knowledge that willful
`
`
`
`18
`
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`
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`
`
`SUPPLEMENTAL DECLARATION OF STUART A. JONES
`
`false statements and the like so made are punishable by fine or imprisonment, or
`
`both, under Section 1001 of Title 18 of the United States Code.
`
`
`
`
`
`
`
`
`
`Date: April 24, 2020
`
`
`
`
`
`
`
`
`Stuart A. Jones, Ph.D.
`
`
`
`
`19
`
`
`
`
`
`
`
`SUPPLEMENTAL DECLARATION OF STUART A. JONES
`
`Short Name
`
`Description
`
`
`
`Supplemental Declaration of Maureen
`Donovan
`
`Alsante 2007 Alsante, K.M. et al., The role of degradant
`profiling in active pharmaceutical
`ingredients and drug products, Adv. Drug.
`Deliv. Rev. 59 (2007) 29–37
`
`Baertschi 2005 Baertschi, S.W. & Jansen, P.J. Stress
`Testing: A Predictive Tool, in
`Pharmaceutical Stress Testing: Predicting
`Drug Degradation 13–50 (S.W. Baertshi,
`ed. 2005)
`
`Borchert 1989 Borchert, S.J., et al., Accelerated
`Extractable Studies of Borosilicate Glass
`Containers, 43 PDA J. Pharm. Sci. &
`Tech. (1989) 67–79
`
`Broxton 1984 Broxton, T.J., et al., Micellar Catalysis of
`Organic Reactions. XIV*: Hydrolysis of
`Some 1,4-Benzodiazepin-2-one Drugs in
`Acidic Solution, 37 Aust. J. Chem. (1984)
`1895–902
`
`Bureš 2019
`
`Bureš, F., Quaternary Ammonium
`Compounds: Simple in Structure, Complex
`in Application, 377(14) Topics in Current
`Chemistry (2019)
`
`Connors 1986 Connors, K. et al., Oxidation and
`Photolysis, in Chemical Stability of
`Pharmaceuticals: A Handbook for
`Pharmacists 82–114 (2d ed. 1986)
`
`Felton 2012
`
`Geiger 1975
`
`Remington: Essentials of Pharmaceutics
`(2012), Linda A. Felton, ed.
`
`Geiger, M.W. and Turro, N.J., Pyrene
`Fluorescence Lifetime as a Probe for
`Oxygen Penetration of Micelles, 22
`Photochem. & Photobiol. (1975) 273–76
`
`’685
`IPR
`
`1201
`
`’688
`IPR
`
`1201
`
`’694
`IPR
`
`1201
`
`2302
`
`2302
`
`2302
`
`2305
`
`2305
`
`2305
`
`2323
`
`2323
`
`2323
`
`2307
`
`2307
`
`2307
`
`1206
`
`1206
`
`1206
`
`1208
`
`1208
`
`1208
`
`2306
`
`2306
`
`2306
`
`2313
`
`2313
`
`2313
`
`
`
`20
`
`
`
`
`
`
`
`SUPPLEMENTAL DECLARATION OF STUART A. JONES
`
`Short Name
`
`Description
`
`Guess 1962
`
`Handa 2014
`
`Hiom 2004
`
`Guess, W.L., et al., The Effect of a
`Quaternary Ammonium Compound on
`Polyvinyl Chloride Used in Medical
`Practice: A preliminary report, 19 Am. J.
`Hosp. Pharm. (1962) 370–74
`
`Handa, S., et al., Aerobic Oxidation in
`Nanomicelles of Aryl Alkynes, in Water at
`Room Temperature, 53 Angew Chem. Int.
`Ed. Engl. (2014) 3432–35
`
`Hiom, S., Preservation of Medicines and
`Cosmetics, in Principles and Practice of
`Disinfection, Preservation & Sterilization
`484–514 (Fraise, A.P. et al., eds., 4th ed.
`2004)
`
`HPE Cetrimide Handbook of Pharmaceutical Excipients,
`152-154 (Rowe, R., et al. eds., 6th ed.
`2009)
`
`Jenke 2014
`
`Okano 2000
`
`Jenke, D., and Carlson, T., A Compilation
`of Safety Impact Information for
`Extractables
`Associated with Materials Used in
`Pharmaceutical Packaging,
`Delivery, Administration, and
`Manufacturing Systems, 68 PDA J. Pharm.
`Sci. & Tech. (2014) 407–55
`
`Okano, L.T. et al., Fluorescence and
`Light-Scattering Studies of the
`Aggregation of Cationic Surfactants in
`Aqueous Solution: Effects of Headgroup
`Structure, 16 Langmuir (2000) 3119–23
`
`’685
`IPR
`
`2321
`
`’688
`IPR
`
`2321
`
`’694
`IPR
`
`2321
`
`2315
`
`2315
`
`2315
`
`1214
`
`1214
`
`1214
`
`2310
`
`2310
`
`2310
`
`2318
`
`2318
`
`2318
`
`2316
`
`2316
`
`2316
`
`Matheson 1978 Matheson, I.B.C., and King, A.D.,
`Solubility of Gases in Micellar Solutions,
`66 J. Colloid Interface Sci. (1978) 464–69
`
`Mollica 1978 Mollica, J.A. et al., Stability of
`Pharmaceuticals, 67 J. Pharm. Sci.,
`(1978) 443–65
`
`2312
`
`2312
`
`2312
`
`2304
`
`2304
`
`2304
`
`
`
`21
`
`
`
`
`
`
`
`SUPPLEMENTAL DECLARATION OF STUART A. JONES
`
`Short Name
`
`Description
`
`Parikh 2011
`
`Pifferi 1999
`
`Prapaitrakul
`1985
`
`Sacha 2010
`
`Samiey 2014
`
`Tsuji 1982
`
`T
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